Defects in Metabolism of Amino Acids

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Chapter 79 Defects in Metabolism of Amino Acids

79.1 Phenylalanine

Phenylalanine is an essential amino acid. Dietary phenylalanine not utilized for protein synthesis is normally degraded by way of the tyrosine pathway (Fig. 79-1). Deficiency of the enzyme phenylalanine hydroxylase (PAH) or of its cofactor tetrahydrobiopterin (BH4) causes accumulation of phenylalanine in body fluids and in the brain. The severity of hyperphenylalaninemia depends on the degree of enzyme deficiency and may vary from very high plasma concentrations (>20 mg/dL or >1,200 µmole/L, classic phenylketonuria [PKU]) to mildly elevated levels (2-6 mg/dL or 120-360 µmole/L). In affected infants with plasma concentrations >20 mg/dL, excess phenylalanine is metabolized to phenylketones (phenylpyruvate and phenylacetate; see Fig. 79-1) that are excreted in the urine, giving rise to the term phenylketonuria (PKU). These metabolites have no role in pathogenesis of central nervous system (CNS) damage in patients with PKU; their presence in the body fluids simply signifies the severity of the condition. The term hyperphenylalaninemia implies lower plasma levels (<20 mg/dL) of phenylalanine; these patients may or may not need dietary therapy based on their blood phenylalanine level. The brain is the main organ affected by hyperphenylalaninemia. The CNS damage in affected patients is caused by the elevated concentration of phenylalanine in brain tissue. The high blood levels of phenylalanine in PKU saturate the transport system across the blood-brain barrier causing inhibition of the cerebral uptake of other large neutral amino acids such as tyrosine and tryptophan. The exact mechanism of damage caused by elevated levels of intracerebral phenylalanine remains elusive. There are a few adults with classic PKU and normal intelligence who have never been treated with a phenylalanine-restricted diet. Phenylalanine content of the brain in these individuals was found to be close to that of normal subjects when studied by magnetic resonance spectroscopy (MRS) and imaging (MRI) techniques.


Figure 79-1 Pathways of phenylalanine and tyrosine metabolism. Enzyme defects causing genetic conditions are depicted as horizontal bars crossing the reaction arrow(s). Pathways for synthesis of cofactor BH4 are shown in purple. PKU* refers to defects of BH4 metabolism that affect the phenylalanine, tyrosine, and tryptophan hydroxylases (see Figs. 79-2 and 79-5). Enzymes: (1) phenylalanine hydroxylase (PAH), (2) pterin-carbinolamine dehydratase (PCD), (3) dihydrobiopterin reductase, (4) guanosine triphosphate (GTP) cyclohydrolase, (5) 6-pyruvoyltetrahydropterin synthase (6-PTS), (6) seriapterin reductase, (7) carbonyl reductase, (8) aldolase reductase, (9) dihydrofolate reductase, (10) tyrosine aminotransferase, (11a) intramolecular rearrangement, (11) 4-hydroxyphenylpyruvate dioxygenase, (12) homogentisic acid dioxygenase, (13) maleylacetoacetate isomerase, (14) fumarylacetoacetate hydroxylase, (NE) nonenzymatic.

Classic Phenylketonuria

Severe hyperphenylalaninemia (plasma phenylalanine levels >20 mg/dL), if untreated, invariably results in the development of signs and symptoms of classic PKU, except in rare unpredictable cases.

Milder Forms of Hyperphenylalaninemia, Non-PKU Hyperphenylalaninemias

In any screening program for PKU, a group of infants are identified in whom initial plasma concentrations of phenylalanine are above normal (2 mg/dL, 120 µmole/L) but <20 mg/dL (1,200 µmole/L). These infants do not excrete phenylketones. The term hyperphenylalaninemia implies lower plasma concentration of phenylalanine, but these patients may still require dietary therapy depending on their untreated plasma phenylalanine level. Attempts have been made to classify these patients in different subgroups depending on the degree of hyperphenylalaninemia, but such a practice has little clinical or therapeutic advantage. The possibility of deficiency of BH4 should be investigated in all infants with the milder forms of hyperphenylalaninemia (see later).


The goal of therapy is to reduce phenylalanine levels in the plasma and brain. It is generally accepted that infants with persistent (more than a few days) plasma levels of phenylalanine >6 mg/dL (360 µmole/L) should be treated with a phenylalanine-restricted diet similar to that for classic PKU. Formulas low in or free of phenylalanine are commercially available. The diet should be started as soon as diagnosis is established. Because phenylalanine is not synthesized endogenously, small amounts of phenylalanine should be added to the diet to prevent phenylalanine deficiency. Dietary deficiency of this amino acid is manifested by lethargy, failure to thrive, anorexia, anemia, rashes, diarrhea, and even death; moreover, tyrosine becomes an essential amino acid in this disorder and its adequate intake must be ensured. Special food items low in phenylalanine is now commercially available for dietary treatment of affected children and adults.

There is no firm consensus concerning optimal level of blood phenylalanine in affected patients either across different countries or among treatment centers in the USA. In 2001, the National Institutes of Health Consensus Development Panel recommended that plasma phenylalanine levels to be maintained between 2 and 6 mg/dL in neonates through 12 yr of age and between 2 and 15 mg/dL in older individuals. The fact that brain development continues in adolescence and even in adulthood, lower plasma phenylalanine levels (2-10 mg/dL) have been encouraged strongly after 12 yr of age. The duration of diet therapy is also controversial. Discontinuation of therapy, even in adulthood, may cause deterioration of IQ and cognitive performance. The current recommendation from the 2001 National Institutes of Health Consensus Development Panel is that all patients be kept on a phenylalanine-restricted diet for life.

Given the difficulty of maintaining a strict low-phenylalanine diet, there are continuing attempts to find other modalities for treatment of these patients. Oral administration of tetrahydrobiopterin (BH4), the cofactor for PAH, may result in reduction of plasma levels of phenylalanine in some patients with PAH deficiency. Plasma levels of phenylalanine in these patients may decrease enough to allow for considerable modification of their dietary restriction. In very rare cases, the diet may be discontinued since the phenylalanine levels remain under 6 mg/dL. The response to BH4 cannot be predicted consistently on the basis of genotype, especially in compound heterozygous patients. Sapropterin, a synthetic form of BH4, which acts as a cofactor in patients with residual PAH activity, is approved by the Food and Drug Administration (FDA) to reduce phenylalanine levels in PKU. At a dose of 10 mg/kg/day, it reduces phenylalanine levels in up to 50% of patients.

Long-term care of these patients is best achieved by a team of experienced professionals (physician specialist, nutritionist, neurologist, geneticist, and psychologist) in a regional treatment center.

Hyperphenylalaninemia due to Deficiency of the Cofactor BH4

In 1-3% of infants with hyperphenylalaninemia, the defect resides in 1 of the enzymes necessary for production or recycling of the cofactor BH4 (Fig. 79-2). If these infants are misdiagnosed as having PKU, they may deteriorate neurologically despite adequate control of plasma phenylalanine. BH4 is synthesized from guanosine triphosphate (GTP) through several enzymatic reactions (see Fig. 79-1). In addition to acting as a cofactor for PAH, BH4 is also a cofactor for tyrosine hydroxylase and tryptophan hydroxylase, which are involved in the biosynthesis of dopamine (see Fig. 79-2) and serotonin (see Fig 79-5), respectively. Therefore, patients with hyperphenylalaninemia due to BH4 deficiency also manifest neurologic findings related to deficiencies of the neurotransmitters dopamine and serotonin. Four enzyme deficiencies leading to defective BH4 formation cause hyperphenylalaninemia and deficiencies of dopamine and serotonin. These include autosomal recessive GTP cyclohydrolase deficiency, pterin-carbinolamine dehydratase (PCD) deficiency, dihydropteridine reductase (DHPR) deficiency, and 6-pyruvoyltetrahydropterin synthase (PTPS or 6-PTS) deficiency. More than half of the reported patients have had a deficiency of 6-pyruvoyltetrahydropterin synthase. Autosomal dominant form of GTP deficiency and sepiapterin reductase deficiency result in deficiencies of neurotransmitters without hyperphenylalaninemia (Chapter 79.11 and Fig. 79-1).


Figure 79-2 Other pathways involving tyrosine metabolism. PKU* indicates hyperphenylalanemia due to tetrahydrobiopterin (BH4) deficiency (see Fig. 79-1). HVA, homovanillic acid; VMA, vanillymandelic acid. Enzymes: (1) tyrosine hydroxylase (TH), (2) aromatic L-amino acid decarboxylase (AADC), (3) dopamine hydroxylase, (4) phenylethanolamine-N-methyltransferase (PNMT), (5) catechol O-methyltransferase (COMT), (6) Monoamine oxidase (MAO).


BH4 deficiency and the responsible enzyme defect may be diagnosed by the following studies:

1 Measurement of neopterin (oxidative product of dihydroneopterin triphosphate) and biopterin (oxidative product of dihydrobiopterin and tetrahydrobiopterin) in body fluids, especially urine (see Fig. 79-1). In patients with GTP cyclohydrolase deficiency, urinary excretion of both neopterin and biopterin is very low. In patients with 6-pyruvoyltetrahydropterin synthase deficiency, there is a marked elevation of neopterin excretion and a concomitant decrease in biopterin excretion. In patients with dihydropteridine reductase deficiency, neopterin is normal, but biopterin is very high. Excretion of biopterin increases in this enzyme deficiency because the quinonoid dihydrobiopterin cannot be recycled back to BH4. Patients with pterin-carbinolamine dehydratase deficiency excrete 7-biopterin (an unusual isomer of biopterin) in their urine. In addition, examination of cerebrospinal fluid (CSF) reveals decreased levels of dopamine, serotonin, and their metabolites in all patients with BH4 deficiency (Chapter 79.11).


The goals of therapy are to correct hyperphenylalaninemia and to restore neurotransmitter deficiencies in the CNS. The control of hyperphenylalaninemia is important in patients with cofactor deficiency, because high levels of phenylalanine interfere with the transport of neurotransmitter precursors (tyrosine, tryptophan) into the brain. Plasma phenylalanine should be maintained as close to normal as possible (<6 mg/dL). This can be achieved by a combination of a low phenylalanine diet and oral supplementation of BH4. Infants with GTP cyclohydrolase or 6-PTS deficiencies respond more readily to BH4 therapy (5-10 mg/kg/day) than those with dihydropteridine reductase deficiency. In the latter patients, doses as high as 20 mg/kg/day may be required. BH4 for replacement therapy is commercially available, although it is expensive.

Lifelong supplementation with neurotransmitter precursors such as L-dopa and 5-hydroxytryptophan, along with carbidopa to inhibit degradation of L-dopa before it enters the CNS, is necessary in most of these patients even when treatment with BH4 normalizes plasma levels of phenylalanine. BH4 does not readily enter the brain to restore neurotransmitter production. Supplementation with folinic acid is also recommended in patients with dihydropteridine reductase deficiency. Unfortunately, attempting to normalize neurotransmitter levels using neurotransmitter precursors usually does not fully resolve the neurologic symptoms due to the inability to attain normal levels of BH4 in the brain. Patients often demonstrate mental retardation, fluctuating abnormalities of tone, eye movement abnormalities, poor balance and coordination, decreased ability to ambulate, and seizures in spite of supplementation with neurotransmitter precursors.

Hyperprolactinemia occurs in patients with BH4 deficiency and may be due to hypothalamic dopamine deficiency. Measurement of serum prolactin levels may be a convenient method for monitoring adequacy of neurotransmitter replacement in affected patients.

Some drugs such as trimethoprim sulfamethoxazole, methotrexate, and other antileukemic agents are known to inhibit dihydropteridine reductase enzyme activity and should be used with great caution in patients with BH4 deficiency.


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Blau N, Bélanger-Quintana A, Demirkol M, et al. Management of phenylketonuria in Europe: survey results from 19 countries. Mol Genet Metab. 2010;99:109-115.

Blau N, van Spronsen FJ, Levy HL. Phenylketonuria. Lancet. 2010;376:1417-1427.

Burton BK, Adams DJ, Grange DK, et al. Tetrahydrobiopterin therapy for phenylketonuria in infants and young children. J Pediatr. 2011;158:410-415.

Cederbaum S. Tetrahydrobiopterin and PKU: into the future. J Pediatr. 2011;158:351-353.

Committee on Genetics. Maternal phenylketonuria. Pediatrics. 2008;122:445-449.

Feillet F, van Spronsen FJ, MacDonald A, et al. Challenges and pitfalls in the management of phenylketonuria. Pediatrics. 2010;126:333-341.

Giovannini M, Verduci E, Salvatici E, et al. Phenylketonuria: dietary and therapeutic challenges. J Inherit Metab Dis. 2007;30:145-152.

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Zurfluh MR, Zschocke J, Lindner M, et al. Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Hum Mutat. 2008;29:167-175.

79.2 Tyrosine

Tyrosine is derived from ingested proteins or is synthesized endogenously from phenylalanine. It is used for protein synthesis and is a precursor of dopamine, norepinephrine, epinephrine, melanin, and thyroxine. Excess tyrosine is metabolized to carbon dioxide and water (see Fig. 79-1). Hereditary causes of hypertyrosinemia include deficiencies of tyrosine aminotransferase, 4-hydroxyphenylpyruvate dioxygenase (4-HPPD), or fumarylacetoacetate hydrolase (FAH). Acquired hypertyrosinemia may occur in severe hepatocellular dysfunction (liver failure), scurvy (vitamin C is the cofactor for the enzyme 4-HPPD), and hyperthyroidism. Hypertyrosinemia is common in blood samples obtained soon after eating.

Tyrosinemia Type I (Tyrosinosis, Hereditary Tyrosinemia, Hepatorenal Tyrosinemia)

This severe disease of the liver, kidney, and peripheral nerve, is caused by a deficiency of the enzyme FAH. Organ damage is believed to result from accumulation of metabolites of tyrosine degradation, especially succinylacetone.

Clinical Manifestations

Untreated, the affected infant appears normal at birth and typically presents between 2 and 6 mo of age but rarely may become symptomatic in the 1st mo or appear healthy beyond the 1st yr of life. The earlier the presentation, the poorer is the prognosis. The 1 yr mortality, which is about 60% in infants who develop symptoms before 2 mo of age, decreases to 4% in infants who become symptomatic after 6 mo of age.

An acute hepatic crisis commonly heralds the onset of the disease and is usually precipitated by an intercurrent illness that produces a catabolic state. Fever, irritability, vomiting, hemorrhage, hepatomegaly, jaundice, elevated levels of serum transaminases, and hypoglycemia are common. An odor resembling boiled cabbage may be present, due to increased methionine metabolites. Most hepatic crises resolve spontaneously, but may progress to liver failure and death. Between the crises, varying degrees of failure to thrive, hepatomegaly, and coagulation abnormalities often persist. Cirrhosis and eventually hepatocellular carcinoma occur with increasing age. Carcinoma is unusual before 2 yr of age.

Episodes of acute peripheral neuropathy resembling acute porphyria occur in ≈40% of affected children. These crises, often triggered by a minor infection, are characterized by severe pain, often in the legs, associated with hypertonic posturing of the head and trunk, vomiting, paralytic ileus, and, occasionally, self-induced injuries of the tongue or buccal mucosa. Marked weakness and paralysis occur in about 30% of episodes, which may lead to respiratory failure requiring mechanical ventilation. Crises typically last 1 to 7 days but recuperation from paralytic crises can be prolonged.

Renal involvement is manifested as a Fanconi-like syndrome with normal anion gap metabolic acidosis, hyperphosphaturia, hypophosphatemia, and vitamin D–resistant rickets. Nephromegaly and nephrocalcinosis may be present on ultrasound examination.

Hypertrophic cardiomyopathy and hyperinsulinism are seen in some infants.

Laboratory Findings

The presence of elevated levels of succinylacetone in serum and urine is diagnostic for tyrosinemia type I (see Fig. 79-1). In untreated patients, routinely available tests have a characteristic pattern. α-Fetoprotein level is increased, often markedly, and liver-synthesized coagulation factors are decreased in most patients; serum levels of transaminases are often increased, with marked increases being possible during acute hepatic episodes. Serum concentration of bilirubin is usually normal but can be increased with liver failure. Increased levels of α-fetoprotein are present in the cord blood of affected infants, indicating intrauterine liver damage. Plasma tyrosine level is usually elevated at diagnosis but this is a nonspecific finding and is dependent on dietary intake. Other amino acids, particularly methionine, may also be elevated in patients with liver damage. Hyperphosphaturia, hypophosphatemia, and generalized aminoaciduria may occur. The urinary level of 5-aminolevulinic acid is elevated (due to inhibition of 5-aminolevulinic hydratase by succinylacetone).

Diagnosis is usually established by demonstration of elevated levels of succinylacetone in urine or blood. Neonatal screening for hypertyrosinemia detects only a minority of patients with tyrosinemia type I. Succinylacetone, which is now assayed by most screening programs, has higher sensitivity and specificity than tyrosine and is the preferable metabolite for screening. Tyrosinemia type I should be differentiated from other causes of hepatitis and hepatic failure in infants, including galactosemia, hereditary fructose intolerance, neonatal iron storage disease, giant cell hepatitis, and citrullinemia type II (Chapter 79.11).

Treatment and Outcome

A diet low in phenylalanine and tyrosine can slow but does not halt the progression of the condition. The treatment of choice is nitisinone (NTBC), which inhibits tyrosine degradation at 4-HPPD (see Fig. 79-1). This treatment prevents acute hepatic and neurologic crises. Although nitisinone stops or greatly slows disease progression, some pretreatment liver damage is not reversible. Therefore, patients must be followed for development of cirrhosis or hepatocellular carcinoma. On imaging, the presence of even a single liver nodule usually indicates underlying cirrhosis. Most liver nodules in tyrosinemic patients are benign but current imaging techniques do not accurately distinguish all malignant nodules. Liver transplantation is an effective therapy for tyrosinemia type I and alleviates the risk of hepatocellular carcinoma. The impact of nitisinone treatment on the need for liver transplantation is still under study but the greatest effect is in patients treated early, such as children detected by neonatal screening, prior to the development of clinical symptoms. Rarely, nitisinone-treated patients develop corneal crystals, presumably of tyrosine, which are reversible by strict dietary compliance. This finding, combined with observations of developmental delay in some patients with chronically elevated tyrosine such as tyrosinemia type II, suggests that a diet low in phenylalanine and tyrosine should be continued in patients treated with nitisinone.

Tyrosinemia Type II (Richner-Hanhart Syndrome, Oculocutaneous Tyrosinemia)

This rare autosomal recessive disorder is caused by deficiency of tyrosine aminotransferase, resulting in palmar and plantar hyperkeratosis, herpetiform corneal ulcers, and mental retardation (see Fig. 79-1). Ocular manifestations include excessive tearing, redness, pain, and photophobia and often occur before skin lesions. Corneal lesions are presumed to be due to tyrosine deposition. In contrast to herpetic ulcers, corneal lesions in tyrosinemia type II stain poorly with fluorescein and often are bilateral. Skin lesions, which may develop later in life, include painful, nonpruritic hyperkeratotic plaques on the soles, palms and fingertips. Mental retardation, which occurs in <50% of patients, is usually mild to moderate.

The principal laboratory finding in untreated patients is marked hypertyrosinemia (20-50 mg/dL; 1,100-2,750 µmole/L). Surprisingly, 4-hydroxyphenylpyruvic acid and its metabolites are also elevated in urine despite being downstream from the metabolic block (see Fig. 79-1). This is hypothesized to occur via the action of other transaminases in the presence of high tyrosine concentrations, producing 4HPP in cellular compartments like the mitochondrion in which it is not further degraded. In contrast to tyrosinemia type I, liver and kidney function are normal, as are serum concentrations of other amino acids and succinylacetone. Tyrosinemia type II is due to TAT gene mutations, causing deficiency of cytosolic tyrosine aminotransferase activity in liver.

Diagnosis of type II tyrosinemia is established by assay of plasma tyrosine concentration in patients with suggestive findings. Molecular diagnosis is possible. Assay of liver tyrosine aminotransferase activity is rarely indicated.

Treatment with a diet low in tyrosine and phenylalanine improves the biochemical abnormalities and can normalize the skin and eye. The claim that mental retardation may be prevented by early diet therapy is reasonable and is supported by some case reports. The TAT gene maps to chromosome 16q and several disease-causing mutations have been identified. About half of reported cases are of Italian descent.

Transient Tyrosinemia of the Newborn

In a small number of newborn infants, plasma tyrosine may be as high as 60 mg/dL (3,300 µmole/L) during the 1st 2 weeks of life. Most affected infants are premature and are receiving high-protein diets. Transient tyrosinemia is felt to result from delayed maturation of 4-HPPD (see Fig. 79-1). Lethargy, poor feeding, and decreased motor activity are noted in some patients. Most are asymptomatic and are identified by a high blood phenylalanine or tyrosine level on screening. Laboratory findings include marked elevation of plasma tyrosine with a moderate increase in plasma phenylalanine. The finding of hypertyrosinemia differentiates this condition from PKU. 4-Hydroxyphenylpyruvic acid and its metabolites are present in the urine. Hypertyrosinemia usually resolves spontaneously in the 1st mo of life. It can be corrected promptly by reducing dietary protein to below 2 g/kg/24 hr and by administering vitamin C (200-400 mg/24 hr). Mild intellectual deficits have been reported in some infants that had this condition, but the causal relationship to hypertyrosinemia is not conclusively established.


This rare (with an incidence of ≈1/250,000) autosomal recessive disorder is due to a deficiency of homogentisic acid oxidase, which causes large amounts of homogentisic acid to accumulate in the body and then to be excreted in the urine (see Fig. 79-1).

Clinical manifestations of alcaptonuria consist of ochronosis and arthritis in adulthood. The only sign in children is a blackening of the urine on standing, caused by oxidation and polymerization of homogentisic acid. A history of grey- or black-stained diapers should suggest the diagnosis. This sign may never be noted, hence, diagnosis is often delayed until adulthood. Ochronosis, which is seen clinically as dark spots on the sclera or ear cartilage, results from the accumulation of the black polymer of homogentisic acid. Arthritis can be disabling with advancing age. It involves the large joints (spine, hip, and knee) and is usually more severe in males. Like rheumatoid arthritis, the arthritis has acute exacerbations, but the radiologic findings are typical of osteoarthritis, with characteristic narrowing of the joint spaces and calcification of the intervertebral discs. High incidences of heart disease (mitral and aortic valvulitis, calcification of the heart valves, and myocardial infarction) have been noted.

The diagnosis is confirmed by finding massive excretion of homogentisic acid on urine organic acid testing. Tyrosine levels are normal. The enzyme is expressed only in the liver and kidneys. The gene for alcaptonuria, HGD, maps to chromosome 3q. Several disease-causing mutations have been identified. Alcaptonuria is commonest in the Dominican Republic and Slovakia.

Treatment of the arthritis is symptomatic. Nitisinone efficiently reduces homogentisic acid production in alkaptonuria. If presymptomatic individuals are detected, treatment with nitisinone, combined with a phenylalanine- and tyrosine-restricted diet, seems reasonable, although no experience is available regarding long-term efficacy.


Albinism is due to deficiency of melanin, the main pigment of the skin and eye (Table 79-1). Melanin is synthesized by melanocytes from tyrosine in a membrane-bound intracellular organelle, the melanosome. Melanocytes originate from the embryonic neural crest and migrate to the skin, eyes (choroid and iris), hair follicles, and inner ear. The melanin in the eye is confined to the retinal pigment epithelium, whereas in skin and hair follicles, it is secreted into the epidermis and hair shaft. Albinism can be caused by deficiencies of melanin synthesis, by some hereditary defects of melanosomes, or by disorders of melanocyte migration. Although albinism is a classical example of a biochemical genetic disease, neither the biosynthetic pathway of melanin nor many facets of melanocyte cell biology are completely elucidated (see Fig. 79-2). The end products are 2 pigments: pheomelanin, which is a yellow-red pigment; and eumelanin, a brown-black pigment.


OCA1 (tyrosinase deficient) TYR 11q
OCA1A (severe deficiency) TYR 11q
OCA1B (mild deficiency)* TYR 11q
OCA2 (tyrosinase positive) P (pink-eyed dilution) 15q
OCA3 (Rufous, red OCA) TYRP1 9p
OCA4 MATP 5p13.3
Hermansky-Pudlak syndrome HPS1 10q
Chédiak-Higashi syndrome LYST 1q
OA1 (Nettleship-Falls type) OA xp
Piebaldism KIT 4q
Waardenburg syndrome I & III PAX3 2q
Waardenburg syndrome II MITF 3p

* This includes Amish, minimal pigment, yellow albinism, and platinum and temperature-sensitive variants.

Includes brown OCA.

Tyrosinase related protein 1.

Clinically, primary albinism can be generalized or localized. Primary generalized albinism can be either ocular or oculocutaneous. Some syndromes feature albinism in association with platelet, immunological, or neurological dysfunction.

In generalized oculocutaneous albinism, hypopigmentation can be either complete or partial. Individuals with complete albinism do not develop detectable skin pigmentation, either generalized (tanning) or localized (pigmented nevi).

The diagnosis of albinism is usually evident, but for some white children whose families are particularly light-skinned, normal variation may be a diagnostic consideration. Such normal fair-skinned children progressively develop pigmentation, the eye manifestations of albinism are absent, and other family members may have had a similar course. The clinical diagnosis of oculocutaneous albinism, as opposed to other types of cutaneous hypopigmentation, requires the presence of characteristic eye findings.

The ocular manifestations of albinism include hypopigmentation, including foveal hypoplasia with reduced visual acuity, refractive errors, nystagmus, alternating strabismus, and a red reflex (diffuse reddish hue of the iris produced during ophthalmoscopic or slit lamp examination of the eye). There is also an abnormality in routing of the optic fibers at the chiasm. Unlike normally pigmented individuals, in patients with albinism the majority of the nerve fibers from the temporal side of the retina cross to the contralateral hemisphere of the brain. This results in lack of biocular (stereoscopic) vision and of depth perception, and in repeated switching of vision from eye to eye, causing alternating strabismus. This abnormality also causes a characteristic pattern of visual evoked potentials. These findings are highly specific for albinism and can be used to formally establish the clinical diagnosis. Regular ophthalmological follow-up is recommended for patients with albinism. For instance, correction of refractive errors can maximize visual function. Normally the alternating strabismus does not result in amblyopia and does not require surgery.

Patients with albinism should be counseled to avoid ultraviolet radiation by wearing protective long-sleeved clothing and by using sunscreens with a sun protection factor (SPF) rating above 30. All forms of oculocutaneous albinism are autosomal recessive traits.

Melanin is also present in the cochlea. Albino individuals may be more susceptible to ototoxic agents such as gentamicin.

Many clinical forms of albinism have been identified. Some of the seemingly distinct clinical forms are caused by different mutations of the same gene. Several genes located on different chromosomes are shown to be involved in melanogenesis (see Table 79-1). Attempts to differentiate types of albinism based on the mode of inheritance, tyrosinase activity, or the extent of hypopigmentation have failed to yield a comprehensive classification. The following classification is based on the distribution of albinism in the body and the type of mutated gene.

Mutation detection is clinically available for most albinism genes (see Table 79-1). Molecular diagnosis is of little use therapeutically in isolated albinism but can be helpful for precise genetic counseling of families.

Oculocutaneous (Generalized) Albinism (OCA)

Lack of pigment is generalized, affecting skin, hair, and eyes. Three genetically distinct forms exist: OCA1, OCA2 and OCA3. The lack of pigment is complete in patients with OCA1 A; the other types may not be clinically distinguishable from one another. All are inherited as autosomal recessive traits.

Syndromic Forms of Generalized Albinism

Chédiak-Higashi Syndrome

Patients with this rare autosomal recessive condition (Chapter 124) have albinism of variable severity and susceptibility to infection. Bacterial infections of skin and upper respiratory tract are common. Giant peroxidase-positive lysosomal granules can be seen in granulocytes in a blood smear. Patients have a reduced number of melanosomes, which are abnormally large (macromelanosomes). The bleeding tendency is typically mild. The major, life-threatening complication is macrophage activation with hemophagocytic lymphohistiocytosis, manifested by fever, lymphadenopathy, hepatosplenomegaly, cytopenias, and elevated plasma ferritin level. Patients surviving childhood may develop cerebellar atrophy, peripheral neuropathy, and cognitive delay. Mutations in the LYST gene on chromosome 1q are the only known cause of this syndrome.

Hypopigmentation is a feature of other syndromes, some with abnormalities of lysosomal biogenesis or melanosome biology, such as Griscelli syndrome (silver-grey hair, pigmentary dilution of skin, and melanosomal clumping in hair shafts and the center of melanocytes, with mental retardation or macrophage activation with hemophagocytosis in different subtypes), Vici syndrome (combined immunodeficiency, mental retardation, agenesis of the corpus callosum, cataracts, and cleft lip and palate), and MAPBPIP protein deficiency (short stature, recurrent infections, neutropenia).

Localized Albinism

This term refers to localized patches of hypopigmentation of skin and hair, which may be evident at birth or develop with time. These conditions are caused by abnormal migration of melanocytes during development.


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79.3 Methionine

The normal pathway for catabolism of methionine, an essential amino acid, produces S-adenosylmethionine, which serves as a methyl group donor for methylation of a variety of compounds in the body, and cysteine, which is formed through a series of reactions collectively called trans-sulfuration (Fig. 79-3).

Homocystinuria (Homocystinemia)

Normally, most homocysteine, an intermediate compound of methionine degradation, is remethylated to methionine. This methionine-sparing reaction is catalyzed by the enzyme methionine synthase, which requires a metabolite of folic acid (5-methyltetrahydrofolate) as a methyl donor and a metabolite of vitamin B12 (methylcobalamin) as a cofactor (see Fig. 79-3). Only 20-30% of total homocysteine (and its dimer homocystine) is in free form in the plasma of normal individuals. The rest is bound to proteins as mixed disulfides. Three major forms of homocystinemia and homocystinuria have been identified.

Homocystinuria Due to Cystathionine β-Synthase (CBS) Deficiency (Classic Homocystinuria)

This is the most common inborn error of methionine metabolism. About 40% of affected patients respond to high doses of vitamin B6 and usually have milder clinical manifestations than those who are unresponsive to vitamin B6 therapy. These patients possess some residual enzyme activity.

Infants with this disorder are normal at birth. Clinical manifestations during infancy are nonspecific and may include failure to thrive and developmental delay. The diagnosis is usually made after 3 yr of age, when subluxation of the ocular lens (ectopia lentis) occurs. This causes severe myopia and iridodonesis (quivering of the iris). Astigmatism, glaucoma, staphyloma, cataracts, retinal detachment, and optic atrophy may develop later in life. Progressive mental retardation is common. Normal intelligence has been reported. In an international survey of >600 patients, IQ scores ranged from 10 to 135. Higher IQ scores are seen in vitamin B6 responsive patients. Psychiatric and behavioral disorders have been observed in >50% of affected patients. Convulsions occur in about 20% of patients. Affected individuals with homocystinuria manifest skeletal abnormalities resembling those of Marfan syndrome (Chapter 693); they are usually tall and thin, with elongated limbs and arachnodactyly. Scoliosis, pectus excavatum or carinatum, genu valgum, pes cavus, high arched palate, and crowding of the teeth are commonly seen. These children usually have fair complexions, blue eyes, and a peculiar malar flush. Generalized osteoporosis, especially of the spine, is the main roentgenographic finding. Thromboembolic episodes involving both large and small vessels, especially those of the brain, are common and may occur at any age. Optic atrophy, paralysis, cor pulmonale, and severe hypertension (due to renal infarcts) are among the serious consequences of thromboembolism, which is caused by changes in the vascular walls and increased platelet adhesiveness secondary to elevated homocystine levels. The risk of thromboembolism increases after surgical procedures. Spontaneous pneumothorax and acute pancreatitis are rare complications.

Elevations of both methionine and homocystine (or homocysteine) in body fluids are the diagnostic laboratory findings. Freshly voided urine should be tested for homocystine because this compound is unstable and may disappear as the urine is stored. Cystine is low or absent in plasma. The diagnosis may be established by assay of the enzyme in liver biopsy specimens, cultured fibroblasts, or phytohemagglutinin-stimulated lymphocytes or by DNA analysis.

Treatment with high doses of vitamin B6 (200-1,000 mg/24 hr) causes dramatic improvement in most patients who are responsive to this therapy. The degree of response to vitamin B6 treatment may be different in different families. Some patients may not respond because of folate depletion; a patient should not be considered unresponsive to vitamin B6 until folic acid (1-5 mg/24 hr) has been added to the treatment regimen. Restriction of methionine intake in conjunction with cysteine supplementation is recommended for patients who are unresponsive to vitamin B6. The need for dietary restriction and its extent remains controversial in patients with vitamin B6 responsive form. In some patients with this form, addition of betaine may obviate the need for any dietary restriction. Betaine (trimethylglycine, 6-9 g/24 hr for adults or 200-250 mg/kg/day for children) lowers homocysteine levels in body fluids by remethylating homocysteine to methionine (see Fig. 79-3); this may result in further elevation of plasma methionine levels. This treatment has produced clinical improvement (preventing vascular events) in patients who are unresponsive to vitamin B6 therapy. Cerebral edema has occurred in a patient with vitamin B6 nonresponsive homocystinuria and dietary noncompliance during betaine therapy. Administration of large doses of vitamin C (1 g/day) has improved the endothelial function; long-term clinical efficacy is not known.

More than 100 pregnancies in women with the classic form of homocystinuria have been reported with favorable outcomes for both mothers and infants. The majority of infants were full term and normal. Postpartum thromboembolic events occurred in a few mothers. All but 1 of the 38 affected male patients has had normal offspring.

The screening of newborn infants for classic homocystinuria has been performed worldwide and a prevalence of 1/200,000 to 1/350,000 has been estimated. The condition seems more common in New South Wales, Australia (1/60,000), and Ireland. Early treatment of patients identified by the screening process has produced favorable results. The mean IQ of 16 patients with vitamin B6 unresponsive form treated in early infancy was 94 ± 4. Dislocation of the lens seemed to be prevented in some patients.

Homocystinuria is inherited as an autosomal recessive trait. The gene for cystathionine β-synthase is located on chromosome 21q22.3. Prenatal diagnosis is feasible by performing an enzyme assay of cultured amniotic cells or chorionic villi or by DNA analysis. Many disease-causing mutations have been identified in different families. The majority of affected patients are compound heterozygotes for 2 different alleles. Heterozygous carriers are usually asymptomatic; thromboembolic events and coronary heart disease are more common in these individuals than in the normal population.

Homocystinuria Due to Defects in Methylcobalamin Formation

Methylcobalamin is the cofactor for the enzyme methionine synthase, which catalyzes remethylation of homocysteine to methionine. There are at least 5 distinct defects in the intracellular metabolism of cobalamin that may interfere with the formation of methylcobalamin. To better understand the metabolism of cobalamin, see methylmalonic acidemia (Fig. 79-4; Chapter 79.6 and Fig. 79-3). The 5 defects are designated as cblC, cblD (including cblD variant 1), cblE (methionine synthase reductase), cblG (methionine synthase), and cblF. Patients with cblC, cblD (not those with cblD variant 2), and cblF defects have methylmalonic acidemia in addition to homocystinuria because formation of both adenosylcobalamin and methylcobalamin is impaired (Chapter 79.6).

Patients with cblE and cblG defects are unable to form methylcobalamin and develop homocystinuria without methylmalonic acidemia (see Fig. 79-4); fewer than 40 patients are known with each of these diseases.

The clinical manifestations are similar in patients with all of these defects. Vomiting, poor feeding, lethargy, hypotonia, and developmental delay may occur in the 1st few months of life. One patient with the cblG defect was not symptomatic (except for mild developmental delay) until she was 21 yr old, however, when she developed difficulty in walking and numbness of the hands. Laboratory findings include megaloblastic anemia, homocystinuria, and hypomethioninemia. The presence of megaloblastic anemia differentiates these defects from homocystinuria due to methylenetetrahydrofolate reductase deficiency (see later). The presence of hypomethioninemia differentiates both of these conditions from cystathionine β-synthase deficiency (see earlier).

Diagnosis is established by complementation studies performed in cultured fibroblasts. Prenatal diagnosis has been accomplished by studies in amniotic cell cultures. All of these conditions are inherited as autosomal recessive traits. The gene for cblE (MTRR) is on chromosome 5p15.3-p15.2 and that for cblG (MTR) is on chromosome 1q43; several disease-causing mutations, including a common missense mutation (P1173L) in the MTR gene, have been described.

Treatment with vitamin B12 in the form of hydroxycobalamin (1-2 mg/24 hr) is used to correct the clinical and biochemical findings. Results vary among both diseases and sibships.

Homocystinuria Due to Deficiency of Methylenetetrahydrofolate Reductase (MTHFR)

This enzyme reduces 5,10-methylenetetrahydrofolate to form 5-methyltetrahydrofolate, which provides the methyl group needed for remethylation of homocysteine to methionine (see Fig. 79-3).

The severity of the enzyme defect and of the clinical manifestations varies considerably in different families. Clinical findings vary from apnea, seizure, microcephaly, coma, and death to developmental delay, ataxia, and motor abnormalities or even psychiatric manifestations. Premature vascular disease or peripheral neuropathy has been reported as the only manifestation of this enzyme deficiency in some patients. Adults with severe enzyme deficiency may even be completely asymptomatic. Exposure to the anesthetic nitrous oxide (which inhibits methionine synthase) in patients with MTHFR deficiency may result in neurologic deterioration and death.

Laboratory findings include moderate homocystinemia and homocystinuria. The methionine concentration is low or low normal. This finding differentiates this condition from classic homocystinuria caused by cystathionine synthase deficiency. Absence of megaloblastic anemia distinguishes this condition from homocystinuria caused by methylcobalamin formation (see earlier). Thromboembolism of vessels has also been observed in these patients. Diagnosis may be confirmed by the enzyme assay in cultured fibroblasts or leukocytes or by finding causal mutation in the MTHR gene.

A number of polymorphisms have been described in the MTHR gene. Two of these (677C → T and 1298A → C) may affect levels of plasma total homocysteine and have been studied as possible risk factors for a wide variety of medical conditions, ranging from birth defects to vascular disease and even cancer, Alzheimer disease, and death from leukemia. To date, the best data support a role for 677C → T polymorphism as a risk factor for neural tube defects. Although a clinical test for this polymorphism is widely available, its predictive value in any given individual has yet to be determined.

Treatment of severe MTHFR deficiency with a combination of folic acid, vitamin B6, vitamin B12, methionine supplementation, and betaine has been tried. Of these, early treatment with betaine seems to have the most beneficial effect.

The condition is inherited as an autosomal recessive trait; the gene for the enzyme has been located on chromosome 1p36.3 and many disease-causing mutations have been reported. Prenatal diagnosis can be offered by measuring MTHFR enzyme activity in cultured chorionic villi cells or amniocytes, by linkage analysis in informative families, or by DNA analysis of the mutation.


Secondary hypermethioninemia occurs in liver disease, tyrosinemia type I, and classic homocystinuria. Hypermethioninemia has also been found in premature and some full-term infants receiving high-protein diets, in whom it may represent delayed maturation of the enzyme methionine adenosyltransferase. Lowering the protein intake usually resolves the abnormality. Primary hypermethioninemia caused by the deficiency of hepatic methionine adenosyltransferase (MAT I/III; MAT II, which is present in other tissues, is not affected; see Fig. 79-3) has been reported in approximately 60 patients. The majority of these patients have been diagnosed in the neonatal period through screening for homocystinuria. Affected individuals with residual enzyme activity remain asymptomatic throughout life despite persistent hypermethioninemia. Some complain of unusual odor to their breath (boiled cabbage). A few patients with complete enzyme deficiency have had neurologic abnormalities related to demyelination (mental retardation, dystonia, dyspraxia). Normal pregnancies producing normal offspring have been reported in mothers with methionine adenoslytransferase deficiency. The condition is inherited as an autosomal recessive trait. The gene for hepatic methionine adenosyltransferase is on chromosome 10q22 and several disease-causing mutations have been identified. A novel defect, glycine N-methyltransferase deficiency, also causes isolated hypermethioninemia.


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79.4 Cysteine/Cystine

Cysteine is a sulfur-containing nonessential amino acid that is synthesized from methionine (see Fig. 79-3). In the presence of oxygen, 2 molecules of cysteine are oxidized to form cystine. The most common disorders of cysteine/cystine metabolism, cystinuria (Chapter 541) and cystinosis (Chapter 523.3).

Sulfite Oxidase Deficiency (Molybdenum Cofactor Deficiency)

At the last step in cysteine metabolism, sulfite is oxidized to sulfate by sulfite oxidase, and the sulfate is excreted in the urine (see Fig. 79-3). This enzyme requires a molybdenum-pterin complex named molybdenum cofactor. This cofactor is also necessary for the function of 2 other enzymes in humans: xanthine dehydrogenase (which oxidizes xanthine and hypoxanthine to uric acid) and aldehyde oxidase. Three enzymes, encoded by 3 different genes, are involved in the synthesis of the cofactor. The genes are mapped to chromosomes 14q24, 6p21.3, and 5q11. Deficiency of any of the 3 enzymes causes cofactor deficiency with identical phenotype. Most patients who were originally diagnosed as having sulfite oxidase deficiency have been proven to have molybdenum cofactor deficiency. Both conditions are inherited as autosomal recessive traits. The gene for sulfite oxidase is on chromosome 12.

The enzyme and the cofactor deficiencies produce identical clinical manifestations. Refusal to feed, vomiting, severe intractable seizures (tonic, clonic, myoclonic), and severe developmental delay may develop within a few weeks after birth. Bilateral dislocation of ocular lenses is a common finding in patients who survive the neonatal period.

These children excrete large amounts of sulfite, thiosulfate, S-sulfocysteine, xanthine, and hypoxanthine in their urine. Urinary and serum levels of uric acid and urinary concentration of sulfate are diminished. Fresh urine should be used for screening purposes and for quantitative measurements of sulfite, because oxidation at room temperature may produce false-negative results.

Diagnosis is confirmed by measurement of sulfite oxidase and molybdenum cofactor in fibroblasts and liver biopsies, respectively. Prenatal diagnosis is possible by performing an assay of sulfite oxidase activity in cultured amniotic cells or in samples of chorionic villi.

No effective treatment is available, and most children die in the 1st 2 yr of life. The prevalence of these deficiencies in the general population is not known.

79.5 Tryptophan

Tryptophan is an essential amino acid and a precursor for nicotinic acid (niacin) and serotonin (Fig. 79-5). The genetic disorders of metabolism of serotonin, 1 of the major neurotransmitters, are discussed in Chapter 79.11.


Figure 79-5 Pathways in the metabolism of tryptophan. PKU* indicates hyperphenylalanemia due to tetrahydrobiopterin deficiency (see Fig. 79-1). Enzymes: (1) tryptophan hydroxylase, (2) aromatic L-amino acid decarboxylase (AADC), (3) monoamine oxidase (MAO).

Hartnup Disorder

In this autosomal recessive disorder, named after the 1st affected family to be reported, there is a defect in the transport of monoamino-monocarboxylic amino acids (neutral amino acids), including tryptophan, by the intestinal mucosa and renal tubules. Decreased intestinal absorption of tryptophan in conjunction with its increased renal loss is believed to cause reduced availability of tryptophan for niacin synthesis. Most children with Hartnup defect remain asymptomatic. The major clinical manifestation in the rare symptomatic patient is cutaneous photosensitivity. The skin becomes rough and red after moderate exposure to the sun, and with greater exposure, a pellagra-like rash may develop. The rash may be pruritic, and a chronic eczema may appear. The skin changes have been reported in affected infants as young as 10 days of age. Some patients may have intermittent ataxia manifested as an unsteady, wide-based gait. The ataxia may last a few days and usually recovers spontaneously. Mental development is usually normal. Two individuals in the original kindred were mentally retarded. Episodic psychologic changes, such as irritability, emotional instability, depression, and suicidal tendencies, have been observed; these changes are usually associated with bouts of ataxia. Short stature and atrophic glossitis are seen in some patients.

Most children diagnosed with Hartnup disorder by neonatal screening have remained asymptomatic. This indicates that other factors are also involved in pathogenesis of the clinical condition.

The main laboratory finding is aminoaciduria, which is restricted to neutral amino acids (alanine, serine, threonine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, histidine). Urinary excretion of proline, hydroxyproline, and arginine remains normal. This finding differentiates Hartnup disorder from other causes of generalized aminoaciduria, such as Fanconi syndrome. Plasma concentrations of neutral amino acids are usually normal. This seemingly unexpected finding is because these amino acids are absorbed as dipeptides and the transport system for small peptides is intact in Hartnup disorder. The indole derivatives (especially indican) may be found in large amounts in some patients, owing to bacterial breakdown of unabsorbed tryptophan in the intestines.

Diagnosis is established by the striking intermittent nature of symptoms and the just described urinary findings.

Treatment with nicotinic acid or nicotinamide (50-300 mg/24 hr) and a high-protein diet results in a favorable response in symptomatic patients. Because of the intermittent nature of the clinical manifestations, the efficacy of these treatments is difficult to evaluate. The prevalence of the disorder is estimated to be 1/20,000 to 1/30,000. Normal outcome both for mother and fetus is reported in affected pregnant women. The gene (SLC6A19) for this condition is on chromosome 5p15.33.

79.6 Valine, Leucine, Isoleucine, and Related Organic Acidemias

The early steps in the degradation of these 3 essential amino acids, the branched-chain amino acids, are similar (see Fig. 79-4). The intermediate metabolites are all organic acids, and deficiency of any of the degradative enzymes, except for the transaminases, causes acidosis; in such instances, the organic acids before the enzymatic block accumulate in body fluids and are excreted in the urine. These disorders commonly cause metabolic acidosis, which usually occurs in the 1st few days of life. Although most of the clinical findings are nonspecific, some manifestations may provide important clues to the nature of the enzyme deficiency. An approach to infants suspected of having an organic acidemia is presented in Figure 79-6. Definitive diagnosis is usually established by identifying and measuring specific organic acids in body fluids (blood, urine), by the enzyme assay, and by identification of the mutant gene.

Organic acidemias are not limited to defects in the catabolic pathways of branched-chain amino acids. Disorders causing accumulation of other organic acids include those derived from lysine (Chapter 79.14), those associated with lactic acid (Chapter 81), and dicarboxylic acidemias associated with defective fatty acid degradation (Chapter 80.1).

Maple Syrup Urine Disease (MSUD)

Decarboxylation of leucine, isoleucine, and valine is accomplished by a complex enzyme system (branched-chain α-ketoacid dehydrogenase) using thiamine pyrophosphate (vitamin B1) as a coenzyme. This mitochondrial enzyme consists of 4 subunits: E, E, E2, and E3. The E3 subunit is shared with 2 other dehydrogenases in the body, namely pyruvate dehydrogenase and α-ketoglutarate dehydrogenase. Deficiency of this enzyme system causes MSUD (see Fig. 79-4), named after the sweet odor of maple syrup found in body fluids, especially urine. Based on clinical findings and response to thiamine administration, 5 phenotypes of MSUD have been identified.

Classic MSUD

This form has the most severe clinical manifestations. Affected infants who are normal at birth develop poor feeding and vomiting in the 1st wk of life; lethargy and coma may ensue within a few days. Physical examination reveals hypertonicity and muscular rigidity with severe opisthotonos. Periods of hypertonicity may alternate with bouts of flaccidity. Neurologic findings are often mistaken for generalized sepsis and meningitis. Cerebral edema may be present; convulsions occur in most infants, and hypoglycemia is common. In contrast to most hypoglycemic states, correction of the blood glucose concentration does not improve the clinical condition. Routine laboratory findings are usually unremarkable, except for metabolic acidosis. Death usually occurs in untreated patients in the 1st few weeks or months of life.

Diagnosis is often suspected because of the peculiar odor of maple syrup found in urine, sweat, and cerumen (see Fig. 79-6). It is usually confirmed by amino acid analysis showing marked elevations in plasma levels of leucine, isoleucine, valine, and alloisoleucine (a stereoisomer of isoleucine not normally found in blood) and depression of alanine. Leucine levels are usually higher than those of the other 3 amino acids. Urine contains high levels of leucine, isoleucine, and valine and their respective ketoacids. These ketoacids may be detected qualitatively by adding a few drops of 2,4-dinitrophenylhydrazine reagent (0.1% in 0.1 N HCl) to the urine; a yellow precipitate of 2,4-dinitrophenylhydrazone is formed in a positive test. Neuroimaging during the acute state may show cerebral edema, which is most prominent in the cerebellum, dorsal brainstem, cerebral peduncle, and internal capsule. After recovery from the acute state and with advancing age, hypomyelination and cerebral atrophy may be seen in neuroimaging of the brain. The enzyme activity can be measured in leukocytes and cultured fibroblasts.

Treatment of the acute state is aimed at hydration and rapid removal of the branched-chain amino acids and their metabolites from the tissues and body fluids. Because renal clearance of these compounds is poor, hydration alone may not produce a rapid improvement. Peritoneal dialysis or hemodialysis is the most effective mode of therapy in critically ill infants and should be instituted promptly; significant decreases in plasma levels of leucine, isoleucine, and valine are usually seen within 24 hr of institution of treatment. Providing sufficient calories and nutrients intravenously or orally should reverse the patient’s catabolic state. Cerebral edema may need to be treated with mannitol, diuretics (e.g., furosemide), or hypertonic saline.

Treatment after recovery from the acute state requires a diet low in branched-chain amino acids. Synthetic formulas devoid of leucine, isoleucine, and valine are available commercially. Because these amino acids cannot be synthesized endogenously, small amounts of them should be added to the diet; the amount should be titrated carefully by performing frequent analyses of the plasma amino acids. A clinical condition resembling acrodermatitis enteropathica occurs in affected infants whose plasma isoleucine concentration becomes very low; addition of isoleucine to the diet causes a rapid and complete recovery. Patients with MSUD should remain on the diet for the rest of their lives. Liver transplantation has been performed in a number of patients with classic MSUD with promising results. These children have been able to tolerate a normal diet.

The long-term prognosis of affected children remains guarded. Severe ketoacidosis, cerebral edema, and death may occur during any stressful situation such as infection or surgery, especially in mid-childhood. Mental and neurologic deficits are common sequelae.

Genetics and Prevalence of MSUD

All forms of MSUD are inherited as an autosomal recessive trait. The gene for each subunit resides on different chromosomes. The gene for E is on chromosome 19q13.1-q13.2; that for E is on chromosome q14; the gene for E2 is on chromosome 1p31; and that for E3 is on chromosome 7q31-q32. Many different disease-causing mutations have been identified in patients with different forms of MSUD. A given phenotype is caused by a variety of genotypes; patients from different pedigrees with the classic form of MSUD have been shown to have mutations in genes for E, E, or E2. Most patients are compound heterozygotes inheriting 2 different mutant alleles. Mutations in genes for E (38%) and E (33%) account for about 70% of cases.

The prevalence is estimated at 1/185,000. The classic form of MSUD is more prevalent in the Old Order Mennonites in the USA, with estimated prevalence of 1/358. Affected patients in this population are homozygous for a specific mutation (Y393N) in the E subunit gene.

Early detection of MSUD is feasible by mass screening of newborn infants. Prenatal diagnosis has been accomplished by enzyme assay of the cultured amniocytes, cultured chorionic villi tissue, or direct assay of the chorionic villi samples and by identification of the mutant gene.

Several successful pregnancies have occurred in women with different forms of MSUD. No ill effects have been observed in the offspring of these patients. Episodes of metabolic decompensations have occurred in the mothers during pregnancy and the postpartum period.