Aminoacidemias and Organic Acidemias

37 

Aminoacidemias and Organic Acidemias Renata C. Gallagher, Gregory M. Enns, Tina M. Cowan, Bryce Mendelsohn, and Seymour Packman

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

Approximately 4% of individuals born in the United States have a genetic or partly genetic disorder. Inborn errors of metabolism contribute significantly to this total. Although each disease is individually rare, the aggregate incidence of metabolic disease is relatively high and may be greater than 1 in 1000 newborns. Newborn screening programs using tandem mass spectrometry, which can detect approximately 20 inborn errors of metabolism, typically have reported an incidence of 1 in 2000 to 1 in 4000. Because there are hundreds of known metabolic conditions, the aggregate estimate seems reasonable. Metabolic diseases infrequently produce symptoms immediately at birth, and they can manifest with slowly progressive encephalopathies. In this setting, histologic or biochemical abnormalities may be present in the fetal central nervous system (CNS) by 4 to 5 months’ gestation. Inborn errors of metabolism also can manifest with rapid clinical deterioration in the newborn period or after an interval period of good health. Presenting clinical features are often nonspecific, and they may be misdiagnosed as infection, cardiovascular compromise or other causes of hypoxemia, trauma, primary brain anomalies, or the effects of a toxin. Recognition of patterns of clinical presentation and rapid implementation of laboratory investigations are essential for the initiation of appropriate therapy without delay. If appropriate therapy is not initiated in a timely manner, there is a high risk of morbidity or mortality, regardless of the cause of the acute illness. This chapter provides an overview of the diagnosis and treatment of two categories of inborn errors: aminoacidopathies and organic acidemias. The general approaches described are broadly applicable to other heritable metabolic disorders, such as disorders of fatty acid oxidation, urea cycle disorders, and lactic acidosis syndromes. Descriptions of selected disorders of amino acid and organic acid metabolism are provided to illustrate and emphasize the approaches to diagnosis, treatment, and genetic counseling in this area of genetic medicine. In this print version of the chapter, we discuss phenylketonuria, followed by representative aminoacidopathies and organic acidemias likely to be encountered by the pediatric neurologist in an acute or critical clinical setting. For a comprehensive and detailed discussion of additional organic acidemias and aminoacidopathies and important general concepts in the diagnosis, treatment, and genetic counseling involved in heritable metabolic disorders, readers are referred to the online version of this chapter.

SIGNS AND SYMPTOMS: GENERAL CONCEPTS See the online version of the chapter.

PHYSICAL FINDINGS: GENERAL CONCEPTS See the online version of the chapter.

286

LABORATORY APPROACHES TO DIAGNOSIS: GENERAL CONCEPTS See the online version of the chapter.

TREATMENT: GENERAL CONCEPTS See the online version of the chapter.

INHERITANCE AND GENETIC COUNSELING: GENERAL CONCEPTS See the online version of the chapter.

AMINOACIDEMIAS Phenylketonuria Phenylketonuria (PKU) is an autosomal-recessive disorder caused by deficient activity of phenylalanine hydroxylase (PAH), a hepatic enzyme that converts phenylalanine to tyrosine (Figure 37-1). The biochemical block results in the accumulation of phenylalanine, which is then converted to phenylpyruvic acid and phenyllactic acid, phenylketones that are excreted in the urine. A range of reduced PAH-specific activity correlates broadly with the severity of the phenotype. Tetrahydrobiopterin is a necessary cofactor in the PAH reaction, and elevated phenylalanine levels rarely may be caused by inherited disorders of tetrahydrobiopterin synthesis (see Figure 37-1). Mandatory population newborn screening for PKU, in combination with postnatal presymptomatic therapy, was begun in the 1960s. Phenylalanine is neurotoxic, and untreated or poorly treated patients with classic phenylketonuria typically have profound intellectual disability. Patients exposed to chronically elevated phenylalanine levels ultimately develop microcephaly, seizures (e.g., tonic-clonic, myoclonic, infantile spasms), tremors, athetosis, and spasticity, and they may be misdiagnosed as having cerebral palsy. Psychiatric and behavior problems, including autistic behavior and attention-deficit hyperactivity disorder, are common. Brain magnetic resonance imaging (MRI) may detect dysmyelination, especially T2 enhancement in the periventricular white matter, a finding that is potentially reversible with the initiation of dietary therapy. Elevated maternal blood phenylalanine levels can cross the placenta and cause fetal birth defects, including microcephaly, dysmorphic features, and congenital heart defects. Dietary control (phenylalanine levels < 360 µM) should ideally be achieved before 3 months before conception, and mothers with PKU should be monitored carefully by an experienced center throughout pregnancy. The presymptomatic institution of and continued adherence to specific dietary therapy prevents intellectual disability. However, children and adults with PKU may experience



Aminoacidemias and Organic Acidemias Phenylalanine

287

Tyrosine

Phenylalanine hydroxylase

(1) 4–Hydroxytetrahydrobiopterin Carbinolamine dehydratase 7,8–Dihydrobiopterin (BH2) (2)

6–Pyruvoyltetrahydropterin 6–Pyruvoyltetrahydropterin (5) synthase

Tetrahydrobiopterin (BH4) (6) Sepiapterin reductase

Dihydroneopterin GTP cyclohydrolase

(4)

Dihydropteridine reductase

GTP

(3) NAD

NADH

Figure 37-1.  Regulation of phenylalanine hydroxylase activity. Phenylalanine is converted to tyrosine (1) by the holoenzyme phenylalanine hydroxylase (PAH). PAH requires tetrahydrobiopterin (BH4) as an active cofactor and is recycled by the sequential actions of carbinolamine dehydratase (2) and dihydropteridine reductase (3). BH4 is synthesized in vivo through a complex series of steps that involve guanosine triphosphate (GTP) cyclohydrolase (4), 6-pyruvoyltetrahydropterin synthase (5), and sepiapterin reductase (6). Genetic defects at any of these steps may be associated with hyperphenylalaninemia. (From Wilcox WR, Cederbaum SD. Amino acid metabolism. In: Rimoin D, Connor J, Pyeritz R, Korf B, eds. Principles and practice of medical genetics, 4th ed. Philadelphia: Churchill Livingstone, 2002:2406.)

cognitive symptoms, such as problems in executive functioning, and disturbance in emotional (e.g., depression, anxiety, phobias) and behavioral (e.g., hyperactivity) functioning despite early and continuous treatment. Selective restriction of phenylalanine intake by using phenylalanine-free medical formulas and foods (and tyrosine supplementation), which provides enough additional protein and nutrients to support normal growth, remains the mainstay of PKU therapy. Most clinics in the United States strive to maintain plasma phenylalanine levels between 120 and 360 µM in children younger than 12 years and between 120 and 600 µM in individuals older than 12 years, although there is some evidence to suggest that lowering upper phenylalanine targets even further improves neurocognitive function. An expert, coordinated team approach is clearly the most effective way of managing phenylketonuria; stricter management improves developmental outcome. In conjunction with dietary therapy, oral administration of tetrahydrobiopterin, the naturally occurring cofactor for the PAH reaction, may be used to control plasma phenylalanine levels. Response to tetrahydrobiopterin is especially robust in mild hyperphenylalaninemia but has also been documented in patients with classic or variant PKU. A trial of tetrahydrobiopterin may be offered to PKU patients of any severity to determine clinical response. Administration of dietary supplementation of large neutral amino acids (LNAAs) is a complementary approach to therapy. LNAAs compete with phenylalanine for transport across the blood–brain barrier by the L-type amino acid carrier and consequently decrease the level of phenylalanine in the central nervous system (CNS) and may increase brain neurotransmitter and essential amino acid concentrations. A novel therapeutic approach currently in clinical trials uses the nonmammalian enzyme phenylalanine ammonia lyase (PAL). This enzyme converts phenylalanine to

transcinnamic acid, a harmless compound, and it has been found to reduce hyperphenylalaninemia in PKU animal models and patients in clinical trials. Other novel therapies are under close investigation, especially given the findings of suboptimal outcomes in phenylketonuria patients who have been continuously treated from the neonatal period. (Enns et al., 2010)

Biopterin Disorders See the online version of the chapter.

Hepatorenal Tyrosinemia See the online version of the chapter.

Other Categories of Tyrosinemia See the online version of the chapter.

Maple Syrup Urine Disease In 1954, John Menkes and colleagues described four siblings who died in early infancy from a cerebral degenerative disease, with onset occurring when they were 3 to 5 days old. Symptoms included feeding difficulty, irregular respiratory pattern, hypertonia, opisthotonus, and failure to thrive. All had urine with the smell of maple syrup. Soon thereafter, another patient with a similar history was found to have elevated levels of branched-chain amino acids in urine and blood, and the syndrome was initially referred to as maple sugar urine disease. Maple syrup urine disease is caused by mitochondrial branched-chain α-ketoacid dehydrogenase complex deficiency. The enzymatic defect leads to accumulation of branched-chain amino acids and branched-chain α-ketoacids. Five forms of

37

288

PART VI  Genetic, Metabolic and Neurocutaneous Disorders

maple syrup urine disease (i.e., classic, intermediate, intermittent, thiamine-responsive, and dihydrolipoyl dehydrogenase [E3] deficiency) have been delineated based on clinical presentation, level of enzyme activity, and response to thiamine administration.

Clinical Manifestations Classic Maple Syrup Urine Disease.  In the classic form, the clinical phenotype is one of severe neonatal encephalopathy, unless presymptomatic therapy is initiated because of abnormal newborn screening, prenatal diagnosis, or positive family history. Untreated neonates typically develop symptoms by the end of the first week of life. Feeding difficulties, alternating hypertonia and hypotonia, opisthotonic posturing, abnormal movements (“fencing” or “bicycling”), and seizures commonly occur. The characteristic urine smell develops on day 5 to 7 of life. Unless an underlying inborn error of metabolism is suspected, affected children may be misdiagnosed as having sepsis and progress to coma and death. Ketosis is often found, and hypoglycemia may occur, but severe metabolic acidosis tends not to occur. Plasma amino acid analysis reveals elevated levels of branchedchain amino acids and the diagnostic presence of alloisoleucine in plasma. Urine organic acid analysis demonstrates excretion of branched-chain α-ketoacids. Hyponatremia and cerebral edema are frequent sequelae during acute metabolic decompensation. Other complications include pseudotumor cerebri, pancreatitis, and eye abnormalities. Ocular findings in untreated or late-diagnosed patients include optic atrophy, gray optic papilla, nystagmus, ophthalmoplegia, strabismus, and cortical blindness. Children who survive the initial metabolic crisis typically have significant neurodevelopmental delays and spasticity. Although motor, visual, and learning deficits may occur, rapid identification of affected infants and careful institution of appropriate therapy can result in normal development. Neuroimaging studies (Figure 37-3) are typically abnormal in patients with untreated classic maple syrup urine disease (MSUD) who are in crisis. Computed tomographic (CT) scans appear normal in the first few days of life, but they reveal progression to marked generalized cerebral edema if the patient remains untreated. An unusual pattern of edema may occur, characterized by involvement of the cerebellar deep white matter, posterior brainstem, cerebral peduncles, posterior limb of the internal capsule, and posterior aspect of the centrum semiovale. Edema tends to subside in the second month of life. Patients with classic maple syrup urine disease in metabolic crisis with associated hyponatremia demonstrate a prominently increased T2 signal on brain MRI in the brainstem reticular formation, dentate nucleus, red nucleus, globus pallidus, hypothalamus, septal nuclei, and amygdala. One report observed that brain MRI abnormalities were absent or only slight in sick patients with maple syrup urine disease in the absence of hyponatremia. Cranial ultrasonography of neonates in acute metabolic crisis reveals symmetrically increased echogenicity of the periventricular white matter, basal ganglia, and thalami. Chronic changes, including hypomyelination of the cerebral hemispheres, cerebellum, and basal ganglia and cerebral atrophy, may supervene in poorly controlled patients. CT- and MRI-defined abnormalities and the clinical phenotype may improve after implementation of appropriate dietary therapy. Diffusion-weighted imaging and spectroscopy have also documented abnormalities during the acute phase of disease. Markedly restricted proton diffusion, suggestive of cytotoxic or intramyelinic sheath edema, was demonstrated in the brainstem, basal ganglia, thalami, cerebellar and periventricular white matter, and cerebral cortex in six patients with maple syrup urine disease.

MR spectroscopy demonstrated abnormal elevations of branched-chain amino acids, branched-chain α-ketoacids, and lactate in the four patients. All of these changes were reversed after the institution of appropriate nutritional and antibiotic therapy to treat intercurrent illness. However, in a recent study of a cohort of classic MSUD adolescents and adults under dietary control, persistent signal changes were noted in the cerebral hemispheres, internal capsule, brainstem, and central cerebellum (Klee et al., 2013). The authors ascribed the signal alterations to dysmyelination and considered them consonant with clinical studies showing that learning disabilities and variable social, educational, and professional outcomes are present in teenagers and adults with MSUD. A characteristic comblike electroencephalogram (EEG) pattern may be demonstrated for some patients with classic MSUD between the second and third weeks of life. This unusual rhythm pattern resolves with the institution of dietary therapy. Intermediate Maple Syrup Urine Disease.  Children who have the intermediate form of MSUD do not present in the neonatal period, despite having persistently elevated plasma levels of branched-chain amino acids. Developmental delay and failure to thrive are common. Severe neurologic impairment is absent; episodes of metabolic decompensation may occur, although severe ketoacidosis episodes are variable. These children have a higher tolerance for dietary protein than those who have the classic form. Rarely, patients with intermediate-type MSUD respond to thiamine administration. Intermittent Maple Syrup Urine Disease.  Patients with intermittent MSUD typically come to medical attention when they are 5 months to 2 years old and after stress induced by infection or high protein intake; some have been detected as late as the fifth decade of life. The intermittent form of MSUD can be particularly difficult to diagnose because affected individuals have normal levels of branched-chain amino acids and no odor between episodes of metabolic decompensation. Episodic decompensation is characterized by ataxia, disorientation, and altered behavior, which may progress to seizures, coma, and even death unless therapy is instituted. Early development and intellect are usually normal. Thiamine-Responsive Maple Syrup Urine Disease.  The clinical course of patients with the thiamine-responsive variant of MSUD is similar to that of the intermediate form of the disease. Plasma levels of branched-chain amino acid and urine excretion of branched-chain α-ketoacids decline days to weeks after thiamine administration (10-1000 mg/day) is started. Patients are also treated with nutritional regimens similar to those used in other forms of MSUD. Developmental delay may be present, but normal intelligence has also been documented. Dihydrolipoyl Dehydrogenase–Deficient Maple Syrup Urine Disease.  The dihydrolipoyl dehydrogenase (E3)– deficient form of MSUD is characterized by ketoacidosis crises in infancy. There is also lactic acidemia because the E3 subunit of the branched-chain α-ketoacid dehydrogenase complex is also required for catalytic function of pyruvate dehydrogenase and α-ketoglutarate dehydrogenase. In addition to the typical MSUD metabolites, urine organic acid analysis reveals the presence of lactate, pyruvate, and α-ketoglutarate. The neonatal period is usually uneventful, but progressive neurologic deterioration, characterized by developmental delay, hypotonia or hypertonia, and dystonia, supervenes. Death in early childhood is common. Attempts at therapy had limited success in early reports. However, more recent case reports and studies have identified patients with a wide clinical spectrum, with survival to at least the third decade. In some such patients, and



Aminoacidemias and Organic Acidemias

289

37

A

B

C Figure 37-3.  Maple syrup urine disease. A, Axial view, T2-weighted image shows edema in the internal capsules, lateral thalami, and globus pallidi. B, Axial view, calculated apparent diffusion coefficient image at the same level shows hypointensity, indicated by reduced water diffusion, in the affected areas. C, Proton MR spectroscopy (echo time of 26 msec) shows a large peak at 0.9 ppm, believed to represent resonances of methyl protons from branched-chain amino acids and branched-chain α-ketoacids that accumulate as a result of defective oxidative decarboxylation of leucine, isoleucine, and valine. (Courtesy of Dr. A James Barkovich, University of California, San Francisco, CA.)

290

PART VI  Genetic, Metabolic and Neurocutaneous Disorders

depending on the mutations, there is a positive clinical response to riboflavin, perhaps based on a chaperone-like effect of enzyme stabilization.

Laboratory Tests MSUD can be detected easily and accurately by tandem mass spectrometry analysis of the newborn blood spot. Plasma amino acid analysis demonstrates elevations of leucine, isoleucine, and valine (5- to 10-fold greater than normal) and the pathognomonic finding of elevated alloisoleucine. Levels of branched-chain amino acids are greatly elevated in urine and cerebrospinal fluid (CSF). The branched-chain α-ketoacids 2-oxoisocaproic acid, 2-oxo-3-methylvaleric acid, and 2oxoisovaleric acid, derived from the branched-chain amino acids leucine, isoleucine, and valine, respectively, are found to be elevated on urine organic acid analysis during metabolic crises. Branched-chain amino acids levels and excretion of branched-chain α-ketoacids may be normal between episodes of decompensation in the intermittent form of disease. The branched-chain α-ketoacid dehydrogenase complex consists of three catalytic components—a thiamine pyrophosphate-dependent carboxylase (E1) with an α2β2 structure, a transacylase (E2), and a dehydrogenase (E3)— and two regulatory enzymes (a kinase and a phosphatase). Deficient activity of this complex leads to the accumulation of leucine, isoleucine, and valine and their corresponding α-ketoacids. The decarboxylation activity can be measured in leukocytes, lymphoblasts, or fibroblasts, and it is loosely related to the clinical phenotype: 0% to 2% of normal activity in classic MSUD, 3% to 30% activity in intermediate, 5% to 20% in intermittent, 2% to 40% in thiamine-responsive, and 0% to 25% in E3 deficiency. Because significant overlap exists between measured enzyme activity and clinical phenotype, enzymatic activity cannot be used to predict the clinical course with certainty. In parallel findings on molecular analyses, identified mutations also cannot be correlated with phenotype.

Genetics MSUD is a pan-ethnic, autosomal-recessive condition that can be caused by mutations in any of the components of the mitochondrial branched-chain α-ketoacid dehydrogenase complex. In a study of 63 individuals, E1β subunit mutations were most common (38%), followed by E1α (33%), and E2 (19%) mutations. Branched-chain α-ketoacid dehydrogenase phosphatase or kinase mutations are also thought to cause MSUD. The overall incidence is approximately 1 case per 150,000 people in the general population, but MSUD is more common in Old Order Mennonites in southeastern Pennsylvania (1 in 176 births). A novel founder mutation in the E1β subunit has been reported in the Ashkenazi Jewish population.

that requires prompt intervention. Initial intervention is aimed at correcting dehydration, starting high-dose intravenous thiamine, and providing adequate calories (approximately 120-140 kcal/kg per day) to prevent further protein catabolism and higher rise in plasma leucine levels. To this end, high-dextrose intravenous fluids (to provide approximately 10 mg/kg per minute) and intralipid are often administered. Branched-chain amino acid–free parenteral nutrition or enteral formula, delivered by continuous nasogastric drip, can also be used. The rate of decrease of leucine is slowed in the face of valine and isoleucine levels inadequate to stimulate protein synthesis. Acute valine and isoleucine deficiency can be avoided by careful supplementation of these amino acids. Leucine is reintroduced to the diet after therapeutic levels are achieved. Hemodialysis and continuous venovenous extracorporeal removal therapies result in more rapid fall in plasma levels of branched-chain amino acids, and this modality is now established as an effective standard-of-care therapy for acute metabolic decompensation. Liver transplantation has been increasingly performed on large numbers of patients as an essential component of longterm therapy in classic MSUD, even in nonexigent (i.e., elective) clinical circumstances (Strauss et al., 2006). It has become apparent that as patients reach adolescence and adulthood, they show variable intellectual deficits, attention deficits, deficits in executive function, psychological symptoms (e.g., anxiety, depression), and poor social adjustment, even with a history of apparently excellent dietary control and an absence of a history of acute metabolic crises (Strauss et al., 2006). Following transplant, leucine levels either remaining normal or are in a treatment range on an unrestricted protein diet. Long-term clinical evaluations are proceeding, but neuropsychological and patient and family reporting appear to support improvement or stabilization of neurologic status. Three patients who underwent successful transplantation were able to resume normal diets and were no longer at risk for metabolic decompensation. In an important variation of the transplant protocol, domino hepatic transplantation for MSUD has been successfully performed. A novel treatment approach under investigation takes advantage of the observation that when used in the treatment of urea cycle disorders, Na phenylbutyrate causes a lowering of branched-chain amino acid levels (Burrage, Nagamani, Campeau, and Lee , 2014). Na phenylbutyrate was found to increase the activity of the branched-chain ketoacid dehydrogenase by preventing phosphorylation—and, thereby, inactivation—of the E1α subunit. The increased residual enzyme activity of the branched-chain ketoacid dehydrogenase would be expected to lower branched-chain amino acid levels. Studies are under way using Na phenylbutyrate in cohorts of MSUD patients (Burrage et al., 2014).

Treatment

Glycine Encephalopathy

Chronic care of the child with MSUD includes regular visits to an integrated metabolic clinic for medical and nutritional assessment. Adequate calories (100-120 kcal/kg per day) and protein (2-3 g/kg per day) are needed for growth. Chronic valine or isoleucine deficiency may cause an exfoliative dermatitis, and supplementation of these amino acids is often needed. Thiamine supplementation is administered to patients with thiamine-responsive forms of MSUD. Because patients on restricted diets are at risk for micronutrient and essential fatty acid deficiencies, patients should be periodically monitored for such deficits and supplementation given as needed. Acute metabolic decompensation (e.g., fasting or illness severe enough to cause catabolism) is a medical emergency

Glycine encephalopathy is an autosomal-recessive disorder caused by defective function of the glycine cleavage enzyme system, leading to accumulation of glycine in all body tissues, including the CNS (Figure 37-4). The glycine cleavage enzyme system has four components: glycine decarboxylase, also known as the P protein (it uses pyridoxal-phosphate as a cofactor); aminomethyltransferase, also known as T protein (it is a tetrahydrofolate dependent protein); the glycine cleavage system H protein (a hydrogen carrier protein); and the L protein or lipoamide dehydrogenase (the cofactor is lipoate). Infants with classic disease present in the first week of life with apnea, lethargy, severe hypotonia, and feeding difficulties. Respiratory failure, hiccups, and intractable seizures develop, and many infants die unless assisted ventilatory support is



Aminoacidemias and Organic Acidemias P

CHO  CH2COOH

P

291

CHNCH2COOH

37

NH2 S

Glycine H

S

CO2 SCH2NH2  P

H

CHO

P

CHNCH2S

HS

H HS

T SH

L

5,10CH2THF  NH3  H SH

NAD

NAD  H

Figure 37-4.  The glycine cleavage system. Circles designate proteins with the active group shown. In the presence of P and H proteins, glycine is decarboxylated, and the remaining aminoethyl group binds to the reduced lipoic acid on the H protein. T protein is required to release ammonia and transfer the x carbon of glycine to tetrahydrofolate (THF), forming 5,10-CH2-THF. The L protein is necessary to regenerate the correct form of the H protein. (From Scriver C, Beudet A, Sly W, Valle D, eds. The metabolic and molecular basis of inherited disease, 8th ed. New York: McGraw-Hill, 2001:2066, Fig, 90-2. Reprinted with permission from The McGraw-Hill Companies.)

provided. The EEG commonly has a burst suppression pattern, but hypsarrhythmia has rarely been reported. There are also later-onset forms, including presentation at greater than 4 months of age. A review of 124 patients stratified affected individuals into four categories. Those who could only smile were termed severe. Those who had achieved additional developmental milestones were termed attenuated. Three attenuated forms were delineated, poor, intermediate, and mild; these were defined as a developmental quotient (ratio of developmental age to chronologic age) of less than 20, between 20 and 50, and greater than 50, respectively. Predictors of outcome included age at seizure onset, CSF glycine value, ratio of CSF to plasma glycine, and the presence of severe brain malformations (Swanson et al., 2015). Of presenting neonates, 85% have the severe form of the disease and 15% the attenuated; the proportion for infantile onset is 50% severe and 50% attenuated. In the previously described series of 124 affected individuals, 21% died in the neonatal period, 45% had the severe form, and 34% had an attenuated form (Swanson et al., 2015). Brain imaging results are normal for about one-half of the neonatal-onset cases. Relatively common brain abnormalities include agenesis of the corpus callosum, progressive atrophy, and delayed myelination. Mild and transient forms of glycine encephalopathy have been reported. Mild forms manifest in infancy or early childhood after an uneventful pregnancy and neonatal period. Clinical features include seizures (in most cases) and relatively mild developmental delay. Transient glycine encephalopathy is characterized by the same initial clinical and biochemical findings as the classic form, but it has only rarely been reported. In the transient form, elevated CSF and plasma glycine levels partially or completely normalize, and most patients have normal development. The diagnosis of glycine encephalopathy is established by detecting an elevated CSF glycine concentration, typically 15 to 30 times normal, in association with an increased ratio of CSF to plasma glycine (normal < 0.02). Classic neonatal-onset patients often have ratios higher than 0.2, whereas atypical patients have ratios of approximately 0.09. A ratio higher than

0.08 is usually considered diagnostic of glycine encephalopathy. The plasma and CSF samples should be obtained as closely as possible to one another, and the presence of blood in the CSF invalidates the amino acid results. Other causes of increased CSF glycine levels include valproate therapy, brain trauma, and hypoxic-ischemic encephalopathy. Secondary elevations of plasma glycine, associated with ketosis, are often encountered in organic acidemias (e.g., methylmalonic, propionic, and isovaleric acidemias and β-ketothiolase deficiency; these are the ketotic hyperglycinemias). Because pyridoxine-dependent epilepsy, pyridoxamine 5’-phosphate oxidase deficiency, and cerebral folate deficiency may have presentations similar to that of glycine encephalopathy, concentrations of alpha-aminoadipic semialdehyde, pyridoxal 5’-phosphate, and 5-methyltetrahydrofolate should also be assessed in the CSF. Urine S-sulfocysteine should be sent to test for isolated sulfite oxidase deficiency and molybdenum cofactor deficiency, which may also present with intractable seizures in the newborn period. Confirmation of the diagnosis may be accomplished by assaying the glycine cleavage system in liver tissue, although, in practice, molecular testing of the genes encoding glycine cleavage system subunits is less invasive and more widely available, and the enzyme defect may be secondary, as described in the following discussion. Comprehensive mutation analysis in 68 families with glycine encephalopathy detected GLDC (P protein gene) or AMT (T protein gene) mutations in 68% of neonatal and 60% of infantile types, respectively. No GCSH (H protein gene) mutations were identified. Strikingly, evaluation of patients with abnormal glycine cleavage activity in liver, but without mutations in genes encoding the enzymes of the glycine cleavage system, were identified to have defects in mitochondrial lipoate synthesis]. These defects include those in enzymes involved in lipoate synthesis and transfer and those in iron-sulfur cluster biogenesis because lipoate synthase is a protein that contains ironsulfur clusters. Importantly, individuals with lipoate synthase defects, sometimes also referred to as variant or atypical glycine encephalopathy, have varied biochemical and clinical

292

PART VI  Genetic, Metabolic and Neurocutaneous Disorders

presentations. It is important to be aware of these classes of defects and the biochemical and phenotypic overlap of lipoate synthesis defects, which include iron-sulfur cluster biogenesis defects, with glycine encephalopathy. Treatment of glycine encephalopathy has not improved the overall dismal prognosis in the classic form of disease. Therapy is focused on controlling seizures with antiepileptic drugs, decreasing tissue glycine levels, and administering N-methylD-aspartate (NMDA) receptor antagonists to diminish glycineinduced neuronal excitotoxicity. Valproate is contraindicated because it can inhibit the glycine cleavage enzyme system and can cause hyperglycinemia in patients without glycine encephalopathy. Sodium benzoate is given because of its ability to conjugate to glycine to form hippurate, which can then be excreted in the urine. A glycine-specific mitochondrial enzyme, benzoyl-coenzyme A (CoA):glycine acyltransferase, catalyzes the condensation of benzoate and glycine to form hippurate. Sodium benzoate therapy can reduce plasma levels of glycine to the normal range and may have a mild effect on CSF glycine levels, but it does not affect the very poor prognosis. Because high-dose sodium benzoate therapy can result in carnitine deficiency, plasma carnitine levels should be monitored closely and appropriate supplementation provided. Dextromethorphan, an antagonist of the NMDA receptor, is also commonly used in therapy. Treatment with dextromethorphan may lead to improved seizure control and level of interaction in some patients. Rarely, ketamine has been used, but it may provide benefit in controlling seizures and improving overall level of interaction. A low-protein diet has no proven efficacy and may result in severe protein malnutrition, micronutrient deficiency, and exfoliative dermatitis if not monitored carefully.

Sulfur Amino Acid Metabolism and the Homocystinurias See the online version of the chapter.

Hartnup’s Disease See the online version of the chapter.

Histidinemia See the online version of the chapter.

ORGANIC ACIDEMIAS Propionic Acidemia See the online version of the chapter.

Methylmalonic Acidemias Multiple genetic defects can lead to methylmalonic acidemia, alone or in combination with elevated homocysteine because both compounds are processed by enzymes that require B12. B12 is acquired through dietary sources and must be appropriately transported and modified to participate in methylmalonic acid and homocysteine metabolism. The isolated methylmalonic acidemias and those in combination with elevated homocysteine are caused by deficiencies in the transport or modification of vitamin B12 (cobalamin) or by mutations in enzymes requiring a B12 cofactor, in addition to several other mechanisms, such as a transcription factor defect that causes combined methylmalonic acidemia and homocystinuria (see Figure 37-6A and B). Because there are a variety of causative defects, this group of conditions has significant

clinical heterogeneity and differences in response to therapy. Incidence is estimated at 1 case per 50,000 persons, or greater.

Pathophysiology The canonical inherited isolated methylmalonic acidemias are caused by defects in the enzyme methylmalonyl-CoA mutase, which requires an adenosylcobalamin cofactor, or in the enzymes that modify B12 to adenosylcobalamin. The latter cases are sometimes denoted by the genetic complementation group because the causative genes were identified over time; these are cblA, cblB, and cblD-MMA. Isolated methylmalonic acidemia can also be caused by a defect in methylmalonylCoA epimerase (encoded by the MCEE gene), which converts D-methylmalonyl-CoA to L-methylmalonyl-CoA; in methylmalonate semialdehyde dehydrogenase (ALDH6A1); in a disorder of mitochondrial energy metabolism, succinyl-CoA synthase deficiency (SUCLA2, SUCLG1); and in association with mutations in ACSF3, in which malonic acid may also be elevated (Pupavac et al., 2016). Elevations of both methylmalonic acid and homocysteine are caused by defects in other genes encoding enzymes, transport proteins, and receptors that affect cobalamin trafficking and modification and can also be caused by dietary deficiency of B12 (Pupavac et al., 2016). Methylmalonyl-CoA is derived from propionyl-CoA; both are intermediates in the catabolism of isoleucine, valine, threonine, methionine, thymine, uracil, cholesterol, and odd-chain fatty acids. Methylmalonyl-CoA mutase converts L-methylmalonyl-CoA to succinyl-CoA, which then enters the tricarboxylic acid cycle. The major causes of isolated methylmalonic acidemia are mutase deficiency (mut0, mut–), cblA, and cblB. CblD-MMA (formerly described as cblH) is also a cause of isolated methylmalonic acidemia but is more rare. Mutase activity is completely and partially abolished in the mut0 and mut– groups, respectively. CblC, cblD-combined, cblF (LMBRD1), and cblJ (ABCD4) are associated with elevations of both methylmalonic acid and homocysteine, as is cblX, an X-linked defect in HCFC1, a transcription factor that affects expression of the gene defective in cblC disease, MMACHC. Defective adenosylcobalamin synthesis is responsible for cblA, cblB, and cblDMMA. CblC and cblD-combined, cblF, and cblJ cause methylmalonic acidemia and homocystinuria because of their effects on both adenosylcobalamin and methylcobalamin biosynthesis (Figure 37-6A and B). CblE (MTRR), cblG (MTR), and cblD-HC affect methylcobalamin synthesis and therefore homocysteine metabolism alone.

Clinical Manifestations As with propionic acidemia and other disorders, there are early- and late-onset forms, which likely result, in part, from residual protein function. There is significant variability in presentation of the methylmalonic acidemias, depending on the particular underlying defect. Common features of the canonical isolated methylmalonic acidemias are failure to thrive, developmental delay, megaloblastic anemia, and neurologic dysfunction. Mut0, cblA, and cblB patients often present in the first days to weeks of life with poor feeding, dehydration, increasing lethargy, emesis, and hypotonia. Metabolic acidosis and secondary hyperammonemia, as with propionic acidemia, may be catastrophic. Mild mut– or other forms of methylmalonic acidemia may present later in infancy or in childhood with hypoglycemia, acidosis, seizures, and lethargy. A patient with cblC disease can present early in infancy with signs and symptoms of metabolic decompensation, in later childhood, or in adulthood with myopathy, lower-extremity paresthesias, and thrombosis as a result of elevated plasma homocysteine. Other features of cblC



Aminoacidemias and Organic Acidemias

293

37

Cell mem bran e

Extracellular space

Biotin

Protein synthesis CH3 CH

CH3

CH3 CH

COOH CH3

CH

CH2

NH2

CH3 CH

COOH

CH3

CH

CH2

NH2

Valine

CH

COOH

Cytosol

NH2

Isoleucine

Leucine

Leucineisoleucinemia

Valinemia

(Dietary form) C N Protein

O Proteolytic degradation

2-Ketoisovaleric acid Maple syrup urine disease

Biocytin

2-Keto-3-methylvaleric acid

Thiamine B1 Thiamine B1

Isobutyryl-CoA

2-Methylbutyryl-CoA

Methacrylyl-CoA

Thiamine B1 Isovaleryl-CoA Isovaleric acidemia

Tiglyl-CoA

3-Methylcrotonyl-CoA

to

so

l

Biotinidase deficiency

2-Ketoisocaproic acid

Maple syrup urine disease

Cy

CO2

3-Hydroxyisobutyryl-CoA 2-Methyl-3-hydroxybutyryl-CoA 3–MethylcrotonylCoA carboxylase deficiency

Methylmalonyl-CoA semialdehyde

Biotin

D-Methylmalonyl-CoA

L-Methylmalonyl-CoA Methylmalonic acidemia

Adenosyl CbI

Succinyl-CoA

3-Methylglutaconic aciduria

Propionyl-CoA Odd-chain fatty acids Threonine Methionine Methylcitric acidCholesterol

Propionic acidemia

Biotin

2-Methylacetoacetyl-CoA 3-Methylglutaconyl-CoA β-Ketothiolase deficiency

CO2

CO2

3-Hydroxyisovaleric acid

3-Hydroxy-3-methylglutaryl-CoA 3-Hydroxy-3methylglutaric aciduria

Acetoacetic acid + Acetyl-CoA cbIB MMA

CbI1

cbIA

CbI2

cbIG CbI2 cbID

CO2 H2O

cbIE

cbIC

OHC3bl Cytosol

Homocysteine

MMA HCU

cbI

F

Acetone Mitochondria

Methyl Cbl

OHC3bl

MM HC A U

Cell membrane

Methionine

Homocystin uria-II

MMA

TCII OHCbl TCII

Lysosome

Extracellular space OHC3bl TCII

A Figure 37-6.  A, Pathways in the metabolism of the branched-chain amino acids, biotin, and vitamin B12 (cobalamin).

294

PART VI  Genetic, Metabolic and Neurocutaneous Disorders

Mitochondrion

(S or R)-MMSA

Valine Isoleucine Methionine Threonine Odd chain fatty acids Cholesterol

MMA semialdehyde dehydrogenase ALDH6A1 Krebs cycle Propionyl-CoA

MMA

SuccinateCoA llgase SUCLA2, SUCLG1

D-Methylmalonyl-CoA

CMAMMA ACSF3 Malonate

mut0 mut MUT

Epimerase MCEE

Succinate

AdoCbl

L-Methylmalonyl-CoA Malonyl-CoA

Succinyl-CoA

cblB MMAB

cblA MMAA

Cbl+2

Lysosome

TCblR CD320

cblD-MMA MMADHC

cblX HCFC1

OH-Cbl

cblF LMBRD1

TCll TCblR

cblJ ABCD4

cblD combined MMADHC

cblC MMACHC R•Cbl+3

Cbl+2

Cbl+2

R

cblD-HC MMADHC cblE MTRR

R OH-Cbl TC TCN2

Cytoplasm

Blood

cblG MTR Homocysteine

MeCbl

Methionine

B Figure 37-6, cont’d  B, Updated depiction of cobalamin metabolism. Cbl, cobalamin; cbl, defect in metabolism of cobalamin; HCU, homocystinuria; MMA, methylmalonic acidemia; OHCbl, hydroxocobalamin; TC, transcobalamin. (A, From Rezvani I. Defects in metabolism of amino acids. In: Behrman R, Kliegman R, Jenson H, eds. Nelson textbook of pediatrics, 16th ed. Philadelphia: WB Saunders, 2000:355. B, With permission from Pagon RA, Adam MP, Ardinger HH, et al., (eds), Isolated Methylmalonic Acidemi, GeneReviews®, Copyright © 1993-2016, University of Washington, Seattle. All rights reserved, www.genereviews.org.)

disease include hemolytic-uremic syndrome, cardiomyopathy, subacute combined degeneration of the cord, and psychiatric manifestations such as psychosis. Children with cblC disease can have ocular abnormalities, including optic atrophy, and progressive pigmentary retinopathy with resultant nystagmus, strabismus, and worsening vision (Fischer et al., 2014). They may also exhibit hydrocephalus and microcephaly. Cranial imaging may reveal pathology of the basal ganglia and white matter. The two initial cases reported with cblD presented in later childhood with mental retardation and behavioral problems, although subsequent reports have documented infantile onset with hypotonia and seizures and early childhood presentations with ataxia and gait abnormalities. CblF patients have been reported to have minor facial anomalies and hematologic defects. Transcobalamin II deficiency, a B12 transport deficiency, can manifest as failure to thrive in the first months of life, with neurologic disease, hematologic disease, and mental retardation. A benign form of methylmalonic acidemia has been reported in otherwise healthy children; some of these may be caused by mutations in the genes encoding mutase, those encoding epimerase, or in ACSF3. There are also reports of individuals with mutations in the receptor for

transcobalamin bound to cobalamin (TCblR); this may be a benign condition.

Laboratory Tests Methylmalonic acidemia can clinically resemble other organic acidemias, necessitating analysis of urine organic acids for diagnosis. Elevated C3 (propionyl) acylcarnitine identifies methylmalonic acidemia, propionic acidemia, and B12 deficiency; therefore, urine organic acid analysis is required after an abnormal newborn screen with elevated C3 acylcarnitine. As with propionic acidemia, some cases are not identified through newborn screening, and some infants will develop clinical symptoms before the newborn screen results are available. Therefore if there is a clinical concern, testing for an organic aciduria should be performed. Ketosis and hyperammonemia are common in the acute neonatal presentation of these conditions, and if these are present, urine organic acids and other biochemical tests should be performed. Urine organic acid analysis reveals large amounts of methylmalonic acid, methylcitrate, propionic acid, and 3-hydroxypropionic acid in mutase deficiency and cblA and cblB disease. Serum



Aminoacidemias and Organic Acidemias

amino acids sometimes demonstrate elevation of glycine. When elevated serum or urine methylmalonic acid is identified, it is critical to obtain a total plasma homocysteine as a specific test to assess for defects that cause elevations of both compounds because elevated homocysteine may not be detected through plasma amino acid analysis. Serum B12 levels must be assessed to ensure that elevated methylmalonic acid and homocysteine levels, if present, are not the result of a nutritional deficiency of cobalamin. Total plasma homocysteine levels are elevated in cblC, cblD-combined, cblF, cblJ, and CblX diseases. Total and free carnitine levels tend to be low. The cobalamin transport deficiencies are assessed by measuring serum cobalamin levels and absorption by the Schilling test, in addition to DNA testing (Pupavac et al., 2016). Determination of the form of methylmalonic acidemia was often performed through complementation studies in fibroblasts, but this does not identify all causes (Pupavac et al., 2016). DNA mutation analysis is now the appropriate first test. One next-generation sequencing panel includes 24 genes associated with elevated methylmalonic acid (Pupavac et al., 2016).

3-Methylcrotonyl-CoA Carboxylase Deficiency

Treatment

See the online version of the chapter.

Guidelines for acute and chronic management of methylmalonic acidemia have been developed (Baumgartner et al., 2014). The principles of management are similar to those for propionic acidemia. One critical difference is that some forms of methylmalonic acidemia are responsive to vitamin B12, and hydroxocobalamin (preferred) or cyanocobalamin should be given empirically to a child presenting with hyperammonemia and ketosis. If methylmalonic acidemia is identified, intramuscular or subcutaneous hydroxocobalamin should be continued if the child appears to have a form that is responsive to B12 (cblA, mut–), which can be difficult to assess. During acute metabolic crises, treatment of known methylmalonic acidemia is directed toward stopping catabolism and restricting protein intake. The usual protein intake is stopped for 12 to 24 hours from last intake, and fat and glucose are given orally or intravenously. Chronic and acute therapy include carnitine; intramuscular, subcutaneous, or intravenous hydroxocobalamin; and metronidazole or neomycin to decrease intestinal propionate production in some cases. Betaine and folate are used if homocysteine is elevated. Treatment of hyperammonemia, which can be marked in the initial presentation, is similar to that for propionic acidemia (Baumgartner et al., 2014). Improved growth and enhanced nutritional status are seen in patients with methylmalonic acidemia fed an elemental medical food. Patients should consume a diet low in the macronutrient precursors proximal to the metabolic block and receive adequate calories and total protein to enable growth. Plasma methylmalonic acid levels are followed for metabolic control. Frequent complications in methylmalonic acidemia include tubulointerstitial nephritis, leading to end-stage renal disease, and basal ganglia stroke, often affecting the globus pallidus. Cardiomyopathy is reported but is less common than in propionic acidemia (Baumgartner et al., 2014). Liver transplantation has been performed but is not curative of the disease. It protects against recurrent metabolic crises but not against metabolic stroke, and it does not lead to a complete clinical or biochemical correction because the pathway is active in other tissues. Kidney transplant, often performed for renal failure, may also protect against metabolic decompensation (Baumgartner et al., 2014), although this is still unclear.

Isovaleric Acidemia See the online version of the chapter.

295

See the online version of the chapter.

Biotinidase Deficiency See the online version of the chapter.

Holocarboxylase Synthetase Deficiency See the online version of the chapter.

3-Methylglutaconic Aciduria See the online version of the chapter.

Beta-Ketothiolase Deficiency See the online version of the chapter.

Canavan’s Disease Glutaric Aciduria Type I In 1975, glutaric acidemia and aciduria were described in siblings with a neurodegenerative disorder beginning in infancy and characterized by opisthotonus, dystonia, and athetosis. Glutaric acidemia type I, also known as glutaryl-CoA dehydrogenase deficiency, is an autosomal-recessive condition caused by deficiency of glutaryl-CoA dehydrogenase and has an estimated prevalence of approximately 1 case per 100,000 persons. In the United States glutaric acidemia type I is relatively common in the Old Order Amish. Glutaric acidemia type II is also known as multiple acyl-CoA dehydrogenase deficiency (MADD) and is associated with defects in mitochondrial electron transfer flavoprotein or electron transfer flavoprotein dehydrogenase; it is discussed further in Chapter 37. Glutaric aciduria type III is not associated with clinical symptoms and is the result of a deficiency of the enzyme that converts glutarate to glutaryl-CoA. Glutaryl-CoA dehydrogenase is a key enzyme in the degradation pathway of lysine, hydroxylysine, and tryptophan. Deficiency results in accumulation of glutarate and, to a lesser extent, of 3-hydroxyglutarate and glutaconate in body tissues, blood, CSF, and urine (Hedlund, Longo, and Pasquali, 2006). The classic symptom of glutaric acidemia type I (GAI) is irreversible focal striatal necrosis during an acute illness, most often between the ages of 3 and 18 months. Such an event is termed an encephalopathic crisis. Sequelae of the acute injury to the basal ganglia include irreversible disabling dystonia and, in some cases, dyskinesia, in addition to shortened life expectancy (Kolker et al., 2006). Crucially, newborn screening has changed the natural history of this condition. The combined use of chronic management and emergency management in the treatment of individuals identified presymptomatically greatly reduces neurologic injury (Hedlund et al., 2006; Kolker et al., 2006). Macrocephaly is a feature of GAI and may not be present at birth, but head growth velocity is increased; in some cases progressive macrocephaly has led to the identification of GAI before striatal injury (Kolker et al., 2006). Intraretinal hemorrhages and subdural hematomata caused by the rupture of bridging veins associated with macrocephaly may be present and may be mistaken for nonaccidental injury; this can also lead to the identification of affected individuals before striatal injury. In some cases, striatal injury is not associated with an identified encephalopathic crisis but is insidious, with gradual appearance of symptoms. Systemic manifestations typical of

37

296

PART VI  Genetic, Metabolic and Neurocutaneous Disorders

many other organic acidemias, such as pronounced metabolic ketoacidosis, hypoglycemia, and hyperammonemia, generally do not occur (Hedlund et al., 2006). There is a window of neurologic susceptibility to striatal damage during the first years of life. A seminal natural history study of 279 individuals in 37 countries demonstrated that 95% of encephalopathic crises occurred before 2 years of age and that additional basal ganglia injury occurred up to roughly 6 years of age but not beyond (Kolker et al., 2006). Crucially, individuals who are identified presymptomatically and treated according to established guidelines may avoid the devastating neurologic injury in the vulnerable period (Kolker et al., 2006). A late-onset leukodystrophy has been described, and the natural history of this manifestation is unknown. A characteristic early brain MRI finding is symmetric widening of the sylvian fissure with poor operculization (“bat wing” appearance) caused by frontotemporal atrophy or hypoplasia (Figure 37-8). Other features include basal ganglia injury, subdural hematomata, ventriculomegaly, and delayed myelination (Hedlund et al., 2006). Diffusion-weighted imaging may be more sensitive in demonstrating brain lesions than CT or MRI. Urine organic acid analysis often documents highly elevated glutaric acid and lesser elevations of 3-hydroxyglutarate and glutaconate, but some children with a classic neurologic phenotype have low or undetectable levels of these metabolites (so-called low excretors). Newborn screening using tandem mass spectrometry has the potential for presymptomatic detection of GAI, although the existence of a low-excretor phenotype can result in missed cases. Roughly one-third of affected individuals have a low excretor phenotype, which is associated with residual enzyme activity of up to 30%. Crucially, these individuals are at no less risk of severe neurologic injury (Kolker et al., 2006). Increased glutarate and 3-hydroxyglutarate levels in the CNS may induce an imbalance in glutamatergic and GABAergic neurotransmission by inhibiting glutamate decarboxylase, the key enzyme in gamma-aminobutyric acid (GABA) synthesis,

A

or through direct damage to striatal GABAergic neurons. 3-Hydroxyglutarate may mimic the excitatory neurotransmitter glutamate and thereby cause excitotoxic cell damage mediated through activation of NMDA receptors. Glutarate was shown to inhibit synaptosomal uptake of glutamic acid and produce striatal lesions when injected directly into the brain of a rat. Other potential contributors to neurotoxicity include cytokine-induced cell damage, mitochondrial dysfunction, increased production of reactive oxygen species, and production of toxic quinolinic acid, an intermediate in tryptophan metabolism in the brain. Other reports have emphasized the relatively weak neurotoxicity of glutarate and 3-hydroxyglutarate in animal models and primary neuronal cell cultures. The pathogenesis of striatal necrosis and brain lesions in GAI remains the subject of intensive investigation. Animal models may help resolve these conflicting results. Presymptomatic treatment of GAI includes restriction of dietary lysine intake, carnitine, and sometimes riboflavin; supplementation; and rapid intervention in times of intercurrent illness (Kolker et al., 2006). This therapy is continued in symptomatic patients, who also require symptom management, which includes anticholinergic drugs such as trihexyphenidyl and botulinum toxin to treat generalized or focal dystonia resulting from striatal injury. Stereotactic pallidotomy has been performed, as has deep brain stimulation.

5-Oxoprolinuria See the online version of the chapter.

Isobutyryl-CoA Dehydrogenase Deficiency See the online version of the chapter.

3-Hydroxyisobutyric Aciduria See the online version of the chapter.

B

Figure 37-8.  Magnetic resonance imaging (MRI) in glutaric acidemia. A, Axial view, T2-weighted image shows markedly enlarged sylvian fissures bilaterally and abnormal hyperintensity of the central tegmental tract. B, Axial view, T2-weighted image at a slightly higher level shows abnormal hyperintensity of the lentiform nuclei bilaterally. (Courtesy of Dr. A James Barkovich, University of California, San Francisco.)



2-Methylbutyryl-CoA Dehydrogenase Deficiency See the online version of the chapter.

Mevalonate Kinase Deficiency See the online version of the chapter. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. REFERENCES Baumgartner, M.R., Horster, F., Dionisi-Vici, C., et al., 2014. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet J. Rare Dis. 9, 130. Burrage, L., Nagamani, S., Campeau, P., et al., 2014. Branched-chain amino acid metabolism: from rare Mendelian diseases to more common disorders. Hum. Mol. Genet. 25, R1R8. Enns, G.M., Koch, R., Brumm, V., et al., 2010. Suboptimal outcomes in patients with PKU treated early with diet alone: revisiting the evidence. Mol. Genet. Metab. 101, 99. Fischer, S., Huemer, M., Baumgartner, M., et al., 2014. Clinical presentation and outcome in a series of 88 patients with the cblC defect. J. Inherit. Metab. Dis. 37, 831–840. Hedlund, G.L., Longo, N., Pasquali, M., 2006. Glutaric Acidemia Type 1. Am. J. Med. Genet. C Semin. Med. Genet. 142C (2), 86–94.

Aminoacidemias and Organic Acidemias

297

Klee, D., Thimm, E., Wittsack, H.J., et al., 2013. Structuralwhite matter changes in adolescents and yound adults with maple syrup urine disease. J. Inher. Metab. Dis. 36, 945–953. Kolker, S., Garbade, S.F., Greenberg, C.R., et al., 2006. Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency. Pediatr. Res. 59, 840–847. Pupavac, M., Tian, X., Chu, J., et al., 2016. Added value of next generation gene panel analysis for patients with elevated methylmalonic acid and no clinical diagnosis following functional studies of vitamin B12 metabolism. Mol. Genet. Metab. 117, 363–368. Strauss, K., Mazariegos, G., Sindhi, R., et al., 2006. Elective liver transplantation for the treatment of classical maple syrup urine disease. Am. J. Transplant. 6, 557–564. Swanson, M.A., Coughlin, C.R., Scharer, G.H., et al., 2015. Biochemical and Molecular Predictors for Prognosis in Nonketotic Hyperglycinemia. Ann. Neurol. 78, 606–618.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 37-2 The tyrosine metabolic pathway. Fig. 37-5 Abbreviated diagram for the transsulfuration pathway. Fig. 37-7 Patient with Canavan’s disease.

37