Advances in biochemistry and molecular genetics have led to the discovery of such a large number of metabolic diseases of the nervous system that it taxes the mind just to remember their names. As the causes and mechanisms of the diseases included in this chapter are increasingly being expressed in terms of molecular genetics, it seems appropriate, by way of introduction, to consider briefly some basic facts pertaining to the genetics of neurologic disease. The reader is referred to the continuously updated database, Online Mendelian Inheritance in Man (), to the four-volume text by Scriver and colleagues, which still serves as an excellent source, and to recent general reviews by Feero and colleagues, and on mitochondrial genetics, by Koopman and coauthors.

The brain is more frequently affected by a genetic abnormality than any other organ, probably because of the large number of genes implicated in its development (an estimated one-third of the human genome). Approximately one-third of all inherited diseases are neurologic in some respect; if one adds the inherited diseases affecting the musculature, skeleton, eye, and ear, the number rises to 80 to 90 percent. Approximately 7 percent of diseases in hospitalized children are estimated to be attributable to single-gene defects and 0.4 to 2.5 percent to a chromosomal abnormality. Another 22 to 31 percent have a disease putatively due to polymorphisms, most of which are yet to be specified. Mitochondrial inheritance of mutations is much less frequent but gives rise to several distinctive diseases.

Although only a minority of inherited diseases is identified as an enzymopathy, this group represents the most direct translation of mendelian disorders to primary defects in proteins. These constitute only one-third of the known recessive (autosomal and X-linked) disorders. Most enzymopathies become manifest in infancy and childhood; only a few appear as late as adolescence or adult life. Many damage the nervous system so severely that survival to adult years and reproduction are impossible, and some cause death in utero. As a group, these diseases—along with congenital anomalies (see Chap. 38), birth injuries, epilepsy, disharmonies of development, and learning disabilities (see Chap. 28)—make up the bulk of the clinical problems with which the pediatric neurologist must contend.

The diseases grouped in this chapter, and many in the next, represent four particular categories of genetic abnormality: (1) monogenic disorders determined by a single mutation that follow a mendelian pattern of inheritance. These mutations can be of a single base pair (point mutation), an insertion or deletion of nucleotides, or structural rearrangements of a sequence of DNA, such as translocations or inversions; because the most important of these involve the coding (exonic) portion of DNA, they are likely to disrupt the structure and function of enzymes or cellular structural proteins. Most of the diseases discussed in this chapter are of this variety; (2) a type of monogenic mutation characterized by duplications or deletions of genes or parts of chromosomes, termed copy number variations; these account for some proportion the heritability of common diseases; (3) single nucleotide polymorphisms, which are variations from the most common, “wild type,” sequence of a gene and are by convention present with a frequency of greater than 1 percent in the population; these play a role in the genesis of disease but do not obligatorily result in a somatic aberration or alternatively, they interact with exogenous environmental factors; and (4) mitochondrial gene mutations that are inherited in a nonmendelian, mainly maternally inherited pattern.

Autosomal and Sex-Linked Inheritance

Traditionally, the recognition of the broad categories of genetically determined diseases has rested on their pattern of occurrence in families, segregated according to mendelian inheritance into autosomal dominant, autosomal recessive, and sex-linked types. As mentioned, mutations of nuclear DNA account for the heritable autosomal and sex-linked diseases described in this chapter, and they are remarkably diverse in nature. Some are lethal and are therefore not transmitted to successive generations; others are less harmful and may conform to one of the classic mendelian patterns. The mutation may be large and result in duplication of a major part of a chromosome or even of the entire gene (diploidy or triploidy) or a deletion (haploidy). Other mutations are quite small, involving only a single base pair (“point mutation”). Between these two extremes are deletions or duplications that include a portion of a gene, an entire gene, or contiguous genes, as mentioned above.

The factors conducive to mutations are poorly understood. The parent’s increasing age is important in relation to some mutations; the size, structure, and placement of the gene on the chromosome are important in others. A mutation of the DNA of a germ cell leaves unchanged the somatic phenotype of the individual in whom it occurs, but it may have a devastating effect on the descendants. Conversely, a DNA mutation of a somatic cell affecting only part of the cell population may change the individual harboring it but is not passed on to the descendants. Such an individual, with both normal cells and cells containing the mutant gene, is referred to as a mosaic. Mutations of somatic cells appear to be most pertinent to cancer and aging.

In the monogenic inheritance of all three mendelian patterns, the mutation usually causes an abnormality of a single protein. It may involve an enzyme, peptide hormone, immunoglobulin, collagen, membrane channel, or coagulation factor. Such abnormalities of single genes have been isolated in several hundred diseases, but less is known of their protein products. About one-quarter of these diseases are apparent soon after birth and more than 90 percent by puberty. More than half of them affect more than one organ. Of the 10 in every 1,000 live births with monogenic diseases, 7 are dominant, 2.5 are recessive, and the remainder are sex-linked.

Autosomal dominant mutations usually cause manifest disease in heterozygotes, but variations in the size of the gene abnormality can produce any one of several phenotypes. This poses a challenge to the current clinical and pathologic classifications of disease. Moreover, an identical clinical syndrome may be traced to a gene on two different chromosomes. Even more surprising, an estimated 28 percent of all gene loci have polymorphic rather than monomorphic effects—that is, the same mutation has several different phenotypic expressions. Another problem is that of differentiating dominant from recessive inheritance. In small families, in which only one descendant is afflicted and the parent is seemingly normal, one may mistakenly conclude that the inheritance is recessive. Other characteristics of mutational diseases are penetrance, a measure of the proportion of individuals with a given genotype who will show the phenotype, and expressivity, referring to the severity of disease in an affected individual. Variable degrees of penetrance and expressivity are characteristic features of dominant patterns of inheritance but not of recessive ones. There is also a general tendency for dominantly inherited disease to first appear long after birth.

Autosomal recessive forms of inherited metabolic diseases, in contrast to dominant ones, occur only in the homozygous state (both alleles are abnormal). They are usually characterized by an onset soon after birth. The basic abnormality in the recessively inherited diseases discussed in this chapter is more often an enzyme deficiency than an abnormality of some other protein.

In disorders of X-linked genes, in which the mutant gene affects mainly one sex, the female will suffer the same fate as the male if one X chromosome has been inactivated, as happens in most cells during embryonic development (the Lyon phenomenon). However, even if the abnormal X chromosome is not widely expressed, the female carrier may still exhibit minor abnormalities. In the latter case, sex-linked inheritance becomes difficult to distinguish from dominant inheritance. Also, sex linkage is deceptive when a disease is lethal to one sex. In contrast to autosomal recessive mutations, the abnormality has more often been one of a basic protein than an enzyme deficiency.

Multifactorial genetic diseases may also be familial. They may present as constitutional disorders with gene abnormalities located on several chromosomes (polygenic, or “complex genetics”) or they may arise from single nucleotide polymorphisms or copy number variations. Here, the relative contributions of genetic and environmental influences are highly variable. The occurrence of many disorders that display high degrees of familial incidence, such as schizophrenia and Gilles de la Tourette syndrome, but do not strictly conform to classic genetic principles has been attributed to this type of complex genetics.

The Genetics of Mitochondrial Disease

An entirely different type of genetic transmission relating to the DNA that lies in the mitochondria has been elucidated. Mitochondria contain their own extrachromosomal DNA, distinct from nuclear DNA. Mitochondrial DNA (“the other human genome”) is a double-stranded, circular molecule that encodes the protein subunits required mainly for translation of the proteins located on the mitochondrial inner membrane. Of the 37 mitochondrial genes, small in number by comparison with nuclear DNA, 13 partake in the cellular processes of oxidative phosphorylation and the production of adenosine triphosphate (ATP). A few genes in the cell’s nucleus also code for a considerable number of oxidative enzymes of the mitochondria, but their inheritance follows a mendelian pattern; consequently, a mitochondrial disorder may fail to display maternal inheritance that is characteristic of mitochondrial mutations as described below.

Each mitochondrion contains up to 10 ringed DNA molecules, and each cell, of course, contains numerous mitochondria. In the cell, mitochondria with mutant genes may exist next to normal mitochondria (heteroplasmy), a state that permits an otherwise lethal mutation to persist (Johns). The presence of either completely normal or completely mutant mitochondrial DNA is termed homoplasmy. The essential feature of mitochondrial genes and the mutations to which they are subject is that they are inherited almost exclusively through maternal lineage. This is explained by the transmission of virtually all mitochondria from the ovum at the time of conception. Moreover, mitochondrial DNA does not recombine, thus permitting the accumulation of mutations through maternal lines. Also, the replication and distribution of mitochondrial DNA during cell division do not follow the nuclear mitotic cycle. Instead, there are contributions during cell division from the genes of various mitochondria to the progeny of dividing cells. The combination of a heteroplasmic state and the capricious dispersion of mitochondria to daughter cells (replicative segregation) explains the variable expression of mitochondrial mutations in different tissues and in different regions of the nervous system.

The genetic error in each of the mitochondrial diseases is most often a single-point mutation that leads to the alteration of a single amino acid, but there are also single or multiple deletions or duplications of mitochondrial genes that do not conform to maternal inheritance because they are caused by nuclear DNA defects. It is important to note that approximately 85 percent of the protein components of the respiratory chain are coded in nuclear DNA and are then imported into the mitochondrion; as mentioned above, this allows for a mitochondrial disease with a mendelian pattern of inheritance rather than a maternal one. Another of the general rules of mitochondrial inheritance is exemplified by an infantile myopathy (cytochrome oxidase deficiency) that is usually fatal but may also occur in a less severe form and have a later onset. In cases of earlier onset, there is less of the normal mitochondrial DNA than in the cases of later onset.

Because the unique function of mitochondria is the production of ATP by oxidative phosphorylation, it is not surprising that many of the genes contained in mitochondria code for proteins in the respiratory chain. However, there is not always concordance between the error in the mitochondrial genome and the enzymatic defect that leads to disease. Of the five complexes that make up the respiratory chain, cytochrome-c oxidase (complex IV) is the one most often disordered, and its deficient function gives rise to lactic acidosis, a feature common to many of the mitochondrial disorders (see further on). In keeping with the mutable nature of this class of disorders, it is thought that some cases of complex IV defect are autosomally transmitted. Complex I defects, which originate in mitochondrial mutations, are seen, for example, in Leber optic atrophy. A more complete account of the disorders of the mitochondrial respiratory chain can be found in the review by Leonard and Schapira.

As one would expect, aberrant function of the ubiquitous energy-producing mitochondria results in disease of many organs besides skeletal muscle (e.g., diabetes and other endocrinopathies and minor dysmorphic features are seen in several mitochondrial disorders). Nevertheless, most of the mitochondrial disorders affect the nervous system prominently and at times exclusively. Two characteristics traceable to mitochondrial abnormalities are particularly common; one is a special change in muscle fibers termed ragged red fibers, a clumping of mitochondria in muscle fibers described in more detail further on, and the other is a systemic lactic acidosis. Other than these, each of the mitochondrial diseases has distinctive features and in their main elements they do not resemble each other. The main syndromes are MELAS and MERRF (acronyms defined further on), Leber hereditary optic atrophy, progressive external ophthalmoplegia, and the Leigh syndrome. These diseases are described in detail in the last part of this chapter.

Diagnostic Features of Hereditary Metabolic Diseases

In clinical practice, one should consider the possibility of a hereditary metabolic disease when presented with the following lines of evidence:

1. 
   

   A neurologic disorder of similar type in a sibling or close relative

   
   
2. 
   

   Recurrent nonconvulsive episodes of impaired consciousness or intractable seizures in infants or young children or infantile spasms and progressive myoclonic seizures in the absence of neonatal hypoxia-ischemia

   
   
3. 
   

   Some combination of unexplained symmetrical or generalized spastic weakness, cerebellar ataxia, extrapyramidal disorder, deafness, or blindness

   
   
4. 
   

   Progression of a neurologic disease measured in months, or a few years

   
   
5. 
   

   Developmental delay in an individual if there are no congenital somatic abnormalities or developmental delay in a sibling or close relative

In the face of such clinical information, one should obtain appropriate biochemical analyses of blood, urine, and cerebrospinal fluid (CSF); MRI of the brain; and, in certain instances, genetic studies.

In addition to the investigation of symptomatic individuals, the array of available genetic and biochemical tests has made practical the mass screening of newborns for inborn metabolic defects. Innovative tests have also led to the discovery of a number of previously unknown diseases and have clarified the basic biochemistry of old ones. As a consequence, the neurologist’s role is changing. No longer must we wait until a disease of the nervous system has declared itself by conventional symptoms and signs, by which time the underlying lesion may have become irreversible. Now it is possible to find patients who, although asymptomatic, are at risk and to introduce dietary and other measures that may prevent injury to the nervous system. This is especially important to families who have already had an affected infant. To assume this new responsibility intelligently requires knowledge of genetics, biochemical screening methods, and public health measures.

The many clinical syndromes by which these inborn errors of metabolism declare themselves vary in accordance with the nature of the biochemical defect and the stage of maturation of the nervous system at which these metabolic alterations become apparent. In phenylketonuria, for example, there is a specific effect on the cerebral white matter, mainly during the period of active myelination; once the stages of myelinogenesis are complete as detailed in Chap. 28, the biochemical abnormality becomes relatively harmless. Even more important from the neurologist’s point of view is the level of function that has been achieved by the developing nervous system when the disease strikes. A derangement of function in a neonate or infant, in whom much of the cerebrum is not fully developed, is much less obvious than one in an older child. Moreover, as the disease evolves, the clinical manifestations are always influenced by the ongoing maturation of the untouched elements in the nervous system. These interactions may give the impression of regression of attained neurologic function, lack of progress of development (developmental delay), or even improvement in function that is attributable to continuing maturation of the normal parts of the nervous system. The separation of metabolic-genetic from degenerative diseases (accorded a separate chapter) may disquiet the reader, for there are many overlaps between the two groups. The current division is tenable only until such time as all the degenerative diseases will have been shown to have a comprehensible pathogenesis.

Because of the overriding importance of the age factor and the tendency of certain pathologic processes to appear in particular epochs of life, it has seemed to the authors logical to group the inherited metabolic diseases not according to their major syndromes of expression, as we have done in other parts of the book, but in relation to the periods of life at which they are most likely to be encountered: the neonatal period, infancy (1 to 12 months), early childhood (1 to 4 years), late childhood, adolescence, and adult life. Only in the last two age periods do we return to the more clinically useful syndromic ordering of diseases.

In adopting this chronological subdivision, we realize that certain hereditary metabolic defects that most typically manifest themselves at a particular period in life are not necessarily confined to that epoch and may appear, sometimes in variant form, at a later age. Such variations are noted at appropriate points in the discussion.

A small number of progressive metabolic diseases become evident in the first few days of life. The importance of these diseases relates not to their frequency (they constitute only a small fraction of diseases that compromise nervous system function in the neonate) but to the fact that they must be recognized promptly if the infant is to be prevented from dying or from suffering a lifelong severe developmental delay. This inherent threat introduces an element of urgency into neonatal neurology. Recognition of these diseases is also important for purposes of family and prenatal testing.

Two approaches to the neonatal metabolic disorders are possible—one, to screen every newborn, using a battery of biochemical tests of blood and urine, and the other, to undertake in the days following birth a detailed neurologic assessment that will detect the earliest signs of these diseases. Unfortunately, not all the biochemical tests have been simplified to the point where they can be adapted to a mass screening program, and many of the commonly used clinical tests at this age have yet to be validated as markers of disease. Moreover, many of the biochemical tests are costly, and practical issues, such as cost-effectiveness, insinuate themselves, to the distress of the pediatrician. The introduction of tandem mass spectrometry for the evaluation of blood and urine has allayed some of the latter concerns.

Neurologic Assessment of Neonates with Metabolic Disease

As pointed out in Chap. 28, the neonate’s nervous system functions essentially at a brainstem–spinal level. The pallidum and visuomotor cortices are only beginning to be myelinated and their contribution to the totality of neonatal behavior cannot be very great. Neurologic examination, to be informative, must therefore be directed to evaluating diencephalic–midbrain, cerebellar–lower brainstem, and spinal functions. The integrity of these functions in the neonate is most reliably assessed by noting the following, as was also described in Chap. 28:

1. 
   

   Control of respiration and body temperature; regulation of thirst, fluid balance, and appetite–hypothalamus–brainstem mechanisms

   
   
2. 
   

   Certain elemental automatisms, such as sucking, rooting, swallowing, grasping—brainstem–cerebellar mechanisms

   
   
3. 
   

   Movements and postures of the neck, trunk, and limbs, such as reactions of support, extension of the neck and trunk, flexion movements, and steppage—lower brainstem (reticulospinal), cerebellar, and spinal mechanisms

   
   
4. 
   

   Muscle tone of limbs and trunk—spinal neuronal and neuromuscular function

   
   
5. 
   

   Reflex eye movements—tegmental midbrain and pontine mechanisms (a modified optokinetic nystagmus can be recognized by the third day of life)

   
   
6. 
   

   The state of alertness and attention (stimulus responsivity and capacity of the examiner to make contact) as well as sleep–waking and electroencephalographic patterns—mesencephalic–diencephalic mechanisms

   
   
7. 
   

   Certain reflexive reactions such as the startle (Moro) response and placing reactions of the foot and hand—upper brainstem–spinal mechanisms with possible cortical facilitation

Derangements of these functions are manifest as impairments of alertness and arousal, hypotonia, disturbances of ocular movement (oscillations of the eyes, nystagmus, loss of tonic conjugate deviation of the eyes in response to vestibular stimulation, i.e., to rotation of the upright infant), failure to feed, tremors, clonic jerkings, tonic spasms, opisthotonos, diminution or absence of limb movements, irregular or chaotic breathing, hypothermia or poikilothermia, bradycardia, circulatory difficulties, poor color, and seizures.

In most instances of neonatal metabolic disease, the pregnancy and delivery proceed without mishap. Birth at full term is usual. The infant is of a size and weight expected for the duration of pregnancy, and there are no signs of a developmental abnormality (in a few instances the infant is somewhat small, and in GM1 gangliosidosis there may be a pseudo-Hurler appearance; see further on). Furthermore, function continues to be normal in the first few days of life. The first hint of trouble may be the occurrence of feeding difficulties: food intolerance, diarrhea, and vomiting. The infant becomes fretful and fails to gain weight and thrive—all of which should suggest a disorder of amino acid, ammonia, or organic acid metabolism.

The first definite indication of disordered nervous system function is likely to be the occurrence of seizures. These usually take the form of unpatterned clonic or tonic contractions of one side of the body or independent bilateral contractions, sudden arrest of respiration, turning of the head and eyes to one side, or twitching of the hands and face. Some of the ill-formed seizures may become generalized. They occur singly or in clusters and in the latter instance, are associated with unresponsiveness, immobility, and arrest of respiration.

The other clinical abnormalities in the motor realm, according to authorities such as Prechtl and Beintema, can be subdivided roughly into three groups, each of which constitutes a kind of syndrome: (1) hyperkinetic–hypertonic, (2) apathetic–hypotonic, or (3) unilateral or hemisyndromic. Prechtl and Beintema, from a study of more than 1,500 newborns, found that if clinical examination consistently discloses any one of the 3 syndromes, the chances are 2 in 3 that by the seventh year the child will be manifestly abnormal neurologically. They found also that certain neurologic signs—such as facial palsy, lack of grasping, excessive floppiness, and impairment of sucking—while sometimes indicative of serious disease of the nervous system, are less dependable; also, being rare, these signs will identify but few brain-damaged infants. It is not the single neurologic sign but groups of them that are held to be the most reliable indices of brain abnormality, and the 3 syndromes mentioned above are the important ones, even though their anatomic and physiologic bases are not completely known.

In cases of hypocalcemia-hypomagnesemia, the hyperkinetic–hypertonic syndrome prevails. Although most of the other diseases tend to induce the apathetic–hypotonic state, the hyperactive–hypertonic syndrome may represent the initial phase of the illness and always carries a less ominous prognosis than the apathetic–hypotonic state, which represents a more severe condition regardless of cause. The third putative group of unilateral abnormalities in the metabolic diseases is less common and more difficult to recognize. These syndromes frequently overlap and seizures may occur in all of them. The anatomic correlate for some of these neurologic abnormalities can be observed by MRI. Clearly what is needed is a more definitive neonatal neurologic semiology utilizing numerous stimulus–response tests, including those described by Andre Thomas and Dargassis.

Neonatal Metabolic Diseases and Their Estimated Frequency

In New England, screening of all newborns for metabolic disorders has been practiced for almost 50 years. Data on the diseases with neurologic implications were in the past collated by our colleague, H.L. Levy of Boston Children’s Hospital, and are summarized in Table 37-1. Some of these disorders can be recognized by simple color reactions in the urine; these are listed in Table 37-2.

To this group should be added the inherited hyperammonemic syndromes and vitamin-responsive aminoacidopathies (such as pyridoxine dependency and biopterin deficiency), as well as certain nonfamilial metabolic disorders that make their appearance in the neonatal period—hypocalcemia, hypothyroidism and cretinism, hypomagnesemia with tetany, and hypoglycemia.

It is important to note that the three most frequently identified hereditary metabolic diseases—phenylketonuria (PKU), hyperphenylalaninemia, and congenital hypothyroidism—do not become clinically manifest in the neonatal period and are therefore discussed in a later portion of this chapter and in Chap. 40 (in the discussion of congenital hypothyroidism). This is fortunate, for it allows time to introduce preventive measures before the first symptoms appear. A number of other metabolic disorders, which can be recognized either by screening or by early signs, are synopsized below.

Vitamin-Responsive Aminoacidopathies

Included under this heading is a group of diseases that respond not to dietary restriction of a specific amino acid but to the oral supplementation of a specific vitamin. Some 30 vitamin-responsive aminoacidopathies are known (they are all rare, but the more frequent ones are listed in Table 41-3), and many of them result in injury to the central nervous system (CNS).

Pyridoxine-Dependent Seizures

Pyridoxine dependency is the prototypic example of a genetic, vitamin-dependent biochemical disorder, albeit a rare disease. It is inherited as an autosomal recessive trait and is characterized by the early onset of convulsions, sometimes occurring in utero; failure to thrive; hypertonia–hyperkinesia; irritability; tremulous movements (“jittery baby”); exaggerated auditory startle (hyperacusis); and later, if untreated, by psychomotor retardation. The specific laboratory abnormality is an increased excretion of xanthurenic acid in response to a tryptophan load. There are decreased levels of pyridoxal-5-phosphate and gamma-aminobutyric acid (GABA) in brain tissue. The mutation is of the ALDH7A1 gene.

The neuropathology has been studied in only a few cases. One patient of our colleague R.D. Adams, a 13.5-year-old boy affected in the neonatal period, was left in a state of mental retardation, with pale optic discs and spastic legs; the brain weight was 350 g below normal. There was a decreased amount of central white matter in the cerebral hemispheres and a depletion of neurons in the thalamic nuclei and cerebellum, with gliosis (Lott et al). Most importantly, in pyridoxine deficiency, the administration of 50 to 100 mg of vitamin B6 suppresses the seizure state, and daily doses of 40 mg permit normal development.

Biopterin Deficiency

Some patients with increased concentrations of serum phenylalanine in the neonatal period are unresponsive to measures that lower phenylalanine. They are usually found to have a defect in biopterin metabolism. If this condition is unrecognized and not treated promptly, it leads to seizures of both myoclonic and, later, grand mal types, combined with a poor level of responsiveness and generalized hypotonia. Swallowing difficulty is another prominent symptom. Within a few months, developmental delay becomes prominent. Unlike in PKU, phenylalanine hydroxylase enzyme levels are normal, but there is a lack of tetrahydrobiopterin, which is a cofactor of phenylalanine hydroxylase. Treatment consists of administration of tetrahydrobiopterin in a dosage of 7.5 mg/kg/d in combination with a low-phenylalanine diet. It is important to recognize this condition early in life by the measurement of urine pterins and to institute appropriate therapy before irreversible brain injury occurs. A later onset form with diurnally fluctuating dystonia has also been described but its nature is not certain.

Galactosemia

Inheritance of this disorder is autosomal recessive. The biochemical abnormality consists of a defect in galactose-1-phosphate uridyl transferase (GALT), the enzyme that catalyzes the conversion of galactose-1-phosphate to uridine diphosphate galactose. Several forms of galactosemia have been described, based on the degree of completeness of the metabolic block and some of these are due to mutations in other galactose pathway genes. In the typical (severe) form, the onset of symptoms is in the first days of life, after the ingestion of milk; vomiting and diarrhea are followed by a failure to thrive. Drowsiness, inattention, hypotonia, and diminution in the vigor of neonatal automatisms then become evident. The fontanels may bulge, the liver and spleen enlarge, the skin becomes yellow (in excess of the common neonatal jaundice), and anemia develops. In a small number, there is thrombocytopenia with cerebral bleeding. Cataracts form as a result of the accumulation of galactitol in the lens. Studies of the outcome of surviving infants have shown delayed psychomotor development (IQ about 85), visual impairment, osteoporosis, ovarian failure, and residual cirrhosis, sometimes with splenomegaly and ascites. This seems to happen even with treatment. However, it is not known whether, in such patients, the treatment is always maintained through a critical developmental period. In one such patient, who died at age 8 years, the main change in the brain was slight microcephaly with fibrous gliosis of the white matter and some loss of Purkinje and granule cells in the cerebellum, and also gliosis (Crome). The diagnostic laboratory findings are an elevated blood galactose level, low glucose, galactosuria, and deficiency of GALT in red and white blood cells and in liver cells. The treatment is essentially dietary, using milk substitutes; if this is instituted early, the brain should be protected from injury.

A late-onset neurologic syndrome has also been observed by Friedman and colleagues in galactosemic patients who had survived the infantile disease. By late adolescence, they were cognitively delayed; some showed cerebellar ataxia, dystonia, and apraxia. One of these patients was middle-aged.

Organic Acidurias of Infancy

These have been divided into ketotic and nonketotic types. Among the ketotic types, the main one is propionic acidemia. This is an autosomal recessive disease caused by a primary defect in organic acid metabolism that is expressed clinically by episodes of vomiting, lethargy, coma, convulsions, hypertonia, and respiratory difficulty. The onset is in the neonatal or early infantile period; in time, psychomotor retardation becomes evident. Death usually occurs within a few months despite dietary treatment. Propionic acid, glycine, various forms of fatty acids, and butanone are elevated in the serum. As with other ketotic organic acidurias, high protein intake induces ketotic attacks. Marked restriction of dietary protein (specifically leucine) may prevent attacks of ketoacidosis and permit relatively good psychomotor development.

A number of other ketotic acidurias also occur in infancy. The most important of these are methylmalonic acidemia, isovaleric acidemia, beta-keto acidemia, and lactic acidemia. Each of these disorders can become manifest with profound metabolic acidosis and intermittent lethargy, vomiting, tachypnea, tremors, twitching, convulsions, and coma, with early death in about half the patients and developmental retardation in those who survive. Rare subtypes of methylmalonic acidemia respond to vitamin B12. Isovaleric acidemia is characterized by a striking odor of stale perspiration, which has given it the sobriquet “sweaty foot syndrome.” Numerous metabolic defects, most commonly of pyruvate decarboxylase and pyruvate dehydrogenase, are responsible for the accumulation of lactic and pyruvic acids. The enzymatic defect of isovaleric acidemia also has been demonstrated in a recurrent form of episodic cerebellar ataxia and athetosis and in a persistent form in mitochondrial encephalopathies (Leigh disease), as described further on in this chapter.

A separate and rare deficiency of aromatic L–amino acid decarboxylase has been described; the chemical signature is low levels of almost all catecholamines. This defect is associated with a peculiar movement disorder of oculogyric crises, dystonia and athetosis, and autonomic failure (see Swoboda et al).

A type II glutaric acidemia has also been observed in the neonatal period and causes episodes of acidosis with vomiting and hyperglycemia. Multiple congenital anomalies of brain and somatic structures and cardiomyopathy are conjoined. A diet low in the specific toxic amino acid and supplements of carnitine and riboflavin are recommended, but the effects are unclear.

In the nonketotic form of hyperglycinemia, there are high levels of glycine but no acidosis. The notable diagnostic finding is an elevation of the CSF glycine, several times higher than that of the blood. The effects on the nervous system are more devastating than in the ketotic form. In reported cases (the authors and our colleagues have seen several), the neonate is hypotonic, listless, and dyspneic, with dysconjugate eye movements, opisthotonic posturing, myoclonus, and seizures. A few such neonates survive to infancy but are extremely cognitively impaired and helpless. Spongy degeneration of the brain has been reported both in this disease and in the ketotic form (Shuman et al). No treatment has been effective in severe cases. In an atypical milder form, with neurologic abnormalities that appear in later infancy or childhood, reduction of dietary protein and administration of sodium benzoate in doses up to 250 mg/kg/d have been beneficial. The use of dextromethorphan, which blocks glycine receptors, is said to be effective in preventing seizures and coma.

Inherited Hyperammonemias

These are a group of six diseases caused by inborn deficiencies of the enzymes of the Krebs-Henseleit urea cycle; they are designated as N-acetyl glutamate synthetase, carbamoyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinic acid synthetase (citrullinemia), argininosuccinase deficiency, and arginase deficiency. Hyperornithinemia-hyperammonemia-homocitrullinemia (HHH) and intrinsic protein intolerance are closely related disorders. They are identified by the finding of a persistent or episodic elevation of ammonia levels in the blood. A detailed account of these inherited hyperammonemic syndromes is contained in the review by Brusilow and Horwich.

The pattern of inheritance of each of these disorders is autosomal recessive except for OTC deficiency, which is X-linked dominant. Their clinical manifestations are a common expression of an accumulation of ammonia or of urea cycle intermediates in the brain; they differ only in severity, in accordance with the degree of completeness of the enzymatic deficiency and with the age of the affected individual. The one exception is arginase deficiency, which commonly appears during later childhood as a progressive spastic paraplegia with mental retardation. Clinically, it has been convenient to divide the hyperammonemias into two groups—one that presents in the neonatal period and another that becomes evident in the weeks or months thereafter. This division is somewhat artificial, the clinical presentation being more in the nature of a continuous spectrum governed by the biologic factors mentioned above and even extending to rare cases that have their first symptoms during adulthood.

In the most severe forms of the hyperammonemic disorders, the infants are asymptomatic at birth and during the first day or two of life, after which they refuse their feedings, vomit, and rapidly become inactive and lethargic, soon lapsing into an irreversible coma. Profuse sweating, focal or generalized seizures, rigidity with opisthotonos, hypothermia, and hyperventilation have been observed in the course of the illness. These symptoms constitute a medical emergency, but even with measures to reduce serum ammonia, the disease is usually fatal.

In less severely affected infants, hyperammonemia develops some months later, when protein feeding is increased. There is a failure to thrive, and attempts to enforce feeding or during periods of constipation (both of which increase ammonia production in the bowel) may result in bouts of vomiting, lethargy, hyperirritability, and screaming. Respiratory alkalosis is a consistent feature. Other manifestations are periods of alternating hypertonia and hypotonia, seizures, ataxia, blurred vision, and of confusion, stupor, and coma. During episodes of stupor, often precipitated by dehydration, an alimentary protein load, or minor surgery, brain edema may be seen by CT and MRI; with repeated relapses, the brain edema gives way to atrophy, which appears as symmetrical areas of decreased attenuation in the cerebral white matter. Between attacks, some patients with partial deficiency may be normal or show only a slight hyperbilirubinemia (DiMagno et al; Rowe et al). With decompensation, the bilirubin rises, as does ammonia, but neither reaches exceedingly high levels. After repeated attacks, signs of developmental delay with motor and mental retardation become evident, and the patient is vulnerable to recurrent infections. Two adult male patients in our care, who were married (but with azoospermia, which is common) and working at technically demanding jobs, came to medical attention because of bouts of visual blurring followed by stupor that evolved over hours (Shih et al, 1999). They had displayed an aversion to protein and milk products as children; in later life, after meals high in protein, they became encephalopathic, one with severe brain swelling. There are few phenotypic differences among the late-onset hyperammonemias except for argininosuccinic aciduria, in which excessive dryness and brittleness of the hair (trichorrhexis nodosa) are notable features, and the aforementioned arginase deficiency with spastic diplegia.

Diagnosis is established by the finding of hyperammonemia, often as high as 1,500 mg/dL. The precise biochemical diagnosis requires testing of blood and urine for amino acids or assays for specific enzymes in red cells, liver, or jejunal biopsies. The primary hyperammonemias must be distinguished from the organic acidurias, including methylmalonic aciduria (see above), in which hyperammonemia can occur as a secondary metabolic abnormality.

In all the neonatal hyperammonemic diseases, the liver is often enlarged and liver cells appear to be inadequate in their metabolic functions, but how the enzymatic deficiencies or other disorders of amino acid metabolism affect the brain remains uncertain. It must be assumed that in some the saturation of the brain by ammonia impairs the oxidative metabolism of cerebral neurons, and when blood levels of ammonium increase (from protein ingestion, constipation, etc.), episodic coma or a more chronic impairment of cerebral functions occurs—as it does in adults with cirrhosis of the liver and portal-systemic encephalopathy. In the acutely fatal cases, the brain is swollen and edematous, and the astrocytes are diffusely increased in number and enlarged. The neurons are normal. Astrocytic swelling has been attributed to the accumulation of glutamate secondary to a suppression of glutamate synthetase. These changes have been reproduced in animals by the injection of ammonium chloride. When the hyperammonemia is abrupt in onset and severe, the resulting combination of encephalopathy, brain swelling, and respiratory alkalosis simulates the Reye syndrome (see “Reye-Johnson Syndrome” in Chap. 40).

As in all forms of liver disease, valproic acid and other hepatic toxins may cause hepatic coma by further impairing the urea cycle enzymes. Notable are a few cases of inherited hyperammonemia that come to light in childhood or adulthood only after the administration of one of these drugs.

Ornithine Transcarbamylase Deficiency and Argininosuccinic Aciduria

Most cases present in the neonatal period with hyperammonemia but milder forms may appear later in life with episodic symptoms such as episodic stupor, ataxia, and seizures. The other features have been mentioned above.

Treatment of the Hyperammonemic Syndromes

The treatment of acute hyperammonemic syndromes is directed at lowering ammonia levels by hemodialysis, exchange transfusions, and administration of arginine and certain organic acids. With subsidence of the acute symptoms, a systematic form of management should be undertaken, as outlined by Brusilow and colleagues and by Msall and colleagues. Sodium benzoate should be given in doses up to 250 mg/d, supplemented by sodium phenylacetate or sodium phenylbutyrate, which, on theoretical grounds, should divert nitrogen from the ureagenesis cycle. Arginine (50 to 150 mg/kg) should be added to the diet, as a deficiency of this substance may be responsible for the mental retardation and skin rashes. In more chronic cases, treatment consists of decreasing the ammonium load by the use of dietary protein restriction and by administration of oral antibiotics and lactulose. In infants with inborn errors of ureagenesis, there is a constant danger of recurrent episodes of hyperammonemia and coma, particularly in response to infections. In a few instances, careful management of the metabolic error has resulted in normal psychomotor development.

Liver transplantation may prove to be a therapeutic option.

Branched-Chain Aminoacidopathies (Maple Syrup Urine Disease)

These conditions are caused by a deficiency of α-keto acid dehydrogenase, resulting in the accumulation of the branched-chain amino acids leucine, isoleucine, and valine and the corresponding branched-chain α-keto acids. Maple syrup urine disease may be taken as the prototype. The pattern of inheritance is autosomal recessive. With the most-severe neonatal type, the infant appears normal at birth, but toward the end of the first week, poor feeding, intermittent hypertonicity, opisthotonos, and respiratory irregularities appear. These are followed by diminished neonatal automatisms, convulsions, severe ketoacidosis, and often coma and death toward the end of the second to fourth week. This disease is one of the causes of the malignant epileptic syndrome of early infancy (Brett). Four milder forms of the disease have been described. In these more chronic cases, feeding difficulties begin somewhat later in the early infantile period. They are manifest as recurrent infections, episodic acidosis, coma, and retarded growth and psychomotor development. Some of these patients, toward the end of the first year, may become quadriparetic or ataxic; or there may be only a nonspecific mental retardation. The disease derives its name from the maple syrup odor of the child’s urine that tests positively for 2,4-dinitrophenylhydrazine (DNPH).

Other important laboratory findings are increased plasma and urine concentrations of leucine, isoleucine, valine, and keto acids. Secondary accumulation of a derivative of α-hydroxybutyric acid probably accounts for the maple syrup odor. The neuropathologic findings are uncertain. In the first acute case described, only interstitial edema was observed; but in more chronic cases, pallor and loss of myelin and gliosis of parts of the cerebral white matter that myelinate after birth may be found. This can be visualized in CT and MRI scans.

Treatment by restriction of foods containing branched-chain amino acids (leucine, isoleucine, and valine) allows reasonably normal mental development, but only if such restriction is begun in the neonatal period and maintained lifelong. A thiamine-responsive variant with a slightly different pattern of keto acids described by Prensky and Moser responds variably to 30 to 300 mg of thiamine. The acute episodes, which threaten life, may require peritoneal dialysis to remove the putative toxic metabolites; they respond to the administration of glucose amino acid mixtures that are free of branched-chain keto acids.

Other Organic Acidemias

In addition to maple syrup urine disease, there are a number of other metabolic disturbances, some of them of mitochondrial origin, that appear in the neonatal period or later and are marked by an organic acidemia. If they are severe, the infant develops a metabolic (lactic) acidosis soon after birth, with lethargy, feeding problems, rapid respirations, and vomiting. Or there may be irritability, jerky limb movements, and hypertonia. Later presentations take the form of feeding difficulties, repeated vomiting, hypotonia, and failure to thrive. With the passage of time, psychomotor retardation and drug-resistant seizures become evident. Metabolic stress—e.g., intercurrent infection or surgical procedures—may precipitate an episode of lactic or ketoacidosis.

Biochemical studies may disclose a biotinidase deficiency, methylmalonic aciduria, glutaric acidemia, methylglutaconic acidemia, or any number of other organic acid abnormalities. The precise abnormality is determined by measuring enzyme activity in white blood cells or cultured skin fibroblasts. As remarked above, some of these enzymes act in conjunction with a specific vitamin cofactor, so that exact diagnosis is imperative. The biotinidase deficiency may respond to 10 mg of biotin per day; the methylmalonic acidemia to 1 to 2 mg of vitamin B12 per day; maple syrup urine disease to 10 to 20 mg of thiamine per day; and glutaric acidemia types I and II to 300 mg of riboflavin per day. The administration of carnitine may increase the elimination of toxic metabolites.

The care of these patients during an acute illness is of extreme importance. See Lyon and colleagues for a more complete description.

Sulfite Oxidase Deficiency with or Without Molybdenum Cofactor Deficiency (See also “Sulfite Oxidase Deficiency”)

These are extremely rare autosomal recessive disorders of sulfur metabolism, manifest clinically during the neonatal period by seizures, axial hypotonia, reduced level of responsivity, and spasms with opisthotonos. There may be added dislocation of lenses, blindness, coloboma, and enophthalmos in combination with severe mental retardation and dysmorphic facial features (widely spaced eyes, long face and philtrum, puffy cheeks). There are no differences between pure sulfite oxidase deficiency and that associated with molybdenum cofactor deficiency. With survival into infancy, episodic confusion and stupor give way to seizures, mental retardation, and ataxia. In one of our cases, described by Shih and colleagues (1977) a stroke-like syndrome of hemiplegia and aphasia appeared during a relapse at the age of 4.5 years, and in one case, subluxation of the lenses and choreoathetosis appeared at 8 months of age.

The biochemical abnormality is the accumulation of sulfite and possibly sulfatase as a result of the enzyme deficiency. Shih and colleagues (1977) have identified sulfite, thiosulfate, and S-sulfocysteine in the urine. Cerebral atrophy with loss and destruction of white matter and gray matter (cerebral cortex, basal ganglia, and cerebellar nuclei) was observed in one postmortem examination. Increasing the intake of molybdenum or lowering the dietary intake of sulfur amino acids is a therapeutic possibility not yet fully evaluated.

Diagnosis of Neonatal Metabolic Diseases

An important clue, of course, is provided by the history of a neonatal disease or unexplained death earlier in the same sibship or in a male maternal relative. A history that protein foods are rejected by the infant, or even a history among relatives of a dislike of protein or feeding difficulties in infancy, should raise the suspicion of an inherited hyperammonemic disorder or an organic acidemia. Measurements of blood ammonia and lactate and of the urine for ketones and reducing substances (that react with cupric sulfate) are the key laboratory tests. A wide-spectrum screening program may disclose a biochemical abnormality; this is the optimal state of affairs, especially when this type of screening provides the information before symptoms appear.

A number of nonhereditary metabolic diseases must be distinguished from the hereditary ones in this period of life. Hypocalcemia is one of the most frequent causes of neonatal seizures; tetany, spasms, and tremulous movements are usually present. Its cause is unknown, but the disorder is easily corrected, with excellent prognosis. Symptomatic hypoglycemic reactions are frequent in neonates. Premature infants are the most susceptible. Seizures, tremulousness, and drowsiness occur with blood sugar levels of less than 30 mg/dL in the mature infant, and less than 20 mg/dL in the premature. Maternal toxemia and diabetes mellitus also predispose to hypoglycemia. Other causes of hypoglycemia are adrenal insufficiency, galactosemia, an idiopathic pancreatic islet-cell hyperplasia, the treatable fatty-acid beta-oxidation disorders, and a congenital deficiency of CSF glucose transport—causing persistent hypoglycorrhachia and refractory seizures unless blood glucose levels are kept high. The damaging effects of untreated hypoglycemia were well documented by Koivisto and colleagues. Also now identified is a disorder of CSF serine transport causing failure to thrive, severe developmental disability with spasticity and intractable epilepsy. The diagnosis is made by measuring CSF amino acids; treatment is with high-dose oral serine. Cretinism and idiopathic hypercalcemia are other recognizable entities that appear during this age period.

Aicardi has described a neonatal myoclonic syndrome, and Ohtahara has described a malignant neonatal seizure disorder. In some of the cases, the neonatal syndrome merged later with the West type of infantile spasms and the Lennox-Gastaut syndrome (see Chap. 16). Some of the cases had developmental abnormalities of the cerebrum, and severe mental retardation was the outcome. In other cases of this type, a familial coincidence was a feature; a metabolic defect has been suspected in these cases but never proved.

The hereditary metabolic diseases must also be distinguished from a number of other catastrophic disorders that occur at or soon after birth, such as asphyxia, perinatal ventricular hemorrhage with the respiratory distress syndrome of hyaline membrane disease, other hypotensive–hypoxic states, erythroblastosis fetalis with kernicterus, neonatal bacterial meningitis, meningoencephalitis (herpes simplex, cytomegalic inclusion disease, listeriosis, rubella, syphilis, and toxoplasmosis), and hemorrhagic disease of the newborn. These are described in Chap. 38, on the developmental diseases.

The hallmark of all the hereditary metabolic diseases is psychosensorimotor regression. However, those that have their onset in the first year of life pose extraordinary problems in neurologic diagnosis. If the onset is in the first postnatal months, before the infant has had time to develop the normal complex repertoire of behavior, the first signs of disease may take the form of subtle delays in maturation rather than of psychomotor regression. Departures from normalcy include a lack of interest in the surroundings, a lack of visual engagement, poor head control, inability to sit up at the usual time, poor hand–eye coordination, and persistence of infantile automatisms. Of course, embryologic maldevelopment of the brain may have similar effects, and systemic diseases and other visceral malformations—such as cystic fibrosis, renal disease, biliary atresia and congenital heart disease, chronic infection, malnutrition, and seizures (with drug therapy)—may appear to impede psychomotor development. Diagnosis becomes somewhat easier in the second half of the first year, especially if development in the first half had proceeded normally. Then an observant mother, usually one with older children, can perceive a loss of certain early acquisitions, attesting to the progressive nature of a disease.

The most distinctive members of this category of neurologic disease are the leukodystrophies and the lysosomal storage diseases. The leukodystrophies are a group of inherited metabolic diseases of the nervous system characterized by progressive, symmetrical, and usually massive destruction of the white matter of the brain and sometimes of the spinal cord; each type of leukodystrophy is distinguished by a specific genetic defect in myelin metabolism. In the lysosomal storage diseases, there is a genetic deficiency of the enzymes (usually one or more of the acid hydrolases) necessary for the degradation of specific glycosidic or of peptide linkages in the intracytoplasmic lysosomes, causing nerve cells to become engorged with material that they would ordinarily degrade. These metabolites eventually damage the nerve cell or its myelin sheath.

Most of these diseases are classed as sphingolipidoses. Brady in 1966 made the observation that in each of these disorders an increased quantity of sphingolipid accumulated in the brain and other tissues. The sphingolipids are a class of intracellular lipids that all have ceramide as their basic structure, but each has a different attached oligosaccharide or phosphorylcholine. The rate of synthesis of the sphingolipids is normal and their accumulation results from a defect of a specific lysosomal enzyme that normally degrades each of the glycoproteins, glycolipids, and mucopolysaccharides by removing a monosaccharide or sulfate moiety. It is the type of enzyme deficiency and accumulated metabolite, as well as the tissue distribution of the nondegradable substrate, that impart a distinctive biochemical and clinical character to each of the diseases in this category.

The concept of lysosomal storage diseases, introduced by Hers in 1965, excited great interest at the time because it provided the potential for prenatal diagnosis and the detection of carriers. The diagnosis of this group of diseases has also been facilitated by the use of CT, MRI, and evoked response techniques, which confirm the existence of leukodystrophies and by the electron microscopic examination of skin, rectal, or conjunctival biopsies, circulating lymphocytes, and cultured amniotic fluid cells, which discloses the lysosomal storage material in nonneural cells.

There are now more than 40 lysosomal storage diseases in which the biochemical abnormalities have been determined. The main ones are listed in Table 37-3, which was adapted originally from the review of Kolodny and Cable and updated by our colleague, E. Kolodny. In addition to the sphingolipidoses, which are the lysosomal storage diseases most likely to be encountered in the first year of life, the table includes the storage diseases that may not appear clinically until a later age (in childhood and adolescence)—to be considered later in this chapter. The frequency of each of the various types, as detected in a comprehensive study of the Australian population, is given by Meikle and colleagues and generally accords with the ordering below. A broad perspective on the frequency of the lysosomal disorders can be appreciated from the report of the Australian national referral laboratory. There were 545 cases (75 detected prenatally) over a 16-year period, a calculated frequency of 1 case per 7,700 live births. This is close to the estimate in the United States, which is approximately 1 per 5,000 births.

The more frequent types of lysosomal storage diseases are as follows:

1. 
   

   Tay-Sachs disease (GM2 gangliosidosis) and variants such as Sandhoff disease

   
   
2. 
   

   Infantile Gaucher disease

   
   
3. 
   

   Infantile Niemann-Pick disease

   
   
4. 
   

   Infantile GM1 generalized gangliosidosis

   
   
5. 
   

   Krabbe globoid-body leukodystrophy

   
   
6. 
   

   Farber lipogranulomatosis

   
   
7. 
   

   Pelizaeus-Merzbacher and other sudanophilic leukodystrophies

   
   
8. 
   

   Spongy degeneration (Canavan-van Bogaert-Bertrand disease)

   
   
9. 
   

   Alexander disease

   
   
10. 
    

    Zellweger encephalopathy

    
    
11. 
    

    Lowe oculorenal-cerebral disease

In the following descriptions, we have summarized the clinical and pathologic features of each of the diseases listed above and have italicized the characteristic clinical signs and corroborative laboratory tests. Leigh disease, which may appear in this age group, is described with the mitochondrial diseases, further on in this chapter.

Tay-Sachs Disease (GM2 Gangliosidosis, Hexosaminidase A Deficiency, HEXA Mutation)

This is an autosomal recessive disease, mostly of Jewish infants of eastern European (Ashkenazic) background. The first description came from Tay, a British ophthalmologist, in 1881, and Sachs, an American neurologist, in 1887; they called it amaurotic family idiocy. The disease becomes apparent in the first weeks and months of life, almost always by the fourth month. The first manifestations are a regression of motor activity and an abnormal startle to acoustic stimuli, accompanied by listlessness, irritability, and poor reactions to visual stimuli. These are followed by a progressive delay in psychomotor development or regression (by 4 to 6 months), with inability to roll over and sit. At first, axial hypotonia is prominent, but later spasticity and other corticospinal tract signs and visual failure become evident. Degeneration of the macular cells exposes the underlying red vascular choroid surrounded by a whitish gray ring of retinal cells distended with ganglioside. The resulting appearance is of the cherry-red spot with optic atrophy (Fig. 37-1). These are observed in the retinas in more than 90 percent of patients (but are also characteristics of other storage diseases—see Table 37-4). In the second year, there are tonic-clonic or minor motor seizures and an increasing size of the head and diastasis of sutures with relatively normal-size ventricles; in the third year, the clinical picture is one of dementia, decerebration, and blindness. Cachexia becomes increasingly severe and death occurs at 2 to 4 years. The electroencephalogram (EEG) becomes abnormal in the early stages (paroxysmal slow waves with multiple spikes). Occasionally, one can find basophilic granules in leukocytes and vacuoles in lymphocytes. There are no visceral, skeletal, or bone marrow abnormalities by light microscopy.

The basic enzymatic abnormality is a deficiency of beta hexosaminidase A, which normally cleaves the N-acetylgalactosamine from gangliosides. As a result of this deficiency, GM2 ganglioside accumulates in the cerebral cortical neurons, Purkinje cells, retinal ganglion cells, and, to a lesser extent, larger neurons of the brainstem and spinal cord. The enzymatic defect can be found in the serum, white blood cells, and cultured fibroblasts from the skin or amniotic fluid, the latter giving parents the option of abortion to prevent a presently untreatable and fatal disease. Testing for hexosaminidase A also permits the detection of heterozygote carriers of the gene defect. Detection of this enzyme defect is complicated by the fact that more than 50 mutations of the HEXA gene have been isolated, coding for alpha subunit of the beta hexosaminidases and the enzyme itself is normal in one form of activator enzyme deficiency. Fortunately, only three mutations account for 98 percent of the form that is common in individuals of Jewish ancestry.

The brain is large, sometimes twice the normal weight. In addition, there is a loss of neurons and a reactive gliosis; remaining nerve cells throughout the CNS are distended with glycolipid. Biopsies of the rectal mucosa disclose glycolipid distention of the ganglion cells of the Auerbach plexus, but the need for this procedure has been obviated by enzyme analysis of white blood cells. Under the electron microscope, the particles of stored material appear as membranous cytoplasmic bodies. Retinal ganglion cells are distended with the same material and, together with fat-filled histiocytes, cause the whitish gray rings around the fovea, where there are no nerve cells, as noted above.

Tay-Sachs disease is untreatable but can be prevented by testing all individuals of Jewish origin for the recessive trait. Where screening has been instituted the disease has become virtually extinct.

In Sandhoff disease, which affects infants of non-Jewish origins, there is a deficiency of both hexosaminidase A and B, moderate hepatosplenomegaly, and coarse granulations in bone marrow histiocytes. The clinical and pathologic picture is the same as in Tay-Sachs disease except for the additional signs of visceral lipid storage. Occasionally, these visceral organs are not enlarged.

In recent years numerous variants of hexosaminidase A and B deficiency have been identified. They differ clinically from Tay-Sachs disease in having a later onset, less-extensive brain involvement (cortical neurons relatively spared and intense affection of basal ganglia, as well as cerebellar and spinal neurons). Accordingly, the clinical expression of the variants appearing in childhood, adolescence, and adult life takes the form of athetosis, dystonia, ataxia, and motor neuron paralysis; mental function can be normal. The process has also been found in a few congenital cases in which there was a rapidly progressive decline of a microcephalic infant.

Infantile Gaucher Disease (Type II Neuronopathic Form, Glucocerebrosidase Deficiency, GBA Mutation)

This is an autosomal recessive disease without ethnic predominance, first described by Gaucher in 1882. The onset of the neuronopathic form is usually before 6 months and frequently before 3 months. The clinical course is more rapid than that of Tay-Sachs disease (most patients with infantile Gaucher disease do not survive beyond 1 year and 90 percent not beyond 2 years). Oculomotor apraxia and bilateral strabismus are early signs and are accompanied by rapid loss of head control, of ability to roll over and sit, and of purposeful movements of the limbs—along with apathy, irritability, frequent crying, and difficulty in sucking and swallowing. In some cases progression is slower, with acquisition of single words by the first year, bilateral corticospinal signs (Babinski signs and hyperactive tendon reflexes), persistent retroflexion of the neck, and strabismus. Laryngeal stridor and trismus, diminished reaction to stimuli, smallness of the head, rare seizures, normal optic fundi, enlarged spleen and slightly enlarged liver, poor nutrition, yellowish skin and scleral pigmentation, osteoporosis, vertebral collapse and kyphoscoliosis, and sometimes lymphadenopathy complete the clinical picture. The CSF is normal; the EEG is abnormal, but nonspecifically so.

The important laboratory findings are an increase in serum acid phosphatase and characteristic histiocytes (Gaucher cells) in marrow smears and liver and spleen biopsies. A deficiency of glucocerebrosidase in leukocytes and hepatocytes is diagnostic; glucocerebroside accumulates in the involved tissues. The characteristic pathologic feature is the Gaucher cell, 20 to 60 μm in diameter, with a wrinkled appearance of the cytoplasm and eccentricity of the nucleus. These cells are found in the marrow, lungs, and other viscera; neuronal storage is seldom evident. In the brain, the main abnormality is a loss of nerve cells—particularly in the bulbar nuclei, but also in the basal ganglia, cortex, and cerebellum—and a reactive gliosis that extends into the white matter.

In contrast to the type II form described above, type I Gaucher disease is a nonneuronopathic and relatively benign form. A less-frequent type III Gaucher disease is neuronopathic. It expresses itself in late childhood or adolescence by a slowly progressive mental decline, seizures, and ataxia, and, later, by spastic weakness and splenomegaly. Vision and retinae remain normal. Highly diagnostic is the defect in voluntary lateral gaze, with full movements on the oculocephalic (“doll’s-head”) maneuver. These signs help to differentiate Gaucher from Niemann-Pick disease, in which vertical eye movements are lost (see below). The nucleotide sequence of the cloned glucocerebrosidase gene of type I Gaucher disease was found by Tsuji and associates (1987) to be different from that of types II and III. There is no treatment for the latter types.

Infantile Niemann-Pick Disease (Sphingomyelinase Deficiency, NPC Mutation)

This is also an autosomal recessive disease. Two-thirds of the affected infants have been of Ashkenazi Jewish parentage. The onset of symptoms in the usual type A disease is between 3 and 9 months of age, frequently beginning with marked enlargement of liver, spleen, and lymph nodes and infiltration of the lungs; rarely, there is jaundice and ascites. Cerebral abnormalities are definite by the end of the first year, often earlier. The usual manifestations are loss of spontaneous movements, lack of interest in the environment, axial hypotonia with bilateral corticospinal signs, blindness and amaurotic nystagmus, and a macular cherry-red spot (in about one-quarter of the patients). Seizures may occur, but are relatively late. There is no acoustic-induced startle or myoclonus, and head size is normal or slightly reduced. Loss of tendon reflexes and slowed conduction in peripheral nerves have been recorded but are rare. Protuberant eyes, mild hypertelorism, slight yellowish pigmentation of oral mucosa, and dysplasia of dental enamel have also been reported but are rare. Most patients succumb to an intercurrent infection by the end of the second year.

Vacuolated histiocytes (“foam cells”) in the bone marrow and vacuolated blood lymphocytes are the important laboratory findings. A deficiency of sphingomyelinase in leukocytes, cultured fibroblasts, and hepatocytes is diagnostic. Pathologic examination reveals a decrease in the number of neurons; many of the remaining ones are pale and ballooned and have a granular cytoplasm. The most prominent neuronal changes are seen in the midbrain, spinal cord, and cerebellum. The white matter is little affected. The retinal nerve cell changes are similar to those in the brain. The foamy histiocytes (Niemann-Pick cells) that fill the viscera contain sphingomyelin and cholesterol; the distended nerve cells contain mainly sphingomyelin.

There are also less-severe late infantile and juvenile forms of Niemann-Pick disease types C and D. These are discussed in a later section of this chapter.

Infantile Generalized GM1 Gangliosidosis (Type I, Beta-Galactosidase Deficiency, Pseudo-Hurler Disease, GLB1 Mutation)

This is probably an autosomal recessive disease without ethnic predominance. The infants appear abnormal at birth. They have dysmorphic facial features, like those of the mucopolysaccharidoses: depressed and wide nasal bridge, frontal bossing, hypertelorism, puffy eyelids, long upper lip, gingival and alveolar hypertrophy, macroglossia, and low-set ears. These features, with the bone changes mentioned below, account for the term pseudo-Hurler. Other indications of the disease are the onset of impaired awareness and reduced responsivity in the first days or weeks of life; lack of psychomotor development after 3 to 6 months; hypotonia, and later hypertonia with lively tendon reflexes and Babinski signs. Seizures are frequent. The head size is variable (microcephaly more often than macrocephaly). Loss of vision, coarse nystagmus and strabismus, macular cherry-red spots (in half the cases), flexion pseudocontractures of elbows and knees, kyphoscoliosis, and enlarged liver and sometimes enlarged spleen are the other important clinical findings. Radiographic abnormalities include subperiosteal bone formation, midshaft widening and demineralization of long bones, and hypoplasia and beaking of the thoracolumbar vertebrae. Vacuoles are seen in 10 to 80 percent of blood lymphocytes and foam cells in the urinary sediment.

A partial or complete deficiency of beta-galactosidase and accumulation of GM1 ganglioside in the viscera and in neurons and glia cells throughout the CNS are the specific biochemical abnormalities. In addition, the epithelial cells of renal glomeruli, histiocytes of the spleen, and liver cells contain a modified keratan sulfate and a galactose-containing oligosaccharide. The changes in the bone are also like those in the Hurler form of mucopolysaccharidosis. The disease should be suspected in an infant having the facial features of mucopolysaccharidosis and severe early-onset neurologic abnormalities.

A remarkably benign variant, also inherited as an autosomal recessive trait, begins later in childhood but may advance so slowly as to allow attainment of adult life. Dystonia, myoclonus, seizures, visual impairment, and macular red spots were features of the two cases described by Goldman and coworkers.

Globoid Cell Leukodystrophy (Krabbe Disease, Galactocerebrosidase Deficiency, GALC Mutation)

This is an autosomal recessive disease without ethnic predilection, first described by Krabbe, a Danish neurologist, in 1916. The onset is usually before the sixth month and often before the third month (10 percent after 1 year). Early manifestations are generalized rigidity, loss of head control, diminished alertness, frequent vomiting, irritability and bouts of inexplicable crying, and spasms induced by stimulation. With increasing muscular tone, opisthotonic recurvation of the neck and trunk develops. Later signs are adduction and extension of the legs, flexion of the arms, clenching of the fists, hyperactive tendon reflexes, and Babinski signs. Later still, the tendon reflexes are depressed or lost but Babinski signs remain, an indication that neuropathy is added to corticospinal damage. This finding, shared with some of the other leukodystrophies, is of diagnostic value. Blindness and optic atrophy supervene. Convulsions occur but are rare and difficult to distinguish from tonic spasms. Myoclonus in response to auditory stimuli is present in some cases. The head size is normal or, rarely, slightly increased. In the last stage of the disease, which may occur from one to several months after the onset, the child is blind and usually deaf, opisthotonic, irritable, and cachectic. Most patients die by the end of the first year and survival beyond 2 years is unusual, although a considerable number of cases of later onset have been reported (see below).

The EEG shows nonspecific slowing without spikes, and the CSF protein is usually elevated (70 to 450 mg/dL). Imaging shows symmetrical nonenhancing areas of increased signal in the internal capsules and basal ganglia. As the disease advances, more of the cerebral white matter and brainstem become involved (Fig. 37-2). An additional feature in many cases is enlargement of the prechiasmatic optic nerves. Neuropathy is a feature in most cases, but clinical signs may be difficult to detect except for a decrease or loss of tendon reflexes; however, there is evidence of denervation and slowed motor and sensory nerve conduction velocities, reflecting a demyelinating polyneuropathy (see later comments on late-onset cases).

The deficient lysosomal enzyme in Krabbe disease is galactocerebrosidase (GALC; also called galactosylceramide beta-galactosidase); it normally degrades galactocerebroside to ceramide and galactose. The deficiency results in the accumulation of galactocerebroside; a toxic metabolite, psychosine, leads to the early destruction of oligodendrocytes and depletion of lipids in the cerebral white matter. The globoid cell reaction, however, indicates that impaired catabolism of galactosylceramide is also important. Gross examination of the brain discloses a marked reduction in the cerebral white matter, which feels firm and rubbery. Microscopically, there is widespread myelin degeneration, absence of oligodendrocytes, and astrocytic gliosis in the cerebrum, brainstem, spinal cord, and nerves. The characteristic globoid cells are large histiocytes containing the accumulated metabolite. Schwann cells have tubular or crystalloid inclusions under electron microscopy.

About a dozen variants of globoid cell leukodystrophy have been reported, many of them allowing survival for years. In these, neurologic regression begins in the 2- to 6-year-old period. Visual failure with optic atrophy and a normal electroretinogram is an early finding. Later there is ataxia, as well as spastic weakness of the legs, mental regression, and finally decerebration. In three patients observed by R.D. Adams, a progressive quadriparesis with mild pseudobulbar signs, slowly progressive impairment of memory and other mental functions, dystonic posturing of the arms, and preserved sphincteric control constituted the clinical picture. The patients were alive at ages 9, 12, and 16 years. We have observed another rare variant, beginning in adult years, with spastic quadriparesis (asymmetrical) and optic atrophy. Mentation was essentially normal and, on imaging, the cerebral lesion was restricted. Unlike typical Krabbe disease, these CNS abnormalities are unaccompanied by any change in the spinal fluid. The nerve conduction velocities in the late-onset form may be either normal or abnormal.

Kolodny and colleagues reported 15 cases of even later onset (ages 4 to 73 years); pes cavus, optic pallor, progressive spastic quadriparesis, a demyelinating sensorimotor neuropathy, and symmetrical parietooccipital white matter changes (on imaging studies) were the main features. Galactocerebrosidase levels were not as reduced as in the infantile form; possibly these late-onset variants represent a structural mutation of the enzyme (see Farrell and Swedberg).

In this disease, as well as others described in this chapter, it has become clear that different mutations involving the same enzyme or metabolic pathway can produce strikingly different phenotypes and that there is a wide range in the age of onset in what had been considered, until relatively recently, a disease confined to infancy and early childhood.

Treatment

In what may be considered a possible breakthrough in the treatment of childhood metabolic disease, Escolar and colleagues reported the successful use of transplanted umbilical cord hematopoietic cells in asymptomatic babies with Krabbe disease. Patients who were treated after becoming symptomatic did not benefit, but 14 patients who had been diagnosed prenatally or very soon after birth demonstrated progressive myelination of the nervous system, normalization of blood galactocerebroside activity, and attained visual, developmental, and cognitive function. The donors were partially human leukocyte antigen (HLA)-matched and substantial antirejection medication was required.

Vanishing White Matter Disease

This more recently described and peculiarly named disease with variable age of onset is most typically manifest in this age group. After a period of normal development, and sometimes precipitated by infection or fever, there is a progressive encephalopathy punctuated by episodes of more rapid deterioration. The core syndrome is of irritability, loss of vision, seizures, ataxia, and coma, sometimes with recovery to a disabled state. The denominative feature is a symmetrical leukodystrophy with progressive disappearance of white matter and replacement by CSF or gliosis. The nature of this disease, metabolic, inflammatory, or genetic (mutations in eIF2B), has not been resolved despite tentative linkage to certain chromosomal regions. We include it in this section because exacerbation with fever, similar to the case in some mitochondrial diseases, is suggestive of a metabolic disorder (see Leegwater et al).

Lipogranulomatosis (Farber Disease, Ceramidase Deficiency)

This is a rare autosomal disorder that is based on a mutation in ASAH1. The onset is in the first weeks of life, with a hoarse cry because of fixation of laryngeal cartilage, respiratory distress, and sensitivity of the joints, followed by characteristic periarticular and subcutaneous swellings and progressive arthropathy, leading finally to ankylosis. Usually there is severe psychomotor delay, but a few patients have been neurologically normal. Inanition and recurrent infections lead to death in the first 2 years. The diagnostic abnormality is a deficiency of ceramidase, leading to accumulation of ceramide. There is widespread lipid storage in neurons, granulomas of the skin, and accumulation of periodic acid-Schiff (PAS)-positive macrophages in periarticular and visceral tissues.

Sudanophilic Leukodystrophies and Pelizaeus-Merzbacher Disease

These are a heterogeneous group of disorders that have in common a defective myelination of the cerebrum, brainstem, cerebellum, spinal cord, and peripheral nerves. Morphologic peculiarities and genetic features separate a certain group called Pelizaeus-Merzbacher disease; other types have been artificially delineated; as a result, a relatively meaningless terminology has been introduced.

Pelizaeus-Merzbacher Disease (PLP1 Mutation)

This is predominantly an X-linked disease of infancy, childhood, and adolescence, and includes other closely related pathologic entities with different modes of inheritance. The affected gene encodes proteolipid protein (PLP), one of the two myelin basic proteins. Koeppen and associates have provided evidence of a defective synthesis of this protein. While one group of PLP mutations causes Pelizaeus-Merzbacher disease, another set causes an infantile spastic paraplegia.

The onset of symptoms is most often in the first months of life; other cases begin later in childhood. The first signs are abnormal movements of the eyes (rapid, irregular, often asymmetrical pendular nystagmus), jerk nystagmus on extremes of lateral movements, upbeat nystagmus on upward gaze, and hypometric saccades (Trobe et al). There is spastic weakness of the limbs, optic atrophy (often with unexplained retention of pupillary light reflex), ataxia of limb movement and intention tremor, choreiform or athetotic movements of the arms, and slow psychomotor development with delay in sitting, standing, and walking. Seizures occur occasionally. In later-developing cases, pendular nystagmus, choreoathetosis, corticospinal signs, dysarthria, cerebellar ataxia, and mental deterioration are the major manifestations. There are milder cases of later onset with behavioral peculiarities and loss of tendon reflexes and, rarely, pure spastic paraparesis.

Imaging confirms the extensive and symmetrical white matter involvement. In the most severe cases, Seitelberger has observed an absence of oligodendrocytes and myelinated fibers. It is hypothesized that proteolipids accumulate in the endoplasmic reticulum of the oligodendrocytes, resulting in apoptosis. Patients may survive to the second and third decades. One group of cases resembles the Cockayne syndrome, with photosensitivity of skin, dwarfism, cerebellar ataxia, corticospinal signs, cataracts, retinitis pigmentosa, and deafness. Pathologically, islands of preserved myelin impart a tigroid pattern of degenerated and intact myelin in the cerebrum. Seitelberger has obtained pathologic verification of this lesion in cases beginning as late as adult years. This disease and Cockayne syndrome are the only leukodystrophies in which nystagmus has been an invariable finding.

Koeppen and Robitaille, in a thorough review of the subject of the pathogenesis of Pelizaeus-Merzbacher disease, summarized the evidence supporting the concept that misfolding of myelin proteins is the essential cause.

Unclassifiable Sporadic and Familial Sudanophilic Leukodystrophies

There are two types of such disorders, one with early and the other with late onset. In the former, the illness begins before 3 months of age, with survival of less than 2 years; in the latter, onset is between ages 3 and 7 years and the course is only slowly progressive to the point of being chronic. Psychomotor regression; spastic paralysis; incoordination; blindness and optic atrophy; seizures (rare); severe microcephaly; and absence of skeletal, visceral, and hematologic evidence of the metabolic abnormality are the main features. No characteristic laboratory abnormalities are known. Diffuse degeneration of myelinated fibers (visible by MRI) with phagocytosis of sudanophilic degeneration products of myelin and gliosis are the major changes. In two cases followed by R.D. Adams and T. Rabinowicz, a brother and sister living to adolescence, the destroyed white matter was widely cavitated.

Spongy Degeneration of Infancy (Canavan-van Bogaert-Bertrand or Canavan Disease, ASPA Mutation)

This is an autosomal recessive disease that was described in 1931 by Myrtelle Canavan as a form of Schilder disease (see Chap. 36), but later categorized as a special spongy degeneration of the brain by van Bogaert and Bertrand. Of 48 affected families reported by Banker and Victor, 28 were of Jewish ancestry. Onset is early, usually recognizable in the first 3 months of life and sometimes in the first neonatal weeks. There is either a lack of development or rapid regression of psychomotor function, loss of sight and optic atrophy, lethargy, difficulty in sucking, irritability, reduced motor activity, hypotonia followed by spasticity of the limbs with corticospinal signs, and an enlarged head (macrocephaly). There are no visceral or skeletal abnormalities but a variable sensorineural hearing loss has been found (Ishiyama et al). Seizures occur in some cases. An interesting but unexplored aspect of the disease is the occurrence of blond hair and light complexion in affected members, in contrast to the darker hair and complexion of their normal siblings (Banker and Victor).

The CSF is usually normal but the protein is slightly elevated in some cases. The disease is characterized by an increased urinary excretion of N-acetyl-L-aspartic acid (NAA), which may be used as a biochemical marker. It reflects the basic enzyme abnormality, a deficiency of aminoacylase II, which catalyzes the breakdown of NAA (Matalon et al). On CT there is attenuation of cerebral and cerebellar white matter in an enlarged brain with relatively normal-size ventricles. The MRI appearance (Fig. 37-3) is that of diffuse, somewhat uneven, high signal intensity on T2-weighted images. A leukodystrophy with behavioral regression, an enlarging head, a characteristic MRI abnormality, and a marked elevation of urinary NAA should leave little doubt about the diagnosis.

The characteristic pathologic changes are an increase in brain volume (and weight), spongy degeneration in the deep layers of the cerebral cortex and subcortical white matter, widespread depletion of myelin involving the convolutional more than the central white matter, loss of Purkinje cells, and hyperplasia of Alzheimer type II astrocytes throughout the cerebral cortex and basal ganglia. Adachi and coworkers have demonstrated an abnormal vacuolar accumulation of fluid in astrocytes and between split myelin lamellae; they have suggested that the loss of myelin is secondary to these changes.

The enlargement of the brain in this disease must be distinguished clinically from GM2 gangliosidosis, Alexander disease, Krabbe disease, and nonprogressive megalocephaly and pathologically from a variety of disorders characterized by vacuolation of nervous tissue. There is no treatment.

Alexander Disease (GFAP Mutation)

This distinctive disease shares certain features with the leukodystrophies and also with gray matter diseases (poliodystrophies), both clinically and pathologically. The onset is in infancy with a failure to thrive, psychomotor retardation, spasticity of the craniospinal musculature, and seizures. An early and progressive macrocephaly has been a consistent feature. Alexander was the first to call attention to the enlargement of the brain, the extensive loss of cerebral white matter, and highly characteristic inclusions (the so-called Rosenthal fibers noted below) in astrocytes, and subpial and periventricular regions.

Pathologically, there are severe destructive changes in the cerebral white matter, most intense in the frontal lobes. Distinctive eosinophilic hyaline bodies, most prominent just below the pia and around blood vessels, are seen throughout the cerebral cortex, brainstem, and spinal cord. These have been identified as Rosenthal fibers and probably represent glial degradation products.

The astrocytic changes have been traced to a mutation in the glial fibrillary acidic protein (GFAP), as described by Gorospe and colleagues. It is usually inherited in an autosomal dominant pattern, and gives rise to the intermediate filament protein in astrocytes and, presumably, to the Rosenthal fiber inclusions. On the basis of this and related gene mutations, apparent milder forms of Alexander disease have been reported in juveniles and adults. They differed clinically in lacking the cerebral leukoencephalopathy. Instead, after a long period of constipation, sleep disorder, and orthostatic hypotension during adolescence, bulbar symptoms (dysarthria, dysphonia, and dysphagia), seizures, and in some cases ataxia gradually emerged during adult years. The myelin changes and atrophy of the medulla seen in MRI were confirmed by postmortem examination and the Rosenthal fibers; GFAP fibers were present in two autopsied cases.

Alpers Disease (POLG Mutation)

This is a progressive disease of the cerebral gray matter, known also as progressive cerebral poliodystrophy or diffuse cerebral degeneration in infancy. A familial form (probably autosomal recessive) as well many sporadic cases has been reported. In both groups there is a certain uniformity of clinical features—loss of smile and disinterest in the surroundings, sweating attacks, seizures, and diffuse myoclonic jerks beginning in early infancy and followed by incoordination of movements; progressive spasticity of limb, trunk, and cranial muscles; blindness and optic atrophy; growth retardation and increasing microcephaly; and finally virtual decortication. In some instances, the late onset of jaundice and fatty degeneration or cirrhosis of the liver have been described (Alpers-Huttenlocher syndrome); the hepatic changes are distinctive and probably not related to the use of anticonvulsant drugs, as had been hypothesized (Harding et al). By the age of 4 years, these patients are hypotonic, anemic, and thrombocytopenic. They also show fragile hair follicles that break at thickened nodes (trichorrhexis nodosa).

The nature of this combined hepatic–cerebral degeneration remains unexplained but some instances have been connected to the mitochondrial disorders, as noted below. EEG abnormalities, progressive atrophy (particularly occipital) on the CT, loss of visual evoked potentials, and abnormal liver function tests are diagnostically useful. Neuropathologic examination shows marked atrophy of the cerebral convolutions and cerebellar cortex, with loss of nerve cells and fibrous gliosis (“walnut brain”). The cerebral white matter and basal ganglia are relatively preserved. In some cases, the spongiform vacuolization of the gray matter of the brain resembles that seen in Creutzfeldt-Jakob disease. Hypoglycemic, hypoxic, and hypotensive encephalopathies must always be considered in the diagnosis but can usually be eliminated by knowledge of the clinical circumstances at the onset of the illness.

A number of biochemical abnormalities have been identified in patients with Alpers disease, including pyruvate dehydrogenase deficiency, decreased pyruvate utilization, dysfunction of the citric acid cycle, and decreased cytochromes a and aa3. The biochemical and pathologic changes suggest a relationship to Leigh encephalomyelopathy and a mitochondrial transmission. Many authoritative texts classify it with the mitochondrial diseases, but its nosologic status is in our opinion still uncertain.

Congenital Lactic Acidosis

This uncommon disease of the neonatal period or early infancy has many biochemical etiologies. The symptoms have consisted of psychomotor regression and episodic hyperventilation, hypotonia, and convulsions, with intervening periods of normalcy. Choreoathetosis has been observed in a few cases. Death often occurs before the third year. The important laboratory findings are acidosis with an anion gap and high serum lactate levels and hyperalaninemia. Defects can be found in the pyruvate dehydrogenase complex of enzymes and the electron transport chain complexes, which function in the oxidative decarboxylation of pyruvate to acetyl coenzyme A (CoA), relating the disease to defects in the mitochondrial respiratory chain enzymes. Indeed, lactic acidosis is a feature of several of the mitochondropathies discussed later in this chapter. Cases examined postmortem have shown necrosis and cavitation of the globus pallidus and cerebral white matter. Possibly this is a variant of Leigh disease. It must be distinguished from the several diseases of infancy that are complicated secondarily by lactic acidosis, especially the organic acidopathies. Cases of benign transient infantile lactic acidosis have been reported, but their etiology is unclear.

Cerebrohepatorenal (Zellweger) Disease and the Peroxisomal Disorders (PEX1 and Other Mutations)

This disease, estimated to occur once in every 100,000 births, is inherited as an autosomal recessive trait. It has its onset in the neonatal period or early infancy and as a rule leads to death within a few months. Motor inactivity and hypotonia, dysmorphic alterations of the skull and face (high forehead, shallow orbits, hypertelorism, high arched palate, abnormal helices of ears, retrognathia), poor visual fixation, multifocal seizures, swallowing difficulties, fixed flexion posture of the limbs, cataracts, abnormal retinal pigmentation, optic atrophy, cloudy corneas, hepatomegaly, and hepatic dysfunction are the usual manifestations. Stippled, irregular calcifications of the patellae and greater trochanters are highly characteristic. Pathologically, there is dysgenesis of the cerebral cortex and degeneration of white matter as well as a number of visceral abnormalities—cortical renal cysts, hepatic fibrosis, intrahepatic biliary dysgenesis, agenesis of the thymus, and iron storage in the reticuloendothelial system.

As to the biochemical abnormality, Moser and coworkers (1984) demonstrated a fivefold increase of very-long-chain fatty acids, particularly hexacosanoic acid, in the plasma and cultured skin fibroblasts from 35 patients with Zellweger disease. A similar abnormality was found in cultured amniocytes of women at risk of bearing a child with Zellweger disease, thus permitting prenatal diagnosis. The findings of Moser and colleagues (1984) are in keeping with current notions about the basic abnormality in Zellweger syndrome, namely, that it is caused by a lack of liver peroxisomes (oxidase-containing, membrane-bound cytoplasmic organelles), in which the very-long-chain fatty acids are normally oxidized (Goldfischer et al).

Currently, a spectrum of at least 12 disorders of peroxisomal function is recognized, all of them characterized by deficiencies in the peroxisomal enzyme of fatty-acid oxidation. The most common form of Zellweger syndrome is due to a mutation in PEX1. However, the most widely recognized peroxisomal disorders are adrenoleukodystrophy and Refsum disease, but the Zellweger cerebrohepatorenal syndrome can be considered a prototype. Each variant can be identified by its characteristic profile of elevated long- and very-long-chain fatty acids, and the specific diagnosis can be confirmed by enzymology of cultured fibroblasts or amniocytes. Several of them become manifest at a later age and are discussed further on. For an authoritative discussion of peroxisomal biogenesis, the reader is referred to the article by Gould and Valle.

The Oculocerebrorenal (Lowe) Syndrome (OCRL1 Mutation)

Here the mode of inheritance is probably X-linked recessive, although sporadic cases have been reported in girls. The abnormal gene is located on chromosome Xq25.26. The clinical abnormalities comprise bilateral cataracts (which may be present at birth), glaucoma, large eyes with megalocornea and buphthalmos, corneal opacities and blindness, pendular nystagmus, hypotonia and absent or depressed tendon reflexes, corticospinal signs without paralysis, slow movements of the hands, tantrums and aggressive behavior, high-pitched cry, occasional seizures, and psychomotor regression. Later the frontal bones become prominent and the eyes sunken. The characteristic biochemical abnormality is a renal tubular acidosis, and death is usually from renal failure. Additional laboratory findings include demineralization of bones and typical rachitic deformities, anemia, metabolic acidosis, and generalized aminoaciduria. The neuropathologic changes are nonspecific; inconstant atrophy and poor myelination have been described in the brain and tubular abnormalities in the kidneys. The primary genetic defects are in the gene encoding inositol polyphosphate phosphatase of the Golgi complex. The main diagnostic distinction is from Zellweger disease. Treatment programs include anticonvulsant medication, correction of electrolyte disorders, and removal of cataracts.

Menkes Disease (Kinky- or Steely-Hair Disease; Trichopoliodystrophy, ATP7A Mutation)

This rare disorder is inherited as a sex-linked recessive trait. In most of the cases known to us, birth was premature. Poor feeding and failure to gain weight, instability of temperature (mainly hypothermia), and seizures become apparent in early infancy. The hair is normal at birth but the secondary growth is lusterless and depigmented and feels like steel wool; hairs break easily and under the microscope they appear twisted (pili torti). Radiologic examination shows metaphysial spurring, mainly of the femurs, and subperiosteal calcifications of the bone shafts. Arteriography discloses tortuosity and elongation of the cerebral and systemic arteries and occlusion of some. The combination of intracerebral hemorrhage and metaphysial bone spurs, which may be interpreted as “corner fractures,” has led in some cases to the erroneous diagnosis of child abuse. There is no discernible neurologic development, and rarely does the untreated child survive beyond the second year. Three of our cases were examined postmortem (Williams et al). There was a diffuse loss of neurons in the relay nuclei of the thalamus, the cerebral cortex, and the cerebellum (granule and stellate cells) and of dendritic arborizations of residual neurons of the motor cortex and Purkinje cells.

The manifestations of this disease are attributable to one of numerous known mutations in a copper- transporting adenosine triphosphatase (ATPase), ATP7A, that is attributed to a failure of absorption of copper from the gastrointestinal tract and a profound deficiency of tissue copper (Danks et al). Furthermore, because copper fails to cross the placenta, a severe reduction of copper in the brain and liver is evident from birth. In this sense, the abnormality of copper metabolism is the opposite of that in Wilson disease. A relationship between Wilson and Menkes disease is nonetheless evident at a genetic level as they arise from genes encoding two different copper-transporting proteins that are both ATPases. The situation, however, may be more complex, as samples of intestinal tissue show a buildup of copper that indicates the problem is in mobilization of copper from the gut to the bloodstream. Other copper-dependent enzymes show impaired function, such as cytochrome oxidase. For the purposes of early diagnosis, Kaler and colleagues have taken advantage of the reduced activity of another copper-dependent enzyme, dopamine–β-hydroxylase, to detect increased plasma levels of its substrates (dopamine and dihydroxyphenylacetic acid [DOPAC]), as well as reduced levels of the enzyme products (norepinephrine and dihydroxyphenylglycol [DHPG]). The ratio of dopamine to norepinephrine and dihydroxyphenylacetic acid to dihydroxyphenylglycol proved, in their study, to be the most sensitive and specific for early detection. This has allowed the neonatal identification of cases in families with affected children and resulted in normal neurodevelopment in a few children who were treated with copper beginning in the first weeks of life. This same group has suggested that only those mutations in ATP7A that allow for some residual copper transport activity are associated with better outcomes.

Parenteral administration of cupric salts, usually in the form of copper histidine administered subcutaneously twice daily by the parents, restores the serum and hepatic copper and may allow normal development in a few children as noted above but it does not materially influence the neurologic symptoms if treatment is started later. However, even early treated cases showing limited neurodevelopment survive and show some neurologic advance, unlike the past experience in which few survived beyond 5 or 6 years.

Diagnosis of Inherited Metabolic Diseases of Infancy

It will be recognized from the foregoing synopses that many of the neurologic manifestations of the inherited metabolic diseases of infancy are nonspecific and are common to most or all of the diseases in this group. In general, in the early stages of all these diseases, there is a loss of postural tone and a paucity of movement without paralysis or loss of reflexes; later there is spasticity with hyperreflexia and Babinski signs. Equally nonspecific are features such as irritability and prolonged crying; poor feeding, difficulty in swallowing, inanition, and retarded growth; failure of fixation of gaze and following movements of the eyes (often misinterpreted as blindness); and tonic spasms, clonic jerks, and focal and generalized seizures.

The differentiation of the inherited metabolic diseases of infancy rests essentially upon four types of data: (1) a few highly characteristic neurologic and ophthalmic signs; (2) the presence of an enlarged liver and/or spleen; (3) special dysmorphic features of the face; and (4) the results of several relatively simple laboratory tests, such as images of the thoracolumbar spine, hips, and long bones; smears of the peripheral blood and bone marrow; CSF examination; and certain urinary tests and other biochemical estimations (serum lactate, glucose, ammonia, and urinary ketones, amino acids, and organic acids). For purposes of differential diagnosis, we have found the flowcharts constructed by our colleague, E. Kolodny, to be very useful. One such schematic, illustrated in Fig. 37-4, is based on the subdivision of patients into three groups: (1) dysmorphic, (2) visceromegalic, and (3) purely neurologic. Only rarely does an inherited metabolic disease fall into more than one of these categories. There is also considerable value in beginning the diagnostic process by classifying the syndrome as a leukodystrophy or a poliodystrophy (disease predominantly affecting neurons, see further on), although this distinction is easier to make in the older child. Once the major category of disease has been identified, correct diagnosis depends on particular clinical and laboratory features tabulated below (Tables 37-5 and 37-6).