Metabolic disorders include a wide array of diseases affecting a number of important pathways that frequently result in neurological consequences. The advances in biochemistry and molecular genetics have revealed much about these disorders. As with most technological advances, as the disorders are better defined, more closely related variants emerge. This further complicates the clinical and diagnostic picture for the pediatrician and subspecialist alike. The introductory section of Chapter 24 discusses these issues in greater detail. The same factors apply to the metabolic disorders, and there is considerable overlap between these two categories of disease.

An often overlooked component of the management of these disorders is a coordinated genetic counseling program. This is more than simply advising a family that a disease is hereditary. There should be coordinated genetic, reproductive, and medical counseling and management.1

Table 23-1 gives an overview of the glycogen storage diseases (GSDs).

Acid Maltase Deficiency—Pompe Disease

Biochemistry and Clinical Characteristics

Acid maltase deficiency (AMD), or Pompe disease (Box 23-1), is an autosomal recessive (AR) glycogen storage disease with several different manifestations.2 Infantile AMD manifests itself within weeks of birth. The clinical manifestations include floppy baby syndrome, generalized and bulbar weakness, macroglossia, cardiomegaly, and hepatomegaly. The symptoms progress to death by age 2 years.

Adult AMD, on the other hand, usually starts in the twenties or thirties. The clinical presentation is different in this population, with the primary findings being respiratory weakness more prominent than limb-girdle weakness and intracranial aneurysms secondary to glycogen accumulation in vessels.

Evaluation and Pathology

The evaluation of AMD reveals increased creatine kinase (CK) with a normal ischemic exercise test. The needle EMG reveals evidence of myopathy and electrical myotonia without clinical myotonia. There is a vacuolar myopathy with accumulation of PAS-positive material in lysosomes on microscopic evaluation (Figure 23-1).

Management

Enzyme replacement may offer an effective treatment for infantile-onset Pompe disease.3,4

Muscle Phosphorylase Deficiency—McArdle Disease

Biochemistry and Clinical Characteristics

Muscle phosphorylase deficiency, or McArdle disease (Box 23-2), is an autosomal recessive glycogen storage disease.5,6 In childhood, it manifests itself with exercise intolerance. In adulthood, cramps and myalgias are more common complaints. Symptoms typically resolve with rest, but permanent weakness occurs in approximately one-third of patients. Acute muscle necrosis can occur but is rare.7

Evaluation and Pathology

The evaluation of muscle phosphorylase deficiency reveals increased creatine kinase (CK) in 90% of patients. The ischemic exercise test is positive with no rise in serum lactate after ischemic exercise. Myoglobinuria with exercise occurs in half the patients. The needle EMG is usually normal. Subsarcolemmal glycogen deposits (blebs) that are PAS positive, intermyofibrillar vacuoles, and immunohistochemical stains showing absent staining for phosphorylase, are evident on microscopic evaluation (Figure 23-2).

Management

Creatine supplementation may offer some treatment benefit for skeletal muscle function in McArdle disease.8

Muscle Phosphofructokinase Deficiency—Tarui Disease

Biochemistry and Clinical Characteristics

Muscle phosphofructokinase deficiency, or Tarui disease (Box 23-3), is an autosomal recessive glycogen storage disease. Tarui disease begins in childhood with premature fatigue, weakness, and stiffness induced by exercise. Myalgias and cramps are common. Symptoms typically resolve with rest.9,10

Evaluation and Pathology

The evaluation of muscle phosphofructokinase deficiency reveals increased creatine kinase (CK) levels.11 The ischemic exercise test is positive, with no rise in serum lactate after ischemic exercise. A mild hemolysis can also occur. The needle EMG is usually normal but some patients have myopathic changes. Subsarcolemmal glycogen deposits (blebs) that are PAS positive, intermyofibrillar vacuoles, and immunohistochemical stains showing absent staining for phosphofructokinase, are the most common findings on microscopic evaluation.

Organic Amino Acidurias

A number of disorders involving amino acid metabolism result in similar symptoms and can be identified via urinary organic acid analysis. A number of different disorders exist and are similar though not directly related. The most important consideration is to recognize the general classification of the disorder by its symptom complex. The urinary organic acid panel can be obtained to identify the exact metabolic defect.12

All the organic acidurias are inherited in an autosomal recessive fashion and begin during infancy. A number of characteristics are common to the organic acidurias including vomiting, anorexia, lethargy, ketoacidosis, dehydration, hyperammonemia, neutropenia, and failure to thrive.13,14 Several neurological manifestations also arise, including seizures, hypomyelination, mental retardation, and coma. Without treatment, these are potentially life-threatening disorders.

Hyperammonemia and hyperglycinemia are common amongst the amino acudurias. Urine and serum organic acid panels can be used to identify the specific disorder.15

Specific Organic Acidurias

Proprionic acidemia is associated with hypotonia, infantile spasms, hypsarrhythmia, and myoclonus in addition to the signs and symptoms common to all the organic acidurias. Treatment includes a diet low in valine, isoleucine, methionine, and threonine. Carnitine supplementation is also necessary.16,17

Methylmalonic aciduria typically becomes symptomatic in the first week of life with vomiting, hypotonia, and metabolic acidosis. This may be followed by spascticity, dystonia, strokes, chorea, and developmental delay. The principle treatment is supplemental vitamin B12. If the patient does not respond to Vitamin B12, then a low-protein diet with supplemental L–carnitine may be required.16,17

Patients with isovaleric aciduria typically have a strong odor of urine and stale perspiration. Pancytopenia may also complicate the clinical course. Oral glycine supplements are the primary treatment.

Glutaric Acidurias

Just as in the organic aminoacidurias, the family of glutaric acidurias is composed of several unrelated diseases.

Glutaric Aciduria Type I

Biochemistry and Clinical Characteristics

Glutaric aciduria type I (Box 23-4) is an autosomal recessive disorder that begins in infancy. The condition presents with a variety of manifestations. Some patients present with an early neurodegenerative disorder with hypotonia, chorea, and seizures. Others have relatively normal early development until the deterioration is suddenly triggered. Macrocephaly is present in 70% and developmental delay is common.16,17

Evaluation and Pathology

The evaluation of glutaric aciduria type I reveals abnormal urine and serum organic acids. Enzyme assays are also helpful in the diagnosis. Neuroimaging reveals cortical atrophy, gliosis in the caudate and putamen, and atrophy of the caudate.

Management

Treatment consists of a low-protein diet, carnitine supplements, and riboflavin supplements. The diet should, however, be high in calories and low in lysine and tryptophan.

Glutaric Aciduria Type II

Biochemistry and Clinical Characteristics

Glutaric aciduria type II (Box 23-5) is also an autosomal recessive (AR) disorder that has several different courses depending on the subtype. There are three subtypes: neonatal with congenital abnormalities, neonatal without congenital abnormalities, and late-onset form. Neonatal glutaric aciduria type II presents with severe metabolic acidosis, cardiomyopathy, and hypoglycemia. The physical features associated with glutaric aciduria type II include macrocephaly, high forehead, flat nasal bridge, and malformed ears.

Evaluation and Pathology

The evaluation of glutaric aciduria type II reveals abnormal urine and serum organic acids. Enzyme assays are also helpful in the diagnosis. Neuroimaging reveals agenesis of the cerebellar vermis and hypoplasia of the temporal lobes.

Management

Treatment consists of a high-carbohydrate, low-fat, low-protein diet. Carnitine supplements and riboflavin supplements may be of benefit.

Phenylketonuria

Biochemistry and Clinical Characteristics

Phenylketonuria (PKU) is an autosomal recessive disorder (Table 23-2, Box 23-6) that results in decreased phenylalanine hydroxylase (conversion of phenylalanine to tyrosine). Patients born with phenylketonuria appear normal at birth, but symptoms begin shortly after birth and after exposure to phenylalanine.18,19 Vomiting is one of the first symptoms. By several months of age, the patients have developmental delay, with seizures in the more severely affected. In untreated patients, a variety of physical signs are noted, including fair skin, blue eyes, blonde hair, hyperreflexia, hyperkinetic activity, photosensitivity, eczema-like rash, and a musty body odor. Malignant PKU, the stiff baby variant, results from dihydropterin reductase (biopterin) deficiency.

Evaluation and Pathology

The phenylalanine screen is positive if phenylalanine level is more than 20 mg/dL. The level should be checked at birth and at 2 weeks of age. If phenylalanine levels are high, a biopterin screen should be obtained. Tyrosine levels are low.

In the untreated, the EEG often reveals paroxysmal activity and hysarrhythmia. The EEG may be normal in the treated patients. Imaging findings remain abnormal even when treated. The MRI reveals atrophy and increased T-2 signal intensity in the posterior deep white matter. There is also decreased metabolism in the caudate and putamen.20

Management

Treatment consists of a low-phenylalanine diet for PKU. Infants with malignant PKU require treatment with supplemental biopterin. Even with treatment, malignant PKU has a poor prognosis.21-23

Nonketotic Hyperglycinemia

Biochemistry and Clinical Characteristics

The nonketotic hyperglycinemias (Box 23-7) are a relatively common group of disorders with widely variable genetics, phenotypes, and severities.24 There are five reported forms of the disease, with four arising during infancy or childhood. The neonatal form is the most common. This form consists of initial hypotonia progressing to hypertonia. Seizures are a common complication. The condition typically progresses to coma, respiratory arrest, and death. Survivors have severe developmental delay and mental retardation.24,25