Inborn Errors of Metabolism

Marc C. Patterson

INTRODUCTION

There are hundreds of inborn errors of metabolism, each individually rare, but collectively sufficiently common to constitute a significant public health burden. Most severe inborn errors of metabolism involve the nervous system, either directly, or by producing neurologic dysfunction through intoxication with toxic substrates, energy deficiency (to which the brain is especially prone), deficiency of essential substrates or neurotransmitters, or combinations thereof. Although the complexity of these disorders defies easy classification, they may be conveniently divided into small and large molecule disorders for clinical purposes. The former group includes amino and organic acidopathies and urea cycle disorders, among others. Most result from enzyme deficiencies that impair the body’s ability to cope with substrate loads. In severe forms, they present in neonates exposed to normal substrates for the first time without their mother’s metabolic machinery to compensate. Lesser degrees of impairment may present later and intermittently under conditions of unusual stress.

In contrast, large molecule disorders, which include the lysosomal, peroxisomal, and glycogen storage diseases, have a slowly but inexorably progressive course, paralleling the accumulation of macromolecules within cells. The most severe phenotypes exhibit specific patterns of neurodegeneration, reflecting the loci of storage in the nervous system. Thus, predominantly neuronal storage, as seen in the neuronal ceroid lipofuscinoses and neuroaxonal dystrophies, presents as poliodystrophies. Disorders in which white matter bears the major burden of disease are designated as leukodystrophies.

This chapter surveys some of the more prominent of these disorders but cannot be comprehensive. Indeed, the major text of inherited metabolic disease (Metabolic and Molecular Bases of Inherited Disease [MMBID]) was last published in print form in 2001 when it was felt that its 4,600 pages spread over four volumes had reached the limits of print publishing. The MMBID is now only available as an electronic text (Online Metabolic and Molecular Bases of Inherited Disease [OMMBID]), and the interested reader is referred to it and the recommended reading lists in each of the following sections for more comprehensive data on disorders of interest.

SMALL MOLECULE DISORDERS

GLUCOSE TRANSPORTER TYPE 1 DEFICIENCY SYNDROME

Clinical Syndrome

In 1991, De Vivo et al. described two children with infantile seizures, delayed motor and behavioral development, acquired microcephaly, and ataxia. Lumbar puncture revealed low cerebrospinal fluid (CSF) glucose concentrations (hypoglycorrhachia) and lownormal to low CSF lactate concentrations.

Seizures begin in early infancy, and the seizure types vary with the age of the patient. In infancy, the dominant seizure types include behavioral arrest, pallor and cyanosis, eye deviation simulating opsoclonus, and apnea. The electroencephalogram (EEG) at this stage may be normal or show focal spikes and evolves to a generalized spike-wave pattern in childhood. In childhood, the seizures typically include astatic seizures, atypical absence seizures, and generalized tonic-clonic seizures. The seizures are refractory to antiepileptic drugs but respond to a ketogenic diet. Other paroxysmal events, including abnormal eye movements, ataxia, paralysis (with or without migraine), and dyskinesias are frequent. Many patients exhibit static defects, of which intellectual disability, ataxia, dystonia, and spasticity are prominent.

Laboratory Data

Diagnosis requires awareness of the clinical manifestations and documentation of hypoglycorrhachia. A low or low-normal CSF lactate concentration strengthens the presumptive diagnosis.

Molecular Genetics and Pathogenesis

D-Glucose is the obligate fuel for brain metabolism under virtually all circumstances. With fasting, the brain adapts to use ketone bodies (β-hydroxybutyrate and acetoacetate) in partial lieu of glucose. The transport of D-glucose across the blood-brain barrier and into brain cells is selectively mediated by glucose transporter 1 (GLUT1), a member of a multigene family of protein transporters that facilitate the diffusion of sugar molecules across tissue barriers. GLUT1 is encoded by SLC2A1 on chromosome 1p34.1 and is present in high abundance in brain capillaries, astroglial cells, and erythrocyte membranes.

The molecular basis of the syndrome is GLUT1 haploinsufficiency; a few patients are hemizygous, but most are heterozygous with a variety of mutations. This syndrome is the first genetically determined abnormality of the blood-brain barrier; it may be familial and transmitted as an autosomal dominant trait.

HYPERAMMONEMIA

Introduction

Hyperammonemia has many genetic and acquired causes. The hepatic urea cycle is the major mammalian system for the detoxification of ammonia and defects have been described in all six
urea cycle enzymes. The prevalence of these disorders is 1:35,000; two-thirds present after the newborn period. The mortality is 24% in neonates and 11% in older individuals. An additional pathway from arginine to citrulline generates the putative second messenger and neurotransmitter, nitric oxide, catalyzed by nitric oxide synthetase. The enzyme is found in many tissues, including brain. Animal studies suggest that derangement of this pathway, cerebral energy metabolism, amino acid and neurotransmitter pathways, mitochondrial permeability, signal transduction, and oxidative stress all contribute to the brain injury associated with exposure to high levels of ammonia.

Neonatal Hyperammonemia

Transient hyperammonemia is occasionally seen in otherwise well premature infants and rarely requires treatment. Hyperammonemia may reflect liver damage associated with birth asphyxia or congenital hepatic disease; the birth history usually establishes the diagnosis.

The ill neonate with hyperammonemia without other explanation often has an inborn error of metabolism that, directly or indirectly, affects the urea cycle. Marked hyperammonemia causes progressive lethargy, vomiting, poor feeding, apneic episodes, and seizures. These nonspecific symptoms occur in many disorders, such as sepsis, that can also precipitate hyperammonemia. The age at onset of these symptoms is a useful differential diagnostic point. Infants with hyperammonemia owing to urea cycle enzymopathies or organic acidurias typically are well until they have received 1 to 3 days of protein feeding. In contrast, infants with hyperammonemia secondary to impaired pyruvate metabolism are symptomatic within the first 24 hours. Pyruvate dehydrogenase and (type B) pyruvate carboxylase deficiencies feature lactic acidosis, and these diagnoses can be confirmed by an assay of enzyme activities in fibroblasts.

Organic acidurias lead to ketoacidosis (but maple syrup urine disease does not), which distinguishes them from urea cycle enzymopathies. Severe deficiency of urea cycle enzymes, other than arginase, causes similar clinical syndromes. The affected child is well for the first 24 hours but signs of hyperammonemia appear as protein feedings continue. Respiratory alkalosis with hyperventilation is classic but not always present, and infants with sepsis or vomiting may have metabolic acidosis or alkalosis. Plasma amino acid and orotic acid assays help to distinguish different urea cycle defects (Table 134.1). Direct sequencing of urea cycle genes will make the diagnosis in more than 80% of cases; tissue enzyme analysis is required in the remainder. All of the urea cycle genes are autosomal recessive, except for ornithine carbamyl transferase deficiency, which is X-linked. Prenatal screening is available.

TABLE 134.1 Plasma Amino Acid and Urinary Orotic Acid Findings in Urea Cycle Defects

Enzymatic Deficiency	Citrulline	Argininosuccinic Acid	Orotic Acid	Arginine
Carbamyl phosphate synthetase (CPS deficiency)	0 to trace	0	↓	↓
Ornithine transcarbamylase (OTC deficiencies)	0 to trace	0	↑↑	↓
Argininosuccinate synthetase (citrullinuria)	↑↑	0	↑	↓
Argininosuccinase (argininosuccinic aciduria)	↑	↑↓	nl	↓
Arginase	nl	0	↑	↑↑
Transient hyperammonemia of newborn	nl or slightly ↑	0	nl	nl
↓, decreased; ↑, increased; nl, normal.

Long exposure to high levels of ammonia damages the brain. Thus, acute hyperammonemic coma in the newborn is a medical emergency, and rapid reduction in ammonia levels is necessary. Peritoneal dialysis is more effective than exchange transfusion; hemodialysis may also be effective. Useful adjuncts include intravenous administration of sodium benzoate and sodium phenylbutyrate. A block in the urea cycle (other than at arginase) renders arginine an essential amino acid, which must be supplemented. Protein catabolism should be minimized by temporarily eliminating protein from the diet and by ensuring adequate caloric intake, principally as glucose. Long-term management depends on the specific enzyme defect.

Hyperammonemia in Older Children and Adults

Primary metabolic disease is much less likely a cause of hyperammonemia in an older child or adult than in neonates. Partial urea cycle defects (as seen in ornithine transcarbamylase [OTC] heterozygotes—i.e., women) may cause episodic hyperammonemia during periods of metabolic stress and should be considered, especially if there are affected relatives. Allopurinol loading, popular historically, has been supplanted by sequencing of urea cycle genes. Heterozygotes for OTC deficiency have impaired neuropsychological function compared to controls; impeccable metabolic control is critical in preserving neurologic function. The older child or adult with hyperammonemia usually has severe liver disease or drug-induced hyperammonemia.

Valproate-Associated Hyperammonemia

Valproate therapy is one of the most common causes of hyperammonemia in clinical neurologic practice. Malnourished patients with carnitine deficiency and those with unrecognized urea cycle and fatty acid oxidation defects seem to be at higher risk of this complication. This dose-related laboratory finding may occur without clinical symptoms. The pathogenesis is disputed but may result from inhibition of hepatic N-acetylglutamate synthase activity by valproyl-coenzyme A (CoA). It is unclear whether patients become symptomatic from the increased ammonia under these circumstances.

L-Carnitine supplementation can prevent the development of hyperammonemia in animals and humans receiving valproate; the clinical significance of this reduction is unclear. Some authors routinely supplement L-carnitine in patients with reduced serum carnitine levels. In severe acute valproate hepatotoxicity with hyperammonemia, a disorder with high mortality, intravenous L-carnitine has been shown to improve survival compared to oral therapy with the same agent.

DISORDERS OF AMINO ACID METABOLISM

Introduction

Mass screening for disorders of amino acid metabolism has resulted in early biochemical diagnosis of phenylketonuria (PKU) and other aminoacidopathies. In one screening program in New South Wales, Australia, the incidence of PKU was 1:10,000 live births per year, the incidence of defects of amino acid transport was about 2:10,000 live births per year, and the combined incidence of all other aminoacidopathies was less than 8:100,000 live births per year. Although these conditions are rare, they are important because neurologic damage is potentially preventable with early treatment and because they provide information about the development and functions of the brain. PKU is described in some detail as a model for this family of disorders.

Phenylketonuria

INTRODUCTION

Phenylalanine hydroxylase deficiency is an autosomal recessive inborn error of metabolism manifested by impaired hepatic hydroxylation of phenylalanine to tyrosine. Untreated, the disorder causes a clinical picture highlighted by intellectual disability, seizures, and imperfect hair pigmentation.

The disease has been found in all parts of the world. The prevalence in the general population of the United States, as determined by screening programs, is about 1:11,700.

PATHOGENESIS AND PATHOLOGY

The hydroxylation of phenylalanine to tyrosine is an irreversible and complex reaction that requires phenylalanine hydroxylase and five other enzymes, in addition to several nonprotein components. Phenylalanine hydroxylase is normally found in liver, kidney, and pancreas but not in brain or skin fibroblasts.

In classic PKU, enzyme activity is generally less than 5% of normal. More than 40% of PKU subjects and more than 80% of those with mild PKU are tetrahydrobiopterin (BH₄) responsive when challenged with 20 mg/kg BH₄.

In some 1% to 3% of subjects, hyperphenylalaninemia results from a deficiency of BH₄. The BH₄-deficient hyperphenylalaninemias comprise a genetically heterogeneous group of disorders caused by mutations in the genes encoding enzymes involved in the synthesis or regeneration of the coenzyme BH₄. Three genetic defects in the synthesis of BH₄ have been described. These involve guanosine-5′-triphosphate (GTP) cyclohydrolase, I,6-pyruvoyltetrahydropterin synthase and sepiapterin reductase. In addition, there are two disorders in the regeneration of the aromatic amino acid-hydroxylating system: dihydropteridine reductase and pterin-4a-carbinolamine dehydratase. All these conditions lead to hyperphenylalaninemia associated with progressive neurologic deterioration, along with a variety of dyskinesias.

Children with classic PKU are born with only slightly elevated phenylalanine blood levels, but these rise rapidly on an unrestricted diet. Phenylalanine is converted to phenylpyruvic acid, phenylacetic acid, and phenylacetylglutamine, which impart a characteristic odor to the urine.

Brain changes are nonspecific and diffuse and involve both gray and white matter; they include interference with normal maturation of the brain, defective myelination, and diminished or absent pigmentation of the substantia nigra and locus ceruleus.

SYMPTOMS AND SIGNS

PKU exhibits a wide range of clinical and biochemical severity. In the classic form, untreated infants appear normal at birth. Vomiting and irritability in the first few months is followed by cognitive delay; ultimate intellectual disability may be severe. Seizures, including epileptic spasms, usually present in the first 18 months.

Untreated children are fairer with lighter irides than unaffected sibs and may have eczema and a peculiar musty (“mousey”) odor. Focal neurologic abnormalities are rare, but microcephaly, mild spastic paraparesis, and tremor may occur.

Magnetic resonance imaging (MRI) usually shows white matter signal hyperintensity on T2-weighted sequences, mainly in the posterior watershed regions.

DIAGNOSIS

Most PKU patients are identified through newborn screening. If the diagnosis of a case of classic PKU is missed, the most likely reason is laboratory error, rather than insufficient protein intake or too early testing of the infant.

Mutation analysis facilitates carrier detection and the prenatal diagnosis of PKU in families with at least one previously affected child. Newborn screening programs have also detected conditions other than PKU with neonatal hyperphenylalaninemia. Patients with moderate and mild PKU and mild hyperphenylalaninemia, as these entities are termed, have phenylalanine levels that tend to be lower than those seen in classic PKU.

TREATMENT

All infants whose blood phenylalanine concentration is greater than 10 mg/dL (600 µM/L) and whose tyrosine concentration is low or normal (i.e., 1 to 4 mg/dL) should be started on a lowphenylalanine diet immediately. Infants whose blood phenylalanine concentrations remain in the range of 6.6 to 10.0 mg/dL (400 to 600 µM/L) on an unrestricted diet are generally not treated, and on follow-up evaluations, children of this group have normal intelligence and a normal MRI.

Therapy for classic PKU is restriction of the dietary phenylalanine using one of several low-phenylalanine formulas. Milk is added to the diet in amounts sufficient to maintain blood levels of the amino acid between 2 and 6 mg/dL (120 to 360 µM/L). Generally, patients tolerate this diet quite well, and within 1 to 2 weeks, the serum concentration of phenylalanine becomes normal.

Weekly serum phenylalanine determinations are essential to monitor dietary adherence for life. Strict dietary control should be maintained for life, and most centers strive to keep levels below 6 mg/dL (360 µM/L) in all patients with PKU. Dietary lapses are frequently accompanied by progressive white matter abnormalities on MRI. The addition of sapropterin (5 to 20 mg/kg/day), an orally active synthetic form of BH₄, permits a less restrictive diet for those patients who respond to a BH₄ challenge.

Phenylalaninemia caused by BH₄ deficiency requires diet, administration of BH₄ or a synthetic pterin, and replacement of neurotransmitter precursors (L-dopa/carbidopa and 5-hydroxytryptophan), whose synthesis is also impaired.

Early detection and dietary control of PKU has increased the number of homozygous PKU women achieving pregnancy. Maternal hyperphenylalaninemia causes intellectual disability, microcephaly, seizures, and congenital heart defects in affected children. During pregnancy, phenylalanine levels must be monitored as closely as during infancy because the fetus is exposed to even higher phenylalanine concentrations than the mother.

OUTCOME

When a child with classic PKU is maintained on a low-phenylalanine diet, seizures disappear and the EEG normalizes. Abnormally blond hair regains natural color, and head growth resumes.

Cognitive effects are less clear cut. In most studies, some deficit in intellectual development has been found, even in infants who had been diagnosed and treated as neonates. This could be a consequence of prenatal brain damage induced by high phenylalanine levels in the fetus.

Although the measured IQ is normal in most, deficits have been noted in executive functioning, attention, verbal memory, verbal fluency, and expressive naming. There is no threshold below which phenylalanine has no effect on cognition. Neurologic deterioration during adult life is generally the consequence of dietary lapses.

Other Amino Acid Disorders

Several other aminoacidopathies have distinguishing features that enable the clinician to suspect the diagnosis. Maple syrup urine disease, a disorder of branched-chain amino acid metabolism, produces a characteristic odor (detectable in cerumen as well as urine) and classically presents in the first week of life with acute encephalopathy and opisthotonic posturing. Isoleucine, leucine, and valine are present in excess in the urine. Emergent diagnosis and management is necessary to preserve life and neurologic function; a few patients are thiamine-responsive. Later onset forms may also occur.

Homocystinuria is manifest as tall stature, dislocated lenses, and varying degrees of intellectual impairment; a subgroup of patients responds to therapy with cobalamin. Thromboembolic episodes may begin in infancy. Disorders of sulfur amino acids are summarized in Table 134.2.

Hartnup disease is a disorder of renal tubular transport of tryptophan and other neutral amino acids; it causes intermittent ataxia with a pellagra-like rash. The disorders of amino acid transport are summarized in Table 134.3.

TABLE 134.2 Disorders of Sulfur Amino Acids

Disorder	Enzyme Deficiency	Neurologic Picture
Homocystinuria	Cystathionine-β-synthase	Multiple thromboembolic episodes starting in first year of life, mental retardation, ectopia lentis
Homocystinuria and mild homocysteinemia	N^5,10-methylenetetrahydrofolate reductase	Seizures, microcephaly, spastic paraparesis, ataxia
Cystathioninuria	γ-Cystathionase	Asymptomatic
Homocystinuria with megaloblastic anemia	—	—
Cbl E	Methionine synthase reductase	Severe developmental delay, lethargy, staring spells, hypotonia
Cbl G	Methionine synthase	Failure to thrive, mental retardation, cerebral atrophy
Cbl C	Synthesis of methyl and adenosyl cobalamin	Marfanoid habitus, mental retardation, acute psychosis, subacute spinal cord degeneration
Cbl D	Synthesis of methyl and adenosyl cobalamin	Acute psychosis, mental retardation, subacute spinal cord degeneration, Marfanoid habitus
Cbl F	Cobalamin lysosomal release	Developmental delay, sudden death in infancy
Sulfite oxidase deficiency	Sulfite oxidase	Seizures starting in neonatal period, profound mental retardation, subluxation of lens
Molybdenum cofactor deficiency	Molybdenum cofactor deficiency	As for sulfite oxidase deficiency
Cbl, cobalamin.

ORGANIC ACIDURIAS

Progress in diagnostic techniques in the 1950s enabled the identification of a family of disorders of distal steps in intermediary metabolism marked by the accumulation of nonamino organic acids, not detectable in bodily fluids by older methods, that are preferentially excreted in the urine. These compounds are mono-, di- and tricarboxylic acids derived from the breakdown of amino acids through the intramitochondrial degradation of CoA-activated carbonic acids. They are separated from the amino acid disorders only because of the analytical methods employed in their diagnosis, not because of any fundamental biologic difference. The classic organic acidurias have a number of common clinical features, including precipitation of acute encephalopathy, acidosis and hyperammonemia, and other multisystem manifestations by an excess substrate load or metabolic stress in the form of fever or other illness. Profound brain and systemic injury follows unless rapid and effective intervention is undertaken. This usually involves substrate restriction; suppression of aberrant pathways by providing alternate energy sources; and removal of offending metabolites by dialysis, hemofiltration, or by activating alternate pathways. The classical organic acidurias include propionic aciduria, methylmalonic aciduria, and isovaleric aciduria. The first named is associated with a poor long-term neurologic outcome, as assessed by cognitive measures and the presence of basal ganglia lesions; isovaleric aciduria with excellent outcome and methylmalonic aciduria is associated with intermediate impairment of neurologic function. Early diagnosis and tight metabolic control are necessary, but not always sufficient, to achieve the best outcome in these disorders.

Most of these diseases result from deficient activity of enzymes or their cofactors and present as neonatal encephalopathies in their most severe forms; less profound defects may present intermittently in older children. Slowly progressive disorders with predominant or exclusive neurologic manifestations are designated as cerebral organic
acidopathies and include glutaric aciduria, type 1, L-2-hydroxyglutaric aciduria, D-2-hydroxyglutaric aciduria, and succinic semialdehyde dehydrogenase deficiency (SSADH) and Canavan disease.

TABLE 134.3 Defects in Amino Acid Trransport

Transport System	Condition	Biochemical Features	Clinical Features
Basic amino acids	Cystinuria (three types) Lowe syndrome	Impaired renal clearance, defective intestinal transport of lysine, arginine, ornithine, and cystine Impaired intestinal transport of lysine and arginine, impaired tubular transport of lysine	Renal stones, no neurologic disease Severe mental retardation, congenital glaucoma, cataracts, myopathy
Acidic amino acids	Dicarboxylic aminoaciduria	Increased excretion of glutamic, aspartic acids	Severe mental retardation glaucoma, cataracts, myopathy, sex-linked transmission
Neutral amino acids	Hartnup disease	Defective intestinal and renal tubular transport of tryptophan and other neutral amino acids	Intermittent cerebellar ataxia, photosensitive rash
Proline, hydroxyproline, glycine	Iminoglycinuria	Impaired tubular transport of proline, hydroxyproline, and glycine	Harmless variant
β-Amino acids	None known	Excretion of β-aminoisobutyric acid and taurine in β-alaninemia is increased due to competition at the tubular level	Harmless variant

Glutaric aciduria, type 1, results from glutaryl-CoA dehydrogenase deficiency and manifests as macrocephaly, hypotonia, and mild motor delay; affected children can decompensate suddenly in the face of metabolic stress and exhibit a hyperkinetic movement disorder that is refractory to most therapy. MRI shows enlarged extra-axial spaces over the frontal and temporal convexities, with widened sylvian fissures. Signal hyperintensity and eventual necrosis occurs in the striatum in untreated cases and corresponds to the presence of movement disorder. Glutaric acid and 3-methylglutaric acid are excreted in excess in the urine, as is glutaryl carnitine. Carnitine supplementation is of proven benefit in preventing neurologic progression but must be introduced before the onset of basal ganglia injury.

L-2-Hydroxyglutaric aciduria is associated with mutations in the L2HGDH gene and presents with progressive ataxia and intellectual disability in children; adult onset with similar, more slowly progressive symptoms also occurs on occasion. MRI shows a characteristic pattern that involves the basal ganglia and dentate nuclei and the subcortical, but not cerebellar, white matter. Patients with this disorder have an increased risk of primary brain tumors, attributed to the putative “oncometabolite” 2-hydroxyglutarate.

D-2-Hydroxyglutaric aciduria (D-2-HGA) is genetically and clinically heterogenous. Some patients who excrete D-hydroxyglutaric acid in the urine are asymptomatic; others exhibit facial dysmorphism, seizures, hypotonia, and developmental delay. About half of the patients have recessive mutations in D2HGDH, designated type 1 D-2-HGA. The remainder, designated type 2 D-2-HGA, harbor dominant mutations in IDH2, a gene which is mutated in some cases of acute myeloid leukemia and gliomas. A few patients have been described with combined D-and L-2-hydroxyglutaric aciduria resulting from mutations in the SLC25A1 gene. The phenotype is severe, with hypotonia, delay, and intractable seizures; it is important to recognize, as it may respond to therapy with citrate.

SSADH deficiency is a disorder of γ-aminobutyric acid (GABA) metabolism that results from mutations in ALDH5A1 and presents with hypotonia, developmental delay, and ataxia. Epilepsy, which may be difficult to control, occurs in more than half of affected children, along with movement disorders and behavioral disturbances. MRI may show hyperintensities in the basal ganglia, specifically the globus pallidus, and less frequently in the dentate nuclei, brain stem, and subcortical white matter. 4-Hydroxybutyric acid is increased in urine and CSF and may be detected by magnetic resonance (MR) spectroscopy. Treatment is symptomatic; vigabatrin (50 mg/kg/day; 500 to 1,500 mg twice daily), which inhibits the production of succinic semialdehyde, is a logical choice as an antiepileptic drug but is not always effective. Valproate (10 to 60 mg/kg/day) is relatively contraindicated but can be cautiously employed if seizures are refractory to other agents. A trial of taurine is currently in progress.

Canavan disease is a spongiform leukodystrophy in which deficient activity of aspartoacylase leads to accumulation of N-acetylaspartic acid (NAA) in bodily fluids and the brain. It is commonly manifest as hypotonia and progressive macrocephaly in infants, followed by loss of milestones, spasticity, seizures, and premature death. MRI shows diffuse white matter hyperintensity, and MR spectroscopy demonstrates marked elevation of NAA. The diagnosis is made by demonstrating defective aspartoacylase activity in leucocytes and corresponding mutations in the ASPA gene. Antenatal diagnosis is possible using gene sequencing. Gene therapy using an AAV2 vector has shown reduced NAA levels and evidence of clinical stabilization in an open-label study in humans with Canavan disease.

DISORDERS OF PURINE AND PYRIMIDINE METABOLISM

Introduction

Purines and pyrimidines are heterocyclic compounds that participate in nucleotide synthesis, generation of energy compounds (i.e., adenosine diphosphate [ADP] and adenosine triphosphate [ATP]), and in signaling pathways (i.e., cyclic adenosine monophosphate [AMP]). Several disorders of purine and pyrimidine metabolism have been recognized; see Table 134.4. Findings include anemia, immunodeficiency, hypo- or hyperuricemia (i.e., with nephrolithiasis and renal failure in severe cases), and a variety of neurologic phenotypes. The latter range through sensorineural hearing loss, developmental delays, intellectual disability, autism, seizures, and movement disorders. The archetype and most frequently recognized of these disorders is the Lesch-Nyhan syndrome, described in more detail in the following paragraphs.

Lesch-Nyhan Syndrome

In 1964, Lesch and Nyhan described two brothers with hyperuricemia, intellectual disability, choreoathetosis, and self-destructive biting of the lips and fingers. Most cases are boys, but at least one symptomatic female with skewed X-inactivation has been described. The trait is X-linked recessive. The basic defect is the lack of hypoxanthine-guanine phosphoribosyltransferase (HPRT). The enzyme deficiency increases the rate of purine biosynthesis, and uric acid reaches high levels in blood, urine, and CSF. Urate is deposited in the kidneys and joints and may result in nephropathy and gout.

TABLE 134.4 Disorders of Purine and Pyrimidine Metabolism

Enzyme	Anemia	ID	Uric Acid	MR	SNHL	Seizures	Ataxia	MD	Other
NT	+	+	–	+		+	+	+	Symptoms improve with uridine
Purine Pathway
PRPS	–	–	+	+	+	–	+	–	Autism
ADSL	–	–	0	+	–	+	–	–	Autism
AMPD1	–	–	0	–	–	–	–	–	Muscle cramps, increased CK
ADA	–	+	0	+	–	–	–	+	Spasticity
NP	+	+	–	+	–	–	–	+	Spasticity
XDH	–	–	–	–	–	–	–	–	Myopathy, arthropathy
HPRT	–	–	+	+	–	+	–	+	Self-mutilation, spasticity, 6-thioguanine resistance
APRT	–	–	+	–	–	–	–	–
Pyrimidine Pathway
UMPS	+	–	0	+	–	–	–	–
UMPH	+	–	0	+	–	–	–	–
DPYD	–	–	0	+	–	+	–	–	Microcephaly, 5-fluorouracil sensitivity, autism
DPYS	–	–	0	+	–	+	–	–
UP	–	–	0	+	–	+	–	+
+, present (or increased for uric acid); _, absent (or decreased for uric acid); 0, unchanged; ID, immunodeficiency; MR, developmental delay, mental retardation; SNHL, sensorineural hearing loss; MD, movement disorder; NT, 5′-nucleotidase; PRPS, phosphoribosyl pyrophosphate synthetase superactivity; ADSL, adenylosuccinate lyase deficiency; AMPD1, adenosine monophosphate deaminase 1; CK, creatine kinase; ADA, adenosine deaminase deficiency; NP, nucleoside phosphorylase deficiency; XDH, xanthine dehydrogenase (= xanthine oxidase) deficiency (xanthinuria; secondary impairment in molybdenum cofactor deficiency); HPRT, hypoxanthine-guanine phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome); APRT, adenosine phosphoribosyltransferase deficiency; UMPS, uridine monophosphate synthase deficiency (hereditary orotic aciduria); UMPH, uridine monophosphate hydrolase (= pyrimidine 5′-nucleotidase) deficiency; DPYD, dihydropyrimidine dehydrogenase deficiency; DPYS, dihydropyrimidinase deficiency; UP, ureidopropionase deficiency.

The neurologic manifestations include severe intellectual disability, spasticity, and choreoathetosis that start in the first year. The characteristic self-mutilating behavior appears in the second year. Death is usually caused by renal failure and may occur in the second or third decade of life. Sudden death may occur at any time because of acute respiratory failure, often related to the motor disorder. Milder variants are recognized, in which self-mutilation may be absent and manifestations may be restricted to cognitive impairment with mild motor symptoms or progressive spastic paraparesis. The pathogenesis of the cerebral symptoms is not known.

Diagnosis depends on recognition of the clinical manifestations and may be made precisely by biochemical assay of the enzyme in erythrocyte hemolysates or cultured fibroblasts. DNA analysis confirms the diagnosis and may be used for prenatal diagnosis and carrier detection; mutations can be detected in most affected individuals. More than 400 mutations have been described.

Gout is treated effectively with allopurinol, but the neurologic disorder is daunting. Restraints may be needed to prevent the child from damaging himself or herself or others; dental extraction is often required to prevent facial mutilation. Diazepam (1 to 2.5 mg by mouth three or four times daily), carbamazepine (10 to 35 mg/kg/day), gabapentin (10 to 40 mg/kg/day), and botulinum
toxin are sometimes helpful, but physical restraint is often required in classic cases. Deep brain stimulation surgery, targeted to the globus pallidus, has improved or abolished self-mutilation in some cases. Neither enzyme replacement nor gene therapy is available for Lesch-Nyhan syndrome.

Other Purine Disorders

Neurologic abnormalities are also seen in patients who are without other enzymes of purine-nucleoside metabolism. Adenosine deaminase deficiency causes severe, combined immunodeficiency in infants; some patients have extrapyramidal or pyramidal signs and psychomotor development and may be retarded. Partial exchange transfusion may be clinically beneficial. Also, a few patients lacking purine-nucleoside phosphorylase with impaired cellular immunity have shown a form of spastic paraparesis in childhood. 5′-Nucleotidase superactivity produces a complex phenotype with all of the features of purine and pyrimidine disorders that responds to oral uridine therapy. These patients may have autistic features that may also be prominent in phosphoribosyl pyrophosphate synthetase (PRPS), adenylosuccinate lyase (ADSL), and dihydropyrimidine dehydrogenase (DPYD) deficiencies.

PORPHYRIA

The porphyrias are a family of disorders in which the synthesis of heme and its precursors are impaired. They are traditionally divided into hepatic and erythropoietic subgroups according to the major sites of gene expression. Acute intermittent porphyria (AIP) is the most frequent of these disorders and the most likely to present to a neurologist.

AIP is an autosomal dominant disorder with low penetrance caused by deficiency of hydroxymethylbilane synthase (HMBS, also known as porphobilinogen deaminase), most frequently observed in Sweden and South Africa, which typically presents as an acute encephalopathy with pronounced behavioral changes (including frank psychosis) that may be accompanied by seizures, autonomic neuropathy causing abdominal pain, tachycardia and hypertension, or a painful motor neuropathy that may progress to quadriplegia with respiratory failure in severe cases. Patients may have hyponatremia as a consequence of inappropriate antidiuretic hormone (ADH) secretion. Decompensation may be provoked by fasting or by exposure to alcohol or any one of a number of drugs that interact with this pathway, including older anesthetic agents, barbiturates, and oral contraceptives; pregnancy may also precipitate an attack. Drugs appear to precipitate attacks of AIP by inducing delta-amino levulinic acid synthase, thereby leading to hepatic heme depletion, or by inhibiting the P-450 cytochrome system. Understanding these mechanisms facilitates prediction of the likely toxicity of drugs in affected individuals.

The diagnosis of AIP requires timely assay of urine porphobilinogen, with subsequent confirmation by sequencing of the HMBS gene. Acute management, which must not be delayed for definitive diagnosis, requires the removal of precipitants, careful attention to fluid and electrolyte balance, the administration of intravenous Panhematin or heme arginate to shut down the synthetic pathway, appropriate analgesia with agents such as gabapentin (10 to 40 mg/kg/day), and management of seizures with safe agents such as benzodiazepines that do not exacerbate the metabolic block.

A number of atypical presentations have been reported in AIP, including posterior reversible encephalopathy syndrome, acute cortical blindness, and progressive muscular atrophy.

Long-term management hinges on education of the patients and their medical providers to recognize and avoid situations and agents that provoke decompensation. In rare cases, liver transplantation may be indicated to manage hepatic failure or recurrent attacks when conservative management is ineffective.

Acute variegate porphyria (AVP), a dominant disorder associated with decreased activity of the mitochondrial enzyme protoporphyrinogen oxidase (PPOX), can present in a clinically indistinguishable fashion from AIP because the typical blistering rash may be absent in as many as half of affected individuals in acute crises. It is managed in the same fashion as AIP.

DISORDERS OF METAL METABOLISM

Several inherited neurologic diseases are associated with abnormal handling of metals in the brain. These may be conveniently divided into disorders of copper and iron metabolism.

Disorders of Copper Metabolism

WILSON DISEASE

Kinnier Wilson described his eponymous disease in 1912 as hepatolenticular degeneration, a disorder characterized by progressive dystonia, tremor, and psychiatric disturbances, usually beginning in adolescence, and accompanied by cirrhosis. A decade earlier, Kayser and Fleischer had reported the brown corneal rings now known to represent the accumulation of copper in Descemet’s membrane. These have proven to be an excellent gauge of excess copper stores, which regress in the face of effective copper removal, only to reappear if treatment is discontinued.

Wilson disease is caused by mutations in the transporter, encoded by the ATP7B gene that transports copper from hepatocytes to the bile and blood; its dysfunction leads to accumulation of copper in the liver, where it provokes fibrosis and eventually cirrhosis. When this store is exhausted, copper begins to deposit in the lenticular nuclei, causing extrapyramidal dysfunction and if untreated, destruction of the nuclei.

Neurologic presentations are rare in the first decade of life; Wilson disease is more likely to present in young children with acute or chronic liver failure, hemolytic anemia, or renal tubular dysfunction, reflecting the tissues in which copper is toxic. Affected adolescents have a typical appearance, in which the upper lip is drawn back to expose the teeth, accompanied by a wingbeating tremor and dystonic posturing. Spasticity, dysphagia, and dysarthria are commonly seen, and parkinsonian features are most prominent in some cases. Psychiatric manifestations are frequent and may dominate the clinical picture.

Laboratory tests may show elevated transaminases, low serum uric acid, and elevated urine copper, amino acids, and urate secondary to tubular dysfunction. Serum copper and ceruloplasmin are low. Apart from the demonstration of two mutations in trans in the ATP7B gene, no single test is diagnostic for Wilson disease. A diagnostic scoring system has been developed to assist the clinician; this includes presence or absence of Kayser-Fleischer rings or neurologic symptoms, serum ceruloplasmin, liver copper content, urinary copper excretion, and mutation analysis of the ATP7B gene.

Penicillamine (750 to 1,500 mg/day administered in two or three divided doses daily for adults; dosing in children is 20 mg/kg/day rounded off to the nearest 250 mg, given in two or three divided doses) is the traditional chelating agent used in Wilson disease, but its adverse effect profile has led to the employment of zinc (which impairs copper absorption) (150-mg elemental zinc/day for adults; for children, 50 kg in body weight, 75 mg/day,
administered in three divided doses, 30 minutes before meals) and trientine (which increases urinary copper excretion) (900 to 2,700 mg/day in two or three divided doses, with 900 to 1,500 mg/day used for maintenance therapy; in children, the weight-based dose is not established, but the dose generally used is 20 mg/kg/day rounded off to the nearest 250 mg, given in two or three divided doses) as preferred treatments today. Vitamin E may have a role as an antioxidant, but no dosage regimen has been widely accepted. If copper stores can be removed before permanent tissue damage has occurred, the prognosis is excellent, provided that treatment is continued lifelong. Liver transplantation is an option in those with irreversible hepatic failure or who cannot tolerate other treatments.

MENKES DISEASE

In contrast to Wilson disease, the manifestations of Menkes disease reflect the effects of copper deficiency on the brain and other tissues. Menkes disease is caused by mutations in the X-linked ATP7A gene that encodes the protein that facilitates transport of copper from the gut to the circulation. The resultant systemic deficiency of copper leads to dysfunction of multiple enzyme systems, including cytochrome c oxidase, lysyl oxidase, and dopamine b-hydroxylase. The disease manifests in boys in the first 2 months with developmental regression; hypotonia; seizures; twisted, sparse, fair hair (often absent through easy breakage); hypothermia; and hypoglycemia. They have a cherubic appearance secondary to abnormal collagen formation, which is also responsible for the bony anomalies (metaphyseal flaring) and dilatation of the urinary collecting system and blood vessels. The latter may rupture spontaneously, leading to intracranial hemorrhage, sometimes mistakenly attributed to child abuse. Without treatment, most boys die by 3 years, although survival into the fourth decade has been reported in one treated patient with a mild phenotype.

The diagnosis is suspected clinically and confirmed by ATP7A mutation analysis. Bypassing the impaired gut absorption by administering subcutaneous copper histidine has shown benefit in morbidity and mortality, provided that treatment is instituted before permanent damage has occurred.

Females with ATP7A mutations can present when X-autosome translocation has occurred or in theory, in cases of Turner syndrome. Their clinical manifestations resemble those in boys.

Two allelic variants have been recognized in patients with ATP7A mutations. The occipital horn syndrome manifests as calcification of the insertions of the trapezius muscles, associated with joint laxity, a dilated urinary collecting system, and tortuous blood vessels, with only mild, if any, cognitive impairment. A distal motor neuropathy resembling Charcot-Marie-Tooth syndrome has also been described in adult males; it lacks any other findings in common with Menkes disease.

Disorders of Iron Metabolism

A family of rare diseases, embraced by the acronym NBIA (neurodegeneration with brain iron accumulation) has been delineated in recent years. All feature varying combinations of basal ganglia dysfunction associated with neuropsychiatric symptoms. Eight of the 10 known subtypes are autosomal recessive disorders; BPAN is X-linked dominant and neuroferritinopathy is autosomal dominant. The core disorders in this family are pantothenate kinase-associated neurodegeneration (PKAN; NBIA 1), formerly known as Hallervorden-Spatz disease and PLA2G6-associated neurodegeneration (PLAN), or NBIA 2.

PKAN or NBIA 1 is a childhood-onset neurodegenerative disorder that most often presents in the first decade with intellectual delay and progressive gait and oromandibular dystonia; more subtle disturbances of cognitive function and gait may occur with later onset forms of the disease. Saccadic eye movement disorders including vertical supranuclear gaze palsy have been described. The classic phenotype also includes retinal pigmentation, acanthocytes, and deposition of iron in the globus pallidus. This causes signal hypointensity in the globus pallidus on MRI early in the course of the disease; with progression, a central area of hyperintensity appears in the medial globus pallidus, producing the “eye of the tiger” sign. Although highly suggestive of the diagnosis, the absence of this finding does not rule out the diagnosis of PKAN, which is established by sequencing of the PANK2 gene. Although there is no definitive therapy for PKAN, small studies suggest a stabilizing effect of iron chelation using deferiprone.

NBIA 2, PARK14, or PLAN, first recognized as infantile neuroaxonal dystrophy, is associated with mutations in PLA2G6, which encodes calcium-independent phospholipase A2. The key features are the combination of ataxia, truncal hypotonia, spasticity, nystagmus, and optic atrophy with peripheral neuropathy. MRI shows cerebellar atrophy and iron deposition in the globus pallidus—without hyperintensity. Later onset forms may have a dystonia-Parkinson phenotype. Axonal spheroids are the pathologic hallmark of the disease, and their demonstration in biopsies was critical to the diagnosis before mutation analysis was available. Only symptomatic therapy is available.

DISORDERS ASSOCIATED WITH ACANTHOCYTOSIS

Acanthocytes are irregularly shaped red cells with spiny projections whose appearance reflects abnormal membrane structure. They are found in PKAN (see the following text) and in Huntington-like disorder 2 (HDL2), a triplet repeat disease affecting the gene encoding junctophilin-3, a protein involved in sarcoplasmic and plasma membranes.

Chorea-acanthocytosis is an autosomal recessive disorder in which patents experience the onset of a hyperkinetic movement disorder in early adulthood, which eventually evolves into parkinsonism. The movements are often drug resistant but may respond to deep brain stimulation. A neuropsychiatric syndrome, beginning with features of obsessive-compulsive disorder may evolve into dementia; some patients also have an axonal neuropathy and seizures. Death usually occurs within 15 years; there is no disease-modifying therapy. Patients have mutations in CHAC, the human analog of the yeast vacuolar protein sorting 13 (VPS13). The gene product, chorein, interacts with β-adducin and β-actin, membrane cytoskeletal proteins expressed at synapses and red cell membranes.

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