- Email: [email protected]
Diagnostic work-up in acute conditions of inborn errors of metabolism and storage diseases
Handbook of Clinical Neurology, Vol. 113 (3rd series) Pediatric Neurology Part III O. Dulac, M. Lassonde, and H.B. Sarnat, Editors © 2013 Elsevier B.V. All rights reserved
Chapter 160
Diagnostic work-up in acute conditions of inborn errors of metabolism and storage diseases VASSILI VALAYANNOPOULOS1* AND BWEE TIEN POLL-THE2 Reference Center for Inherited Metabolic Disease of Children and Adults, Hoˆpital Universitaire Necker-Enfants Malades, Paris, France
1
2
Department of Pediatric Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
INTRODUCTION Inborn errors of metabolism may present with acute neurological symptoms at any age. However, especially in neonates and infants these conditions may be acute, and, if untreated, may lead to permanent cerebral lesions or to death (Saudubray et al., 2002; Leonard and Morris, 2006). Knowledge of the main signs and symptoms of these conditions may be lifesaving, especially for conditions that are treatable. Several clinical situations can be distinguished. From the pathophysiological perspective, inborn errors of metabolism can be divided in three groups: (1) disorders causing an “intoxication;” (2) disorders impairing energy production; and (3) disorders involving complex molecules. From the clinical perspective, four distinct circumstances may be encountered: (1) acute symptoms in the neonatal period and early infancy (<1 year); (2) lateonset acute and recurrent attacks; (3) chronic and progressive (nonspecific) symptoms; and (4) specific and permanent organ symptoms suggestive of an inborn error of metabolism.
ACUTE SYMPTOMS IN THE NEONATAL PERIOD AND EARLY INFANCY (<1 YEAR) Coma, hypotonia, and seizures are the major clinical expressions of metabolic distress in the newborn. The occurrence of lethargy or coma in a neonate after a free interval where the neonate appears to be normal is characteristic of “intoxication” disorders. Muscle tone
changes and involuntary movements are important diagnostic hallmarks. Such conditions result from: Aminoacidopathies: the clinical hallmark of maple syrup urine disease, the most common of these conditions, is coma associated with abnormal movements described as “boxing” or “pedaling” movements of the four limbs. Usually the neonate has a distinctive body and urine odor of maple syrup or burned sugar. Organic acidurias (methylmalonic, propionic, isovaleric). Axial hypotonia contrasts with limb hypertonia associated with slow limb elevation, tremor, and involuntary movements of short amplitude. Superficial polypnea due to acidosis is common. In isovaleric acidemia, a sweaty-feet odor is usually present. Urea cycle disorders. Axial hypotonia contrasts with limb hypertonia. However, there are usually no abnormal movements. Hepatomegaly may be present indicating hepatic dysfunction. Ketolysis defects may display similar signs to organic acidurias, or mimic neonatal diabetes mellitus, due to the accumulation of massive amounts of ketone bodies and organic acids deriving from branched-chain amino acids. In the absence of a specific treatment, all the above conditions may produce brain edema with increased intracranial pressure and seizures leading to death. Coma with global hypotonia associated with specific organ symptoms (heart, liver, muscle, kidney) is characteristic of “energy deficiency” disorders. Lactic acidosis causing polypnea or symptoms related to brainstem dysfunction may occur (tachycardia or bradycardia, body temperature changes, respiratory irregularities). This group comprises: (1) respiratory chain defects;
*Correspondence to: Dr Vassili Valayannopoulos, Centre de Re´fe´rence des Maladies He´re´ditaires du Me´tabolisme de l’Enfant et de l’Adulte, Necker-Enfants Malades Hospital, 149 rue de Sevres, 75743 Paris Cedex 15, France. Tel: þ33-1-44-49-48-52/þ33-1-44-4948-58, Fax: þ33144494850, E-mail: [email protected]
1554
V. VALAYANNOPOULOS AND B.T. POLL-THE
(2) pyruvate metabolism defects: pyruvate dehydrogenase and pyruvate carboxylase deficiencies, neonatal (“French”) type. Coma may be associated with specific symptoms or organ manifestations: ●
●
Coma with hypoglycemia may result from: (1) hyperinsulinism: hypoglycemia may occur independently of feeding or fasting and even in patients receiving intravenous glucose; (2) glycogen storage diseases: hypoglycemia occurs in the fasting state and in most cases there is an enlarged liver; (3) gluconeogenesis defects: hypoglycemia occurs in the fasting state, transient liver enlargement may be found during hypoglycemic episodes; (4) fatty acid b-oxidation defects: hypoglycemia occurs after prolonged fasting usually associated with other organ failure or impairment (liver, muscle, heart and kidney); (5) ketogenesis defects: the clinical presentation is similar to fatty acid oxidation defects. Coma with hepatic involvement may result from: (1) fatty acid b-oxidation defects; (2) urea cycle disorders; (3) respiratory chain disorders (Clayton, 2002).
Even though hypotonia is a common symptom in sick neonates and a hallmark of severe neuromuscular disorders, isolated severe hypotonia can be encountered in a few inborn errors of metabolism. The latter include amino acid metabolism disorders, energy deficiency disorders, peroxisomal disorders, lysosomal storage disease, and congenital disorders of glycosylation. Amino acid disorders mainly consist of nonketotic hyperglycinemia and sulfite oxidase deficiency. Nonketotic hyperglycinemia causes global hypotonia associated with impaired consciousness and myoclonic jerks. Severe encephalopathy with epilepsy may occur. In the severe form of sulfite oxidase deficiency, hypotonia and seizures, mainly consisting of myoclonus, are the clinical hallmarks. Energy deficiency disorders consist of respiratory chain disorders, pyruvate dehydrogenase and pyruvate carboxylase deficiencies, and fatty acid b-oxidation defects. Peroxisomal disorders consist of defects either of single or multiple peroxisomal enzymes, or of peroxisomal biogenesis that are responsible for neonatal hypotonia associated with seizures, hepatomegaly, and dysmorphic features (high forehead, large fontanel, short limbs). The main lysosomal storage disorder presenting with muscular hypotonia is acid maltase deficiency or Pompe disease; the disease presents with hypotonia (in general during the first months of life) associated with progressive hypertrophic cardiomyopathy. Congenital disorders of glycosylation combine in neonates generalized hypotonia associated with strabismus, hyporeflexia, and dysmorphic features.
Seizures may occur in several inherited metabolic disorders where they may constitute an important revealing manifestation (De Vivo, 2002; Prietsch et al., 2002; BahiBuisson et al., 2006). The range of metabolic disorders that cause seizures in the neonatal period is very large. It includes all causes of hypoglycemia, vitaminresponsive conditions, aminoacidopathies, peroxisomal and lysosomal defects, neurotransmitter disorders, and congenital disorders of glycosylation, namely those involving O-glycosylation defects. Vitamin-responsive seizures mainly consist of B6-responsive seizures due to antiquitin deficiency, pyridoxamine phosphate oxidase deficiency responding to pyridoxal phosphate, and folinic acid-responsive seizures (for which the molecular basis is not completely elucidated even though some patients with antiquitin deficiency may respond to folinic acid). Among aminoacidopathies, nonketotic hyperglycinemia, sulfite oxidase deficiency, and serine synthesis defects are the most epileptogenic. In the latter, severe congenital (or in some cases acquired) microcephaly associated with early spasticity and dystonia are characteristic. Lysosomal disorders that cause seizures are mainly infantile neuronal ceroid lipofuscinoses.
Metabolic derangement and diagnostic tests In most metabolic disorders presenting with coma, the clinical presentation, along with a few simple biochemical tests, may orient the diagnosis (Saudubray et al., 2002; Leonard and Morris, 2006). These include: acid– base balance (pH and bicarbonate), glucose in plasma and cerebrospinal fluid (CSF), ammonia and lactate in plasma, and ketone bodies in urine (urine dipstick). Body odor may be a diagnostic clue in maple syrup urine disease and in isovaleric aciduria, as mentioned above. Ketosis detected in urine by a dipstick is always abnormal in a newborn and a possible sign of metabolic disease. Dinitrophenylhydrazine is a specific solution detecting the presence of a-keto acids such as seen in maple syrup urine disease. From a practical viewpoint, measurement of blood gases, electrolytes, ammonia, lactate, and glucose, and the search for ketone bodies and for a-keto acids with dinitrophenylhydrazine in urine permit an initial diagnostic orientation. Several major types of metabolic disorders presenting with neurological distress may be distinguished: Neurological distress without acidosis, mild ketosis, normal or mildly elevated ammonia, normal lactate, normal glucose. The dinitrophenylhydrazine test is positive. This association is characteristic of maple syrup urine disease.
DIAGNOSTIC WORK-UP IN ACUTE CONDITIONS OF INBORN ERRORS OF METABOLISM Neurological distress with severe ketoacidosis, hyperammonemia, hyperlactatemia and variable glucose levels (normal, hyper- or hypoglycemia) is highly suggestive of organic acidurias (methylmalonic, propionic, and isovaleric acidemias). The same findings without hyperammonemia are characteristic of ketolysis defects; when associated with hyperglycemia this condition may mimic neonatal diabetes mellitus. Neurological distress with lactic acidosis, mild or no ketosis, normal or mildly elevated ammonia, and variable glucose levels is suggestive of “energy deficiency” disorders responsible for congenital lactic acidosis: pyruvate dehydrogenase or carboxylase deficiencies, or respiratory chain deficiency. Neurological distress with severe hyperammonemia, no acidosis but alkalosis, no ketosis, normal or mildly elevated lactate, and normal glucose often corresponds to urea cycle disorders. Liver dysfunction may occur secondarily. Neurological distress with predominant hypoglycemia and hepatomegaly, liver dysfunction (liver enzyme elevation and/or hepatic failure), no ketosis, mild hyperammonemia, and mild hyperlactatemia is suggestive of fatty acid oxidation defects. Other visceral signs such as cardiac failure or heartbeat disorders and renal failure may occur. Neurological distress with severe hypotonia, seizures, myoclonic jerks, or abnormal head circumference presence or absence of dysmorphic features, and virtually no secondary biochemical abnormalities is usually caused by nonketotic hyperglycinemia or sulfite oxidase deficiency, pyridoxine and pyridoxal-phosphate responsive seizures, peroxisomal defects or neurotransmitter disorders. The electroencephalogram (EEG) shows nonspecific encephalopathic changes, often progressing to a burst-suppression pattern indicative of severe diffuse encephalopathy. Besides the five metabolic screening tests (blood gases and electrolytes, ammonia, lactate, glucose, and urinary ketones), specific tests should then be performed in order to identify the impaired metabolic pathway: Amino acid chromatogram is performed in plasma, urine, and CSF for aminoacidopathies. It may identify the accumulation of amino acids (e.g., leucine in maple syrup urine disease, glycine in nonketotic hyperglycinemia, sulfocysteine in sulfite oxidase deficiency) or display a suggestive profile for urea cycle disorders. Analyses of organic acid in urine and amino acids in plasma indicate a diagnosis of organic acidurias or ketolysis defects. Acylcarnitine analysis in plasma may allow the physician to establish a diagnosis of fatty acid b-oxidation defects or organic acidurias by finding a diagnostic elevation of specific acylcarnitines.
1555
Lactate and pyruvate in blood and CSF, and ketone bodies’ ratio (b-hydroxybutyrate, acetoacetate, and the b-hydroxybutyrate/acetoacetate ratio) may be important diagnostic clues for pyruvate dehydrogenase deficiency (high lactate and pyruvate with normal lactate/pyruvate – L/P ratio < 15), pyruvate carboxylase deficiency (high lactate and pyruvate ratio with high L/P ratio but low b-hydroxybutyrate/acetoacetate ratio), or respiratory chain deficiency (high lactate and pyruvate ratio with high L/P ratio and high b-hydroxybutyrate/acetoacetate ratio). Specific organelle biomarkers may be studied for peroxisomal disorders (long-chain fatty acids, phytanic acid, pristanic acid, plasmalogens, bile acids, and pipecolic acid) or for congenital glycosylation deficiencies (western blot of glycosylated proteins or isoelectrofocalization of transferrin). In neonatal seizures, neurotransmitters in CSF and specific markers of B6-responsive seizures such as pipecolic acid and a-aminoadipic semialdehyde should be studied. For all the disorders mentioned above, specific enzyme measurement or molecular analysis will confirm the diagnosis. In urea cycle disorders or respiratory chain deficiencies tissue analysis (liver, muscle, fibroblasts) is often required for enzyme measurement (e.g., urea cycle enzymes or respiratory chain enzymatic complexes I–V). When one of these disorders is suspected, tissue sample biopsy should be considered, especially for neonates with a fatal course. Also, a blood sample for DNA extraction and storage should be performed systematically. Table 160.1 summarizes the neurological and simple biochemical patterns in inborn errors of metabolism during the neonatal period and early infancy.
LATE-ONSET ACUTE AND RECURRENT ATTACKS (BEYOND THE FIRST YEAR OF LIFE, INCLUDING ADOLESCENCE) In 50% of patients presenting with inborn errors of intermediary metabolism, disease onset occurs after the first year of life, during childhood, adolescence, or even adulthood (Saudubray et al., 2006). Each attack may result either in spontaneous improvement or in death despite supportive measures. Notably, the patient may be asymptomatic between two attacks. Onset of symptoms may be triggered by fever, minor infection, excessive fasting or excessive protein intake, or may occur without any apparent cause.
Coma without focal signs As in the neonate, disorders of intermediary metabolism result from organic acidurias, including ketolysis defects, maple syrup urine disease, and respiratory chain deficiency
Table 160.1 Neurological and simple biochemical patterns in inborn errors of metabolism during the neonatal period and early infancy (<1 year) Leading symptoms
Disorder
Other features
Diagnostic tests
Neurological distress HyperNH3: mild or 0 Acidosis: 0 Ketosis: þ or 0 Lactate: N Glycemia: N, low Liver enzymes: N
Maple syrup urine disease
Distinctive odor of urine (maple syrup, curry) Boxing or pedaling
Amino acid chromatography: high branched-chain amino acids
Neurological distress, dehydration, polypnea HyperNH3: þ or þþ Acidosis: þþþ Ketosis: þþþ Lactate: þ Glycemia: high, N, low Liver enzymes: N
Organic acidurias propionic, methylmalonic, isovaleryic acidurias Ketolysis defects
Abnormal movements “Sweaty feet” odor in isovaleric aciduria Peripheral hypertonia May mimic neonatal diabetes when hyperglycemia with glycosuria/ketonuria
Organic acid chromatography: Ketonuria Accumulation of the corresponding organic acids
Neurological distress, liver or cardiac symptoms HyperNH3: þ Acidosis: þ or N Ketosis: Lactate: þ or þþ Glycemia: low Liver enzymes: abnormal
Fatty acid oxidation defects (or ketogenesis defects)
“Energy deficiency” may involve heart, muscle, liver, kidney
Organic acid chromatography: accumulation of dicarboxylic acids Acylcarnitines: low free carnitine, elevation of corresponding acylcarnitines
Neurological distress HyperNH3: 0 Acidosis: þþ Ketosis: þ or 0 Lactate: þþþ Glycemia: high, N, low Liver enzymes: N, abnormal
Congenital lactic acidosis: pyruvate carboxylase, pyruvate dehydrogenase, respiratory chain deficiencies
Global hypotonia Respiratory distress
Lactate/pyruvate ratio: high in pyruvate carboxylase and respiratory chain, N in pyruvate dehydrogenase) 3-hydroxybutyrate/acetoacetate ratio: >1 in respiratory chain, pyruvate dehydrogenase; <1 in pyruvate carboxylase
Neurological distress, liver involvement HyperNH3: þþþ Acidosis: 0 or þ Ketosis: 0 or þ Lactate: þþ Glycemia: N, low Liver enzymes: abnormal
Congenital hyper NH3: urea cycle disorders
Axial hypotonia Peripheral hypertonia
Amino acid chromatography: high glutamine Mitochondrial defects ¼ low citrulline Ornithine-carbamyl transferase deficiency ¼ high orotic acid Cytosolic defects: elevation of specific amino acids
Neurological distress, hypotonia, seizures, myoclonic jerks HyperNH3: 0 Acidosis: 0 Ketosis: 0 Lactate: 0 Glycemia: N
Nonketotic hyperglycinemia Sulfite oxidase deficiency B6 and pyridoxal phosphate-responsive epilepsy Neurotransmitter disorders Peroxisomal disorders Congenital deficiency of glycosylation syndrome
EEG: suppression-burst pattern Dysmorphic features
Amino acid chromatography in plasma and CSF (glycine) Amino acid chromatography: sulfocysteine aminoadipic semialdehyde in urine, CSF pipecolic acid 5-HIAA, HVA, pterins in CSF VLCFA, plasmalogens, pipecholic acid, biliary acids Transferrin western blot
CSF, cerebrospinal fluid; 5-HIAA, 5-hydroxy-indolacetic acid; HVA, homovanillic acid; N, normal; NH3, ammonia; VLCFA, very long chain fatty acids; 0, absence; þ, present; þþ, high; þþþ, very high.
DIAGNOSTIC WORK-UP IN ACUTE CONDITIONS OF INBORN ERRORS OF METABOLISM presenting with metabolic acidosis and ketosis and often associated with or preceded by vomiting; urea cycle disorders when hyperammonemia is the predominant biological hallmark; fatty acid b-oxidation defect and ketogenesis defects (HMGCoA-lyase deficiency), gluconeogenesis defects when hypoglycemia is the presenting sign; energy deficiency disorders such as pyruvate kinase, pyruvate dehydrogenase, Krebs cycle defects or multiple carboxylase deficiency when hyperlactatemia is the presenting feature (in the absence of hypoglycemia), or fatty acid b-oxidation defect and gluconeogenesis defects when associated with hypoglycemia.
1557
and due to a-galactosidase deficiency). “Stroke-like” episodes (clinical presentation of stroke contrasting with focal ischemic pattern on brain computed tomography (CT) or magnetic resonance imaging (MRI) scans not corresponding to a specific vascular territory) may be seen during the disease course or be inaugural in (Testai and Gorelick, 2010a, b): congenital disorders of glycosylation, urea cycle disorders, respiratory chain defects, pyruvate dehydrogenase deficiency, maple syrup urine disease, and organic acidurias.
Recurrent ataxia Coma with focal neurological signs, strokes, seizures, or increased intracranial pressure Coma associated with hemiplegia and cerebral edema may be seen in urea cycle disorders (ornithine transcarbamylase or ornithine-carbamyl transferase deficiency), organic acidurias (methylmalonyl acidemia, propionic aciduria) and maple syrup urine disease. When extrapyramidal signs are associated, methylmalonyl acidemia, glutaric aciduria type I (associated with macrocephaly), Wilson’s disease (a copper transporter deficiency, ATP7B) and homocystinuria should be considered.
Hepatic coma Acute encephalopathy associated with liver dysfunction and hyperammonemia (Reye-like syndrome) may be due to urea cycle disorders or fatty acid b-oxidation defects. When associated with hyperlactatemia, respiratory chain deficiency may be suspected (especially DNA depletion syndromes such as POLG or DGUOK defects). If associated with cirrhosis, tyrosinemia type I is suspected even though encephalopathy is rare in this condition. The diagnosis of these disorders may be established as discussed previously. Glutaric aciduria type I can be diagnosed through organic acid chromatography and plasma acylcarnitine profile, homocystinuria by amino acid chromatography in plasma and urine, Wilson’s disease by measuring copper in plasma and urine, and plasma ceruloplasmin. Tyrosinemia type I may be diagnosed by succinyl acetone in urine (organic acid).
Stroke (or stroke-like) Several inborn errors of metabolism may be responsible for stroke due to a vascular disease (Testai and Gorelick, 2010a, b): homocystinuria by cystathione b-synthase deficiency and hyperhomocysteinemia by methylene tetrahydrofolate reductase deficiency, Fabry disease (an X-linked lysosomal disorder affecting predominantly males even though females may be affected
Intermittent acute ataxia can be the presenting sign of intermediary metabolism defects such as maple syrup urine disease (late-onset), organic acidurias, urea cycle disorders and “energy deficiency” disorders such as pyruvate dehydrogenase deficiency and respiratory chain defect (Garcia-Cazorla et al., 2009). Hartnup disease manifests during infancy with variable clinical presentations: failure to thrive, photosensitivity, intermittent ataxia, nystagmus, and tremor. Hartnup disease is a disorder of amino acid transport in the intestine and kidneys due to mutations in SLC6A19; the symptoms mainly affect the brain (headache, ataxia) and skin (rash). They may be triggered by sunlight, fever, drugs, or stress. Urinary amino acid analysis permits screening for this disorder.
Extrapyramidal signs (or movement disorders) Energy deficiency disorders may present with intermittent extrapyramidal signs (Garcia-Cazorla et al., 2009; Gouider-Khouja et al., 2009): pyruvate dehydrogenase deficiency, respiratory chain disorders, and GLUT1 deficiency. In the latter, the defect in GLUT1, a brain glucose transporter, results in a reduction of glucose supply in the central nervous system (CNS); glucose plasma/CSF ratio is low (<0.40). Molecular analysis confirms the diagnosis. Biotin-responsive basal ganglia disease also belongs to this group. It associates acute dystonia with basal ganglia involvement and a good clinical response to high doses of biotin. The molecular defect was identified and concerns SLC19A3, a thiamin transporter. In other disorders including glutaric aciduria type I, late-onset nonketotic hyperglycinema and Wilson’s disease, dystonia occurs more progressively and does not regress. Neurotransmitter defects such as monoamine synthesis defects may also account for abnormal movements occurring progressively and may be screened through CSF analysis.
1558
V. VALAYANNOPOULOS AND B.T. POLL-THE
Leigh syndrome Leigh syndrome is an early-onset progressive neurodegenerative disorder with characteristic neuropathology consisting of focal bilateral lesions in one or more areas of the central nervous system, including the brainstem, thalamus, basal ganglia, cerebellum, and spinal cord, that can be identified by brain MRI. Clinical symptoms depend on which areas of the central nervous system are involved and include impaired consciousness, extrapyramidal syndrome, and signs related to brainstem dysfunction (breathing irregularities, heart rhythm disorders) Finsterer, 2008. The most common underlying cause is a defect in energy production in the brain. Inborn errors of metabolism presenting with Leigh syndrome include: pyruvate dehydrogenase deficiency, glutaric aciduria type I, respiratory chain disorders, pyruvate carboxylase deficiency, organic acidurias, and sulfite oxidase deficiency; biotinidase deficiency resulting from biotin deficiency, a coenzyme of carboxylases (pyruvate carboxylase, propionyl CoA carboxylase, acetyl CoA carboxylase) associated with high lactate and in some cases treatable by biotin administration; fumarase deficiency: a Krebs cycle enzyme associated to excretion of high amounts of fumarate in urine; ethylmalonic acid 1 encephalopathy, which is characterized by ethylmalonic and methylsuccinic aciduria and lactic acidemia associated with developmental delay, acrocyanosis, petechiae, and chronic diarrhea. ETHE1 is a gene coding for a mitochondrial dioxygenase; loss of function of this gene causes fatal sulfide toxicity; 3-methylglutaconic aciduria type I (3-MGA-I): this entity must be distinguished from other conditions such as X-linked Barth syndrome (cardiomyopathy, neutropenia), Costeff syndrome (optic atrophy), and respiratory chain deficiency, where elevated excretion of 3-methylglutaconic acid may occur. 3-MGA-I presenting with encephalopathy and basal ganglia involvement is characterized by urinary excretion of 3-MGC and 3-methylglutaric acids due to 3-MGC-CoA hydratase deficiency.
Neuropsychiatric or behavioral manifestations Inborn errors of metabolism may present as psychiatric disorders in childhood and adolescence (Sedel et al., 2007). In some instances, an inborn error of metabolism is suspected because of a positive family history or because psychiatric symptoms form part of a more diffuse clinical picture with systemic and hard neurological signs. However, in some cases, psychiatric disturbance may be the only, or at least the predominant, sign of disease for years. Acute psychiatric symptoms may be encountered in late-onset urea cycle disorders, especially in ornithine
carbamyl transferase deficiency mimicking encephalitis. If untreated this condition may lead to coma and death. Hyperammonemia is the biological hallmark. Acute intermittent porphyria and hereditary coproporphyria may present with recurrent vomiting, acute abdominal pain, neuropathy and psychiatric symptoms. “Port wine urine” is characteristic. Specific measurement of porphyrins in urine confirms the diagnosis. Wilson disease associates psychiatric problems, extrapyramidal signs, liver dysfunction, and Kayser–Fleischer rings. The diagnostic hallmarks are mentioned above. Homocysteine metabolism defects (homocystinuria, MTHFR deficiency) may present with schizophrenialike episodes that are folate responsive. Homocysteine detection in urine suggests the diagnosis. In succinic semialdehyde dehydrogenase deficiency the most frequent clinical features include developmental delay of motor, mental, and language skills, hypotonia, seizures, hyporeflexia, ataxia, behavioral problems. Psychosis with visual hallucinations may be seen in older patients. Excretion of 4-hydroxybutyric acid in urine detected by organic acid analysis suggests this diagnosis; it can be confirmed by enzymatic and molecular analysis.
Muscular manifestations Acute muscular symptoms include muscular pain and rhabdomyolysis. Inborn errors of metabolism presenting as an acute myopathy are commonly the result of defects in energy metabolism (Olpin, 2005). These can present as an acute intermittent muscle weakness, exercise intolerance with cramps and myoglobinuria. The most frequent conditions actually observed are mitochondrial respiratory chain and fatty acid oxidation defects, muscular glycogenolysis defects and mutations in LPIN1 gene. In respiratory chain deficiencies, muscle biopsy may display histological abnormalities (such as ragged-red fibers) and specific enzymatic defects of respiratory chain complexes. Fatty acid oxidation defects can be screened by acylcarnitines, where glycogenolysis defects require specific enzyme analysis screened in lymphocytes or in muscle tissue and LPIN1 mutations by molecular studies with a frequent intragenic deletion accounting for about half of all known caucasian patients (Michot et al., 2010). Table 160.2 summarizes inborn errors of metabolism associated with late-onset recurrent comas, ataxia, and psychiatric signs.
TREATMENT APPROACHES As soon as the diagnosis of a metabolic disorder is suspected, emergency management has to be started (Leonard and Morris, 2006; Saudubray et al., 2006). Immediate contact should be made with an expert metabolic
DIAGNOSTIC WORK-UP IN ACUTE CONDITIONS OF INBORN ERRORS OF METABOLISM
1559
Table 160.2 Late-onset (late infancy to adulthood) recurrent comas, ataxia, psychiatric signs Metabolic coma without focal neurological signs, or acute ataxia with lethargy
Metabolic acidosis/ ketosis
HyperNH3 Hypoglycemia Hyperlactacidemia Neurological coma with focal signs, seizures, or intracranial hypertension
Cerebral edema Extrapyramidal signs (dystonia, Parkinson) Stroke and “stroke-like”
Leigh syndrome
Hepatic coma Elevated liver enzymes Reye syndrome Psychiatric symptoms, hallucinations, delirium
Muscular signs (rhabdomyolysis) Hyperammonemia Hyperlactatemia Jaundice Hyperammonemia Ketoacidosis Hyperhomocysteinemia Port wine urine
Multiple carboxylase deficiency, organic acidurias, maple syrup urine disease, ketolysis, ketogenesis defects, fatty acid b-oxidation defects Fructose bisphosphatase deficiency, pyruvate dehydrogenase deficiency Urea cycle disorders, triple H, lysinuric protein intolerance Fatty acid b-oxidation defects, HMGCoA lyase deficiency Gluconeogenesis defects, glycogen synthetase deficiency HMGCoA lyase/synthetase deficiency, fatty acid b-oxidation defects Multiple carboxylase deficiency, pyruvate dehydrogenase deficiency Gluconeogenesis defects, fatty acid b-oxidation defects Maple syrup urine disease, ornithine-carbamyl transferase deficiency, organic acidurias Glutaric aciduria type I, methylmalonic aciduria Wilson disease, homocystinuria, late-onset nonketotic hyperglycinemia Biotin-responsive basal ganglia disease Homocystinurias, Fabry disease Urea cycle defect, organic acidurias, respiratory chain deficiency, pyruvate dehydrogenase deficiency, maple syrup urine disease Glutaric aciduria 1, organic acidurias, respiratory chain deficiency, pyruvate dehydrogenase deficiency, sulfite oxidase deficiency, biotinidase deficiency, fumarase deficiency, ethylmalonyl encephalopathy 1, 3MGA Fatty acid b-oxidation defects, respiratory chain deficiency LPIN1 mutations Fatty acid b-oxidation defects, urea cycle defect Fatty acid b-oxidation defects, respiratory chain deficiency (mtDNA depletion syndromes) Wilson disease Urea cycle defect (ornithine-carbamyl transferase), lysinuric protein intolerance Organic acid disorders Methyltetrahydrofolate reductase deficiency, CblC deficiency Acute intermittent porphyria Hereditary coproporphyria Wilson disease Succinic semialdehyde dehydrogenase deficiency
center to guide the treatment or to organize an emergency transfer. Emergency treatments should be available (see list in Table 160.3). Intoxication disorders are treated by an emergency diet with high caloric intake and no protein given enterally or by infusion. Specific amino acid mixtures may be required in order to enhance anabolism (for instance in maple syrup urine disease). Ammonia scavengers such as sodium benzoate or phenylbutyrate may be used. In the most severe cases, renal replacement therapy may be required (congenital hyperammonemias and maple syrup urine disease). Vitamins and cofactors such as Lcarnitine, L-glycine, biotin, cobalamin (B12) should be included in the treatment. In all conditions presenting with hypoglycemia an intravenous infusion with sufficient
glucose supply (4–10 mg/kg/minute according to age) should be given. L-carnitine should be added if a fatty acid b-oxidation defect is suspected. In congenital lactic acidosis, high levels of glucose should be avoided and lipid intake should be preferred. Vitamin B1 (thiamin) and biotin are cofactors of pyruvate dehydrogenase and carboxylase deficiencies, respectively. In respiratory chain deficiency, cofactors such as vitamins B1, B2, biotin, coenzyme Q10 may be useful, and arginine may also be helpful (Koga et al., 2010). In neonatal seizures, vitamin B6 (pyridoxine), pyridoxal phosphate, and folinic acid may dramatically improve the clinical course. Table 160.3 summarizes emergency medications and common doses used in the treatment of inborn errors of metabolism.
Table 160.3 Medications used in the emergency treatment of inherited metabolic disorders Medication
Mode of action
Disorders
Recommended dose
Route
Remarks
Biotin
Cofactor for carboxylases
Biotinidase deficiency
5–20 mg/day
Oral or intravenous
Glycine
Forms isovalerylglycine with high renal clearance Cofactor for methylmalonyl mutase
Isovaleric acidemia
150 mg/kg per day in three divided doses 1 mg intramuscularly daily; oral dose 10 mg once or twice daily 50–170 mg/kg (Ornithine carbamyl transferase and carbamoyl phosphate synthase deficiency) up to 700 mg/kg in AL and argininosuccinate synthase deficiency) 100–200 mg/kg per day
Oral
Multiple carboxylase deficiency Treatment of presumed transporter defect Biotin-responsive basal ganglia disease Up to 600 mg/kg per day during decompensation Dose may be reduced to once or twice weekly according to response
Hydroxycobalamin (vitamin B12)
Disorders of cobalamin metabolism
L-Arginine
Replenishes arginine; substrate of nitrous oxide
L-Carnitine
Primary and secondary Replenishes body stores; carnitine deficiencies removes toxic acyl-CoA intermediates from within the mitochondria Replenishes citrulline and Used as an alternative to arginine arginine in carbamoyl phosphate synthase deficiency and orithine carbamyl transferase deficiency
L-Citrulline
N-Carbamoylglutamate NTBC (2-(2-nitro-4trifluoromethylbenzoyl)1,3-cyclohexanedione) (nitisinone)
Stimulates N-acetylglutamate synthase Inhibits 4hydroxyphenylpyruvate dioxygenase
Urea cycle disorders; mitochondrial encephalopathy, lactic acidosis and stroke-like episodes
N-Acetylglutamate synthase deficiency Tyrosinemia type I
Intramuscular or oral
Oral or intravenous
Oral or intravenous
Carbamoyl phosphate Oral synthase and ornithine carbamyl transferase deficiency:170 mg/kg per day or 3.8 g/m2/day in divided doses, lysinuric protein intolerance: 100 mg/ kg per day in 3–5 doses 100–250 mg/kg per day in four Oral divided doses 1–2 mg/kg in 1–2 divided Oral doses
Combine with low-tyrosine, low-phenylalanine diet
Continued
Table 160.3 Continued Medication
Mode of action
Disorders
Pyridoxine
Cofactor
Pyridoxal phosphate
Active cofactor
Riboflavin
Coenzyme glutaric aciduria I
Sodium benzoate
Combines with glycine to form hippuric acid which has high renal clearance
50–500 mg per day Pyridoxine-responsive Pyridoxine dependency homocystinuria by with seizures: 100 mg cystathionine b-synthase intravenously with EEG deficiency; pyridoxine monitoring or 30 mg/kg per dependency with seizures; day for 7 days (maintenance type I 5–10 mg per day) Pyridox(am)ine 5-P oxidase 40 mg/kg per day in four deficiency divided doses 100 mg per day in 2–3 divided Mild variants of electron doses transfer flavoprotein/ electron transfer flavoprotein dehydrogenase and shortchain acyl-CoA dehydrogenase; congenital lactic acidosis (complex I deficiency) Hyperammonemia 250–500 mg per day in divided doses or by continuous intravenous infusion
Sodium phenylbutyrate
Converted to phenylacetate, which combines with glutamine to form phenylglutamine which has high renal clearance Cofactor
Thiamin
Hyperammonemia
Recommended dose
250–500 mg/kg per day; maximum dose 20 g/day
Thiamin-responsive variants 10–50 mg per day of maple syrup urine disease, pyruvate dehydrogenase deficiency and complex I deficiency
Route
Remarks
Oral or intravenous
Peripheral neuropathy can occur with doses > 1000 mg daily
Oral Oral
Oral or intravenous Intravenous loading dose: 250 mg/kg over 90 minutes Oral
Removes N2 to ammonia and reduces blood ammonia Dose may be doubled if severe hyperammonemia
Oral
Oral doses of up to 300 mg have been used in congenital lactic acidosis; 500–2000 mg per day in thiamin-responsive pyruvate dehydrogenase?
1562
V. VALAYANNOPOULOS AND B.T. POLL-THE
CONCLUSION Progress in the treatment of inborn errors of metabolism has been slower than progress towards insight into the many aspects of the metabolic and molecular bases of inborn errors of metabolism. Nevertheless, outcomes are improving, with prevention, earlier diagnosis, and appropriate management, the use of dialysis and drugs to promote the removal of toxic metabolites, and measures to keep catabolism to a minimum. Early intervention is crucial when neurological sequelae could be avoided, which requires constant vigilance and routine measurement of diagnostic biochemical markers in suspected cases.
REFERENCES Bahi-Buisson N, Mention K, Leger PL et al. (2006). Neonatal epilepsy and inborn errors of metabolism. Arch Pediatr 13: 284–292. Clayton PT (2002). Inborn errors presenting with liver dysfunction. Semin Neonatol 7: 49–63. De Vivo DC (2002). Inherited metabolic disorders and seizures in infancy. J Child Neurol 17: 3S1–3S2. Finsterer J (2008). Leigh and Leigh-like syndrome in children and adults. Pediatr Neurol 39: 223–235. Garcia-Cazorla A, Wolf NI, Serrano M et al. (2009). Inborn errors of metabolism and motor disturbances in children. J Inherit Metab Dis 32: 618–629. Gouider-Khouja N, Kraoua I, Benrhouma H et al. (2009). Movement disorders in neuro-metabolic diseases. Eur J Paediatr Neurol 14: 304–307.
Koga Y, Povalko N, Nishioka J et al. (2010). MELAS and L-arginine therapy: pathophysiology of stroke-like episodes. Ann N Y Acad Sci 1201: 104–110. Leonard JV, Morris AA (2006). Diagnosis and early management of inborn errors of metabolism presenting around the time of birth. Acta Paediatr 95: 6–14. Michot C, Hubert L, Brivet M et al. (2010). LPIN1 gene mutations: a major cause of severe rhabdomyolysis in early childhood. Hum Mutat 31: E1564–73. Olpin SE (2005). Fatty acid oxidation defects as a cause of neuromyopathic disease in infants and adults. Clin Lab 51: 289–306. Prietsch V, Lindner M, Zschocke J et al. (2002). Emergency management of inherited metabolic diseases. J Inherit Metab Dis 25: 531–546. Saudubray JM, Nassogne MC, de Lonlay P et al. (2002). Clinical approach to inherited metabolic disorders in neonates: an overview. Semin Neonatol 7: 3–15. Saudubray JM, Sedel F, Walter JH (2006). Clinical approach to treatable inborn metabolic diseases: an introduction. J Inherit Metab Dis 29: 261–274. Sedel F, Baumann N, Turpin JC et al. (2007). Psychiatric manifestations revealing inborn errors of metabolism in adolescents and adults. J Inherit Metab Dis 30: 631–641. Testai FD, Gorelick PB (2010a). Inherited metabolic disorders and stroke, part 2: homocystinuria, organic acidurias, and urea cycle disorders. Arch Neurol 67: 148–153. Testai FD, Gorelick PB (2010b). Inherited metabolic disorders and stroke, part 1: Fabry disease and mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. Arch Neurol 67: 19–24.
Chapter 160
Diagnostic work-up in acute conditions of inborn errors of metabolism and storage diseases VASSILI VALAYANNOPOULOS1* AND BWEE TIEN POLL-THE2 Reference Center for Inherited Metabolic Disease of Children and Adults, Hoˆpital Universitaire Necker-Enfants Malades, Paris, France
1
2
Department of Pediatric Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
INTRODUCTION Inborn errors of metabolism may present with acute neurological symptoms at any age. However, especially in neonates and infants these conditions may be acute, and, if untreated, may lead to permanent cerebral lesions or to death (Saudubray et al., 2002; Leonard and Morris, 2006). Knowledge of the main signs and symptoms of these conditions may be lifesaving, especially for conditions that are treatable. Several clinical situations can be distinguished. From the pathophysiological perspective, inborn errors of metabolism can be divided in three groups: (1) disorders causing an “intoxication;” (2) disorders impairing energy production; and (3) disorders involving complex molecules. From the clinical perspective, four distinct circumstances may be encountered: (1) acute symptoms in the neonatal period and early infancy (<1 year); (2) lateonset acute and recurrent attacks; (3) chronic and progressive (nonspecific) symptoms; and (4) specific and permanent organ symptoms suggestive of an inborn error of metabolism.
ACUTE SYMPTOMS IN THE NEONATAL PERIOD AND EARLY INFANCY (<1 YEAR) Coma, hypotonia, and seizures are the major clinical expressions of metabolic distress in the newborn. The occurrence of lethargy or coma in a neonate after a free interval where the neonate appears to be normal is characteristic of “intoxication” disorders. Muscle tone
changes and involuntary movements are important diagnostic hallmarks. Such conditions result from: Aminoacidopathies: the clinical hallmark of maple syrup urine disease, the most common of these conditions, is coma associated with abnormal movements described as “boxing” or “pedaling” movements of the four limbs. Usually the neonate has a distinctive body and urine odor of maple syrup or burned sugar. Organic acidurias (methylmalonic, propionic, isovaleric). Axial hypotonia contrasts with limb hypertonia associated with slow limb elevation, tremor, and involuntary movements of short amplitude. Superficial polypnea due to acidosis is common. In isovaleric acidemia, a sweaty-feet odor is usually present. Urea cycle disorders. Axial hypotonia contrasts with limb hypertonia. However, there are usually no abnormal movements. Hepatomegaly may be present indicating hepatic dysfunction. Ketolysis defects may display similar signs to organic acidurias, or mimic neonatal diabetes mellitus, due to the accumulation of massive amounts of ketone bodies and organic acids deriving from branched-chain amino acids. In the absence of a specific treatment, all the above conditions may produce brain edema with increased intracranial pressure and seizures leading to death. Coma with global hypotonia associated with specific organ symptoms (heart, liver, muscle, kidney) is characteristic of “energy deficiency” disorders. Lactic acidosis causing polypnea or symptoms related to brainstem dysfunction may occur (tachycardia or bradycardia, body temperature changes, respiratory irregularities). This group comprises: (1) respiratory chain defects;
*Correspondence to: Dr Vassili Valayannopoulos, Centre de Re´fe´rence des Maladies He´re´ditaires du Me´tabolisme de l’Enfant et de l’Adulte, Necker-Enfants Malades Hospital, 149 rue de Sevres, 75743 Paris Cedex 15, France. Tel: þ33-1-44-49-48-52/þ33-1-44-4948-58, Fax: þ33144494850, E-mail: [email protected]
1554
V. VALAYANNOPOULOS AND B.T. POLL-THE
(2) pyruvate metabolism defects: pyruvate dehydrogenase and pyruvate carboxylase deficiencies, neonatal (“French”) type. Coma may be associated with specific symptoms or organ manifestations: ●
●
Coma with hypoglycemia may result from: (1) hyperinsulinism: hypoglycemia may occur independently of feeding or fasting and even in patients receiving intravenous glucose; (2) glycogen storage diseases: hypoglycemia occurs in the fasting state and in most cases there is an enlarged liver; (3) gluconeogenesis defects: hypoglycemia occurs in the fasting state, transient liver enlargement may be found during hypoglycemic episodes; (4) fatty acid b-oxidation defects: hypoglycemia occurs after prolonged fasting usually associated with other organ failure or impairment (liver, muscle, heart and kidney); (5) ketogenesis defects: the clinical presentation is similar to fatty acid oxidation defects. Coma with hepatic involvement may result from: (1) fatty acid b-oxidation defects; (2) urea cycle disorders; (3) respiratory chain disorders (Clayton, 2002).
Even though hypotonia is a common symptom in sick neonates and a hallmark of severe neuromuscular disorders, isolated severe hypotonia can be encountered in a few inborn errors of metabolism. The latter include amino acid metabolism disorders, energy deficiency disorders, peroxisomal disorders, lysosomal storage disease, and congenital disorders of glycosylation. Amino acid disorders mainly consist of nonketotic hyperglycinemia and sulfite oxidase deficiency. Nonketotic hyperglycinemia causes global hypotonia associated with impaired consciousness and myoclonic jerks. Severe encephalopathy with epilepsy may occur. In the severe form of sulfite oxidase deficiency, hypotonia and seizures, mainly consisting of myoclonus, are the clinical hallmarks. Energy deficiency disorders consist of respiratory chain disorders, pyruvate dehydrogenase and pyruvate carboxylase deficiencies, and fatty acid b-oxidation defects. Peroxisomal disorders consist of defects either of single or multiple peroxisomal enzymes, or of peroxisomal biogenesis that are responsible for neonatal hypotonia associated with seizures, hepatomegaly, and dysmorphic features (high forehead, large fontanel, short limbs). The main lysosomal storage disorder presenting with muscular hypotonia is acid maltase deficiency or Pompe disease; the disease presents with hypotonia (in general during the first months of life) associated with progressive hypertrophic cardiomyopathy. Congenital disorders of glycosylation combine in neonates generalized hypotonia associated with strabismus, hyporeflexia, and dysmorphic features.
Seizures may occur in several inherited metabolic disorders where they may constitute an important revealing manifestation (De Vivo, 2002; Prietsch et al., 2002; BahiBuisson et al., 2006). The range of metabolic disorders that cause seizures in the neonatal period is very large. It includes all causes of hypoglycemia, vitaminresponsive conditions, aminoacidopathies, peroxisomal and lysosomal defects, neurotransmitter disorders, and congenital disorders of glycosylation, namely those involving O-glycosylation defects. Vitamin-responsive seizures mainly consist of B6-responsive seizures due to antiquitin deficiency, pyridoxamine phosphate oxidase deficiency responding to pyridoxal phosphate, and folinic acid-responsive seizures (for which the molecular basis is not completely elucidated even though some patients with antiquitin deficiency may respond to folinic acid). Among aminoacidopathies, nonketotic hyperglycinemia, sulfite oxidase deficiency, and serine synthesis defects are the most epileptogenic. In the latter, severe congenital (or in some cases acquired) microcephaly associated with early spasticity and dystonia are characteristic. Lysosomal disorders that cause seizures are mainly infantile neuronal ceroid lipofuscinoses.
Metabolic derangement and diagnostic tests In most metabolic disorders presenting with coma, the clinical presentation, along with a few simple biochemical tests, may orient the diagnosis (Saudubray et al., 2002; Leonard and Morris, 2006). These include: acid– base balance (pH and bicarbonate), glucose in plasma and cerebrospinal fluid (CSF), ammonia and lactate in plasma, and ketone bodies in urine (urine dipstick). Body odor may be a diagnostic clue in maple syrup urine disease and in isovaleric aciduria, as mentioned above. Ketosis detected in urine by a dipstick is always abnormal in a newborn and a possible sign of metabolic disease. Dinitrophenylhydrazine is a specific solution detecting the presence of a-keto acids such as seen in maple syrup urine disease. From a practical viewpoint, measurement of blood gases, electrolytes, ammonia, lactate, and glucose, and the search for ketone bodies and for a-keto acids with dinitrophenylhydrazine in urine permit an initial diagnostic orientation. Several major types of metabolic disorders presenting with neurological distress may be distinguished: Neurological distress without acidosis, mild ketosis, normal or mildly elevated ammonia, normal lactate, normal glucose. The dinitrophenylhydrazine test is positive. This association is characteristic of maple syrup urine disease.
DIAGNOSTIC WORK-UP IN ACUTE CONDITIONS OF INBORN ERRORS OF METABOLISM Neurological distress with severe ketoacidosis, hyperammonemia, hyperlactatemia and variable glucose levels (normal, hyper- or hypoglycemia) is highly suggestive of organic acidurias (methylmalonic, propionic, and isovaleric acidemias). The same findings without hyperammonemia are characteristic of ketolysis defects; when associated with hyperglycemia this condition may mimic neonatal diabetes mellitus. Neurological distress with lactic acidosis, mild or no ketosis, normal or mildly elevated ammonia, and variable glucose levels is suggestive of “energy deficiency” disorders responsible for congenital lactic acidosis: pyruvate dehydrogenase or carboxylase deficiencies, or respiratory chain deficiency. Neurological distress with severe hyperammonemia, no acidosis but alkalosis, no ketosis, normal or mildly elevated lactate, and normal glucose often corresponds to urea cycle disorders. Liver dysfunction may occur secondarily. Neurological distress with predominant hypoglycemia and hepatomegaly, liver dysfunction (liver enzyme elevation and/or hepatic failure), no ketosis, mild hyperammonemia, and mild hyperlactatemia is suggestive of fatty acid oxidation defects. Other visceral signs such as cardiac failure or heartbeat disorders and renal failure may occur. Neurological distress with severe hypotonia, seizures, myoclonic jerks, or abnormal head circumference presence or absence of dysmorphic features, and virtually no secondary biochemical abnormalities is usually caused by nonketotic hyperglycinemia or sulfite oxidase deficiency, pyridoxine and pyridoxal-phosphate responsive seizures, peroxisomal defects or neurotransmitter disorders. The electroencephalogram (EEG) shows nonspecific encephalopathic changes, often progressing to a burst-suppression pattern indicative of severe diffuse encephalopathy. Besides the five metabolic screening tests (blood gases and electrolytes, ammonia, lactate, glucose, and urinary ketones), specific tests should then be performed in order to identify the impaired metabolic pathway: Amino acid chromatogram is performed in plasma, urine, and CSF for aminoacidopathies. It may identify the accumulation of amino acids (e.g., leucine in maple syrup urine disease, glycine in nonketotic hyperglycinemia, sulfocysteine in sulfite oxidase deficiency) or display a suggestive profile for urea cycle disorders. Analyses of organic acid in urine and amino acids in plasma indicate a diagnosis of organic acidurias or ketolysis defects. Acylcarnitine analysis in plasma may allow the physician to establish a diagnosis of fatty acid b-oxidation defects or organic acidurias by finding a diagnostic elevation of specific acylcarnitines.
1555
Lactate and pyruvate in blood and CSF, and ketone bodies’ ratio (b-hydroxybutyrate, acetoacetate, and the b-hydroxybutyrate/acetoacetate ratio) may be important diagnostic clues for pyruvate dehydrogenase deficiency (high lactate and pyruvate with normal lactate/pyruvate – L/P ratio < 15), pyruvate carboxylase deficiency (high lactate and pyruvate ratio with high L/P ratio but low b-hydroxybutyrate/acetoacetate ratio), or respiratory chain deficiency (high lactate and pyruvate ratio with high L/P ratio and high b-hydroxybutyrate/acetoacetate ratio). Specific organelle biomarkers may be studied for peroxisomal disorders (long-chain fatty acids, phytanic acid, pristanic acid, plasmalogens, bile acids, and pipecolic acid) or for congenital glycosylation deficiencies (western blot of glycosylated proteins or isoelectrofocalization of transferrin). In neonatal seizures, neurotransmitters in CSF and specific markers of B6-responsive seizures such as pipecolic acid and a-aminoadipic semialdehyde should be studied. For all the disorders mentioned above, specific enzyme measurement or molecular analysis will confirm the diagnosis. In urea cycle disorders or respiratory chain deficiencies tissue analysis (liver, muscle, fibroblasts) is often required for enzyme measurement (e.g., urea cycle enzymes or respiratory chain enzymatic complexes I–V). When one of these disorders is suspected, tissue sample biopsy should be considered, especially for neonates with a fatal course. Also, a blood sample for DNA extraction and storage should be performed systematically. Table 160.1 summarizes the neurological and simple biochemical patterns in inborn errors of metabolism during the neonatal period and early infancy.
LATE-ONSET ACUTE AND RECURRENT ATTACKS (BEYOND THE FIRST YEAR OF LIFE, INCLUDING ADOLESCENCE) In 50% of patients presenting with inborn errors of intermediary metabolism, disease onset occurs after the first year of life, during childhood, adolescence, or even adulthood (Saudubray et al., 2006). Each attack may result either in spontaneous improvement or in death despite supportive measures. Notably, the patient may be asymptomatic between two attacks. Onset of symptoms may be triggered by fever, minor infection, excessive fasting or excessive protein intake, or may occur without any apparent cause.
Coma without focal signs As in the neonate, disorders of intermediary metabolism result from organic acidurias, including ketolysis defects, maple syrup urine disease, and respiratory chain deficiency
Table 160.1 Neurological and simple biochemical patterns in inborn errors of metabolism during the neonatal period and early infancy (<1 year) Leading symptoms
Disorder
Other features
Diagnostic tests
Neurological distress HyperNH3: mild or 0 Acidosis: 0 Ketosis: þ or 0 Lactate: N Glycemia: N, low Liver enzymes: N
Maple syrup urine disease
Distinctive odor of urine (maple syrup, curry) Boxing or pedaling
Amino acid chromatography: high branched-chain amino acids
Neurological distress, dehydration, polypnea HyperNH3: þ or þþ Acidosis: þþþ Ketosis: þþþ Lactate: þ Glycemia: high, N, low Liver enzymes: N
Organic acidurias propionic, methylmalonic, isovaleryic acidurias Ketolysis defects
Abnormal movements “Sweaty feet” odor in isovaleric aciduria Peripheral hypertonia May mimic neonatal diabetes when hyperglycemia with glycosuria/ketonuria
Organic acid chromatography: Ketonuria Accumulation of the corresponding organic acids
Neurological distress, liver or cardiac symptoms HyperNH3: þ Acidosis: þ or N Ketosis: Lactate: þ or þþ Glycemia: low Liver enzymes: abnormal
Fatty acid oxidation defects (or ketogenesis defects)
“Energy deficiency” may involve heart, muscle, liver, kidney
Organic acid chromatography: accumulation of dicarboxylic acids Acylcarnitines: low free carnitine, elevation of corresponding acylcarnitines
Neurological distress HyperNH3: 0 Acidosis: þþ Ketosis: þ or 0 Lactate: þþþ Glycemia: high, N, low Liver enzymes: N, abnormal
Congenital lactic acidosis: pyruvate carboxylase, pyruvate dehydrogenase, respiratory chain deficiencies
Global hypotonia Respiratory distress
Lactate/pyruvate ratio: high in pyruvate carboxylase and respiratory chain, N in pyruvate dehydrogenase) 3-hydroxybutyrate/acetoacetate ratio: >1 in respiratory chain, pyruvate dehydrogenase; <1 in pyruvate carboxylase
Neurological distress, liver involvement HyperNH3: þþþ Acidosis: 0 or þ Ketosis: 0 or þ Lactate: þþ Glycemia: N, low Liver enzymes: abnormal
Congenital hyper NH3: urea cycle disorders
Axial hypotonia Peripheral hypertonia
Amino acid chromatography: high glutamine Mitochondrial defects ¼ low citrulline Ornithine-carbamyl transferase deficiency ¼ high orotic acid Cytosolic defects: elevation of specific amino acids
Neurological distress, hypotonia, seizures, myoclonic jerks HyperNH3: 0 Acidosis: 0 Ketosis: 0 Lactate: 0 Glycemia: N
Nonketotic hyperglycinemia Sulfite oxidase deficiency B6 and pyridoxal phosphate-responsive epilepsy Neurotransmitter disorders Peroxisomal disorders Congenital deficiency of glycosylation syndrome
EEG: suppression-burst pattern Dysmorphic features
Amino acid chromatography in plasma and CSF (glycine) Amino acid chromatography: sulfocysteine aminoadipic semialdehyde in urine, CSF pipecolic acid 5-HIAA, HVA, pterins in CSF VLCFA, plasmalogens, pipecholic acid, biliary acids Transferrin western blot
CSF, cerebrospinal fluid; 5-HIAA, 5-hydroxy-indolacetic acid; HVA, homovanillic acid; N, normal; NH3, ammonia; VLCFA, very long chain fatty acids; 0, absence; þ, present; þþ, high; þþþ, very high.
DIAGNOSTIC WORK-UP IN ACUTE CONDITIONS OF INBORN ERRORS OF METABOLISM presenting with metabolic acidosis and ketosis and often associated with or preceded by vomiting; urea cycle disorders when hyperammonemia is the predominant biological hallmark; fatty acid b-oxidation defect and ketogenesis defects (HMGCoA-lyase deficiency), gluconeogenesis defects when hypoglycemia is the presenting sign; energy deficiency disorders such as pyruvate kinase, pyruvate dehydrogenase, Krebs cycle defects or multiple carboxylase deficiency when hyperlactatemia is the presenting feature (in the absence of hypoglycemia), or fatty acid b-oxidation defect and gluconeogenesis defects when associated with hypoglycemia.
1557
and due to a-galactosidase deficiency). “Stroke-like” episodes (clinical presentation of stroke contrasting with focal ischemic pattern on brain computed tomography (CT) or magnetic resonance imaging (MRI) scans not corresponding to a specific vascular territory) may be seen during the disease course or be inaugural in (Testai and Gorelick, 2010a, b): congenital disorders of glycosylation, urea cycle disorders, respiratory chain defects, pyruvate dehydrogenase deficiency, maple syrup urine disease, and organic acidurias.
Recurrent ataxia Coma with focal neurological signs, strokes, seizures, or increased intracranial pressure Coma associated with hemiplegia and cerebral edema may be seen in urea cycle disorders (ornithine transcarbamylase or ornithine-carbamyl transferase deficiency), organic acidurias (methylmalonyl acidemia, propionic aciduria) and maple syrup urine disease. When extrapyramidal signs are associated, methylmalonyl acidemia, glutaric aciduria type I (associated with macrocephaly), Wilson’s disease (a copper transporter deficiency, ATP7B) and homocystinuria should be considered.
Hepatic coma Acute encephalopathy associated with liver dysfunction and hyperammonemia (Reye-like syndrome) may be due to urea cycle disorders or fatty acid b-oxidation defects. When associated with hyperlactatemia, respiratory chain deficiency may be suspected (especially DNA depletion syndromes such as POLG or DGUOK defects). If associated with cirrhosis, tyrosinemia type I is suspected even though encephalopathy is rare in this condition. The diagnosis of these disorders may be established as discussed previously. Glutaric aciduria type I can be diagnosed through organic acid chromatography and plasma acylcarnitine profile, homocystinuria by amino acid chromatography in plasma and urine, Wilson’s disease by measuring copper in plasma and urine, and plasma ceruloplasmin. Tyrosinemia type I may be diagnosed by succinyl acetone in urine (organic acid).
Stroke (or stroke-like) Several inborn errors of metabolism may be responsible for stroke due to a vascular disease (Testai and Gorelick, 2010a, b): homocystinuria by cystathione b-synthase deficiency and hyperhomocysteinemia by methylene tetrahydrofolate reductase deficiency, Fabry disease (an X-linked lysosomal disorder affecting predominantly males even though females may be affected
Intermittent acute ataxia can be the presenting sign of intermediary metabolism defects such as maple syrup urine disease (late-onset), organic acidurias, urea cycle disorders and “energy deficiency” disorders such as pyruvate dehydrogenase deficiency and respiratory chain defect (Garcia-Cazorla et al., 2009). Hartnup disease manifests during infancy with variable clinical presentations: failure to thrive, photosensitivity, intermittent ataxia, nystagmus, and tremor. Hartnup disease is a disorder of amino acid transport in the intestine and kidneys due to mutations in SLC6A19; the symptoms mainly affect the brain (headache, ataxia) and skin (rash). They may be triggered by sunlight, fever, drugs, or stress. Urinary amino acid analysis permits screening for this disorder.
Extrapyramidal signs (or movement disorders) Energy deficiency disorders may present with intermittent extrapyramidal signs (Garcia-Cazorla et al., 2009; Gouider-Khouja et al., 2009): pyruvate dehydrogenase deficiency, respiratory chain disorders, and GLUT1 deficiency. In the latter, the defect in GLUT1, a brain glucose transporter, results in a reduction of glucose supply in the central nervous system (CNS); glucose plasma/CSF ratio is low (<0.40). Molecular analysis confirms the diagnosis. Biotin-responsive basal ganglia disease also belongs to this group. It associates acute dystonia with basal ganglia involvement and a good clinical response to high doses of biotin. The molecular defect was identified and concerns SLC19A3, a thiamin transporter. In other disorders including glutaric aciduria type I, late-onset nonketotic hyperglycinema and Wilson’s disease, dystonia occurs more progressively and does not regress. Neurotransmitter defects such as monoamine synthesis defects may also account for abnormal movements occurring progressively and may be screened through CSF analysis.
1558
V. VALAYANNOPOULOS AND B.T. POLL-THE
Leigh syndrome Leigh syndrome is an early-onset progressive neurodegenerative disorder with characteristic neuropathology consisting of focal bilateral lesions in one or more areas of the central nervous system, including the brainstem, thalamus, basal ganglia, cerebellum, and spinal cord, that can be identified by brain MRI. Clinical symptoms depend on which areas of the central nervous system are involved and include impaired consciousness, extrapyramidal syndrome, and signs related to brainstem dysfunction (breathing irregularities, heart rhythm disorders) Finsterer, 2008. The most common underlying cause is a defect in energy production in the brain. Inborn errors of metabolism presenting with Leigh syndrome include: pyruvate dehydrogenase deficiency, glutaric aciduria type I, respiratory chain disorders, pyruvate carboxylase deficiency, organic acidurias, and sulfite oxidase deficiency; biotinidase deficiency resulting from biotin deficiency, a coenzyme of carboxylases (pyruvate carboxylase, propionyl CoA carboxylase, acetyl CoA carboxylase) associated with high lactate and in some cases treatable by biotin administration; fumarase deficiency: a Krebs cycle enzyme associated to excretion of high amounts of fumarate in urine; ethylmalonic acid 1 encephalopathy, which is characterized by ethylmalonic and methylsuccinic aciduria and lactic acidemia associated with developmental delay, acrocyanosis, petechiae, and chronic diarrhea. ETHE1 is a gene coding for a mitochondrial dioxygenase; loss of function of this gene causes fatal sulfide toxicity; 3-methylglutaconic aciduria type I (3-MGA-I): this entity must be distinguished from other conditions such as X-linked Barth syndrome (cardiomyopathy, neutropenia), Costeff syndrome (optic atrophy), and respiratory chain deficiency, where elevated excretion of 3-methylglutaconic acid may occur. 3-MGA-I presenting with encephalopathy and basal ganglia involvement is characterized by urinary excretion of 3-MGC and 3-methylglutaric acids due to 3-MGC-CoA hydratase deficiency.
Neuropsychiatric or behavioral manifestations Inborn errors of metabolism may present as psychiatric disorders in childhood and adolescence (Sedel et al., 2007). In some instances, an inborn error of metabolism is suspected because of a positive family history or because psychiatric symptoms form part of a more diffuse clinical picture with systemic and hard neurological signs. However, in some cases, psychiatric disturbance may be the only, or at least the predominant, sign of disease for years. Acute psychiatric symptoms may be encountered in late-onset urea cycle disorders, especially in ornithine
carbamyl transferase deficiency mimicking encephalitis. If untreated this condition may lead to coma and death. Hyperammonemia is the biological hallmark. Acute intermittent porphyria and hereditary coproporphyria may present with recurrent vomiting, acute abdominal pain, neuropathy and psychiatric symptoms. “Port wine urine” is characteristic. Specific measurement of porphyrins in urine confirms the diagnosis. Wilson disease associates psychiatric problems, extrapyramidal signs, liver dysfunction, and Kayser–Fleischer rings. The diagnostic hallmarks are mentioned above. Homocysteine metabolism defects (homocystinuria, MTHFR deficiency) may present with schizophrenialike episodes that are folate responsive. Homocysteine detection in urine suggests the diagnosis. In succinic semialdehyde dehydrogenase deficiency the most frequent clinical features include developmental delay of motor, mental, and language skills, hypotonia, seizures, hyporeflexia, ataxia, behavioral problems. Psychosis with visual hallucinations may be seen in older patients. Excretion of 4-hydroxybutyric acid in urine detected by organic acid analysis suggests this diagnosis; it can be confirmed by enzymatic and molecular analysis.
Muscular manifestations Acute muscular symptoms include muscular pain and rhabdomyolysis. Inborn errors of metabolism presenting as an acute myopathy are commonly the result of defects in energy metabolism (Olpin, 2005). These can present as an acute intermittent muscle weakness, exercise intolerance with cramps and myoglobinuria. The most frequent conditions actually observed are mitochondrial respiratory chain and fatty acid oxidation defects, muscular glycogenolysis defects and mutations in LPIN1 gene. In respiratory chain deficiencies, muscle biopsy may display histological abnormalities (such as ragged-red fibers) and specific enzymatic defects of respiratory chain complexes. Fatty acid oxidation defects can be screened by acylcarnitines, where glycogenolysis defects require specific enzyme analysis screened in lymphocytes or in muscle tissue and LPIN1 mutations by molecular studies with a frequent intragenic deletion accounting for about half of all known caucasian patients (Michot et al., 2010). Table 160.2 summarizes inborn errors of metabolism associated with late-onset recurrent comas, ataxia, and psychiatric signs.
TREATMENT APPROACHES As soon as the diagnosis of a metabolic disorder is suspected, emergency management has to be started (Leonard and Morris, 2006; Saudubray et al., 2006). Immediate contact should be made with an expert metabolic
DIAGNOSTIC WORK-UP IN ACUTE CONDITIONS OF INBORN ERRORS OF METABOLISM
1559
Table 160.2 Late-onset (late infancy to adulthood) recurrent comas, ataxia, psychiatric signs Metabolic coma without focal neurological signs, or acute ataxia with lethargy
Metabolic acidosis/ ketosis
HyperNH3 Hypoglycemia Hyperlactacidemia Neurological coma with focal signs, seizures, or intracranial hypertension
Cerebral edema Extrapyramidal signs (dystonia, Parkinson) Stroke and “stroke-like”
Leigh syndrome
Hepatic coma Elevated liver enzymes Reye syndrome Psychiatric symptoms, hallucinations, delirium
Muscular signs (rhabdomyolysis) Hyperammonemia Hyperlactatemia Jaundice Hyperammonemia Ketoacidosis Hyperhomocysteinemia Port wine urine
Multiple carboxylase deficiency, organic acidurias, maple syrup urine disease, ketolysis, ketogenesis defects, fatty acid b-oxidation defects Fructose bisphosphatase deficiency, pyruvate dehydrogenase deficiency Urea cycle disorders, triple H, lysinuric protein intolerance Fatty acid b-oxidation defects, HMGCoA lyase deficiency Gluconeogenesis defects, glycogen synthetase deficiency HMGCoA lyase/synthetase deficiency, fatty acid b-oxidation defects Multiple carboxylase deficiency, pyruvate dehydrogenase deficiency Gluconeogenesis defects, fatty acid b-oxidation defects Maple syrup urine disease, ornithine-carbamyl transferase deficiency, organic acidurias Glutaric aciduria type I, methylmalonic aciduria Wilson disease, homocystinuria, late-onset nonketotic hyperglycinemia Biotin-responsive basal ganglia disease Homocystinurias, Fabry disease Urea cycle defect, organic acidurias, respiratory chain deficiency, pyruvate dehydrogenase deficiency, maple syrup urine disease Glutaric aciduria 1, organic acidurias, respiratory chain deficiency, pyruvate dehydrogenase deficiency, sulfite oxidase deficiency, biotinidase deficiency, fumarase deficiency, ethylmalonyl encephalopathy 1, 3MGA Fatty acid b-oxidation defects, respiratory chain deficiency LPIN1 mutations Fatty acid b-oxidation defects, urea cycle defect Fatty acid b-oxidation defects, respiratory chain deficiency (mtDNA depletion syndromes) Wilson disease Urea cycle defect (ornithine-carbamyl transferase), lysinuric protein intolerance Organic acid disorders Methyltetrahydrofolate reductase deficiency, CblC deficiency Acute intermittent porphyria Hereditary coproporphyria Wilson disease Succinic semialdehyde dehydrogenase deficiency
center to guide the treatment or to organize an emergency transfer. Emergency treatments should be available (see list in Table 160.3). Intoxication disorders are treated by an emergency diet with high caloric intake and no protein given enterally or by infusion. Specific amino acid mixtures may be required in order to enhance anabolism (for instance in maple syrup urine disease). Ammonia scavengers such as sodium benzoate or phenylbutyrate may be used. In the most severe cases, renal replacement therapy may be required (congenital hyperammonemias and maple syrup urine disease). Vitamins and cofactors such as Lcarnitine, L-glycine, biotin, cobalamin (B12) should be included in the treatment. In all conditions presenting with hypoglycemia an intravenous infusion with sufficient
glucose supply (4–10 mg/kg/minute according to age) should be given. L-carnitine should be added if a fatty acid b-oxidation defect is suspected. In congenital lactic acidosis, high levels of glucose should be avoided and lipid intake should be preferred. Vitamin B1 (thiamin) and biotin are cofactors of pyruvate dehydrogenase and carboxylase deficiencies, respectively. In respiratory chain deficiency, cofactors such as vitamins B1, B2, biotin, coenzyme Q10 may be useful, and arginine may also be helpful (Koga et al., 2010). In neonatal seizures, vitamin B6 (pyridoxine), pyridoxal phosphate, and folinic acid may dramatically improve the clinical course. Table 160.3 summarizes emergency medications and common doses used in the treatment of inborn errors of metabolism.
Table 160.3 Medications used in the emergency treatment of inherited metabolic disorders Medication
Mode of action
Disorders
Recommended dose
Route
Remarks
Biotin
Cofactor for carboxylases
Biotinidase deficiency
5–20 mg/day
Oral or intravenous
Glycine
Forms isovalerylglycine with high renal clearance Cofactor for methylmalonyl mutase
Isovaleric acidemia
150 mg/kg per day in three divided doses 1 mg intramuscularly daily; oral dose 10 mg once or twice daily 50–170 mg/kg (Ornithine carbamyl transferase and carbamoyl phosphate synthase deficiency) up to 700 mg/kg in AL and argininosuccinate synthase deficiency) 100–200 mg/kg per day
Oral
Multiple carboxylase deficiency Treatment of presumed transporter defect Biotin-responsive basal ganglia disease Up to 600 mg/kg per day during decompensation Dose may be reduced to once or twice weekly according to response
Hydroxycobalamin (vitamin B12)
Disorders of cobalamin metabolism
L-Arginine
Replenishes arginine; substrate of nitrous oxide
L-Carnitine
Primary and secondary Replenishes body stores; carnitine deficiencies removes toxic acyl-CoA intermediates from within the mitochondria Replenishes citrulline and Used as an alternative to arginine arginine in carbamoyl phosphate synthase deficiency and orithine carbamyl transferase deficiency
L-Citrulline
N-Carbamoylglutamate NTBC (2-(2-nitro-4trifluoromethylbenzoyl)1,3-cyclohexanedione) (nitisinone)
Stimulates N-acetylglutamate synthase Inhibits 4hydroxyphenylpyruvate dioxygenase
Urea cycle disorders; mitochondrial encephalopathy, lactic acidosis and stroke-like episodes
N-Acetylglutamate synthase deficiency Tyrosinemia type I
Intramuscular or oral
Oral or intravenous
Oral or intravenous
Carbamoyl phosphate Oral synthase and ornithine carbamyl transferase deficiency:170 mg/kg per day or 3.8 g/m2/day in divided doses, lysinuric protein intolerance: 100 mg/ kg per day in 3–5 doses 100–250 mg/kg per day in four Oral divided doses 1–2 mg/kg in 1–2 divided Oral doses
Combine with low-tyrosine, low-phenylalanine diet
Continued
Table 160.3 Continued Medication
Mode of action
Disorders
Pyridoxine
Cofactor
Pyridoxal phosphate
Active cofactor
Riboflavin
Coenzyme glutaric aciduria I
Sodium benzoate
Combines with glycine to form hippuric acid which has high renal clearance
50–500 mg per day Pyridoxine-responsive Pyridoxine dependency homocystinuria by with seizures: 100 mg cystathionine b-synthase intravenously with EEG deficiency; pyridoxine monitoring or 30 mg/kg per dependency with seizures; day for 7 days (maintenance type I 5–10 mg per day) Pyridox(am)ine 5-P oxidase 40 mg/kg per day in four deficiency divided doses 100 mg per day in 2–3 divided Mild variants of electron doses transfer flavoprotein/ electron transfer flavoprotein dehydrogenase and shortchain acyl-CoA dehydrogenase; congenital lactic acidosis (complex I deficiency) Hyperammonemia 250–500 mg per day in divided doses or by continuous intravenous infusion
Sodium phenylbutyrate
Converted to phenylacetate, which combines with glutamine to form phenylglutamine which has high renal clearance Cofactor
Thiamin
Hyperammonemia
Recommended dose
250–500 mg/kg per day; maximum dose 20 g/day
Thiamin-responsive variants 10–50 mg per day of maple syrup urine disease, pyruvate dehydrogenase deficiency and complex I deficiency
Route
Remarks
Oral or intravenous
Peripheral neuropathy can occur with doses > 1000 mg daily
Oral Oral
Oral or intravenous Intravenous loading dose: 250 mg/kg over 90 minutes Oral
Removes N2 to ammonia and reduces blood ammonia Dose may be doubled if severe hyperammonemia
Oral
Oral doses of up to 300 mg have been used in congenital lactic acidosis; 500–2000 mg per day in thiamin-responsive pyruvate dehydrogenase?
1562
V. VALAYANNOPOULOS AND B.T. POLL-THE
CONCLUSION Progress in the treatment of inborn errors of metabolism has been slower than progress towards insight into the many aspects of the metabolic and molecular bases of inborn errors of metabolism. Nevertheless, outcomes are improving, with prevention, earlier diagnosis, and appropriate management, the use of dialysis and drugs to promote the removal of toxic metabolites, and measures to keep catabolism to a minimum. Early intervention is crucial when neurological sequelae could be avoided, which requires constant vigilance and routine measurement of diagnostic biochemical markers in suspected cases.
REFERENCES Bahi-Buisson N, Mention K, Leger PL et al. (2006). Neonatal epilepsy and inborn errors of metabolism. Arch Pediatr 13: 284–292. Clayton PT (2002). Inborn errors presenting with liver dysfunction. Semin Neonatol 7: 49–63. De Vivo DC (2002). Inherited metabolic disorders and seizures in infancy. J Child Neurol 17: 3S1–3S2. Finsterer J (2008). Leigh and Leigh-like syndrome in children and adults. Pediatr Neurol 39: 223–235. Garcia-Cazorla A, Wolf NI, Serrano M et al. (2009). Inborn errors of metabolism and motor disturbances in children. J Inherit Metab Dis 32: 618–629. Gouider-Khouja N, Kraoua I, Benrhouma H et al. (2009). Movement disorders in neuro-metabolic diseases. Eur J Paediatr Neurol 14: 304–307.
Koga Y, Povalko N, Nishioka J et al. (2010). MELAS and L-arginine therapy: pathophysiology of stroke-like episodes. Ann N Y Acad Sci 1201: 104–110. Leonard JV, Morris AA (2006). Diagnosis and early management of inborn errors of metabolism presenting around the time of birth. Acta Paediatr 95: 6–14. Michot C, Hubert L, Brivet M et al. (2010). LPIN1 gene mutations: a major cause of severe rhabdomyolysis in early childhood. Hum Mutat 31: E1564–73. Olpin SE (2005). Fatty acid oxidation defects as a cause of neuromyopathic disease in infants and adults. Clin Lab 51: 289–306. Prietsch V, Lindner M, Zschocke J et al. (2002). Emergency management of inherited metabolic diseases. J Inherit Metab Dis 25: 531–546. Saudubray JM, Nassogne MC, de Lonlay P et al. (2002). Clinical approach to inherited metabolic disorders in neonates: an overview. Semin Neonatol 7: 3–15. Saudubray JM, Sedel F, Walter JH (2006). Clinical approach to treatable inborn metabolic diseases: an introduction. J Inherit Metab Dis 29: 261–274. Sedel F, Baumann N, Turpin JC et al. (2007). Psychiatric manifestations revealing inborn errors of metabolism in adolescents and adults. J Inherit Metab Dis 30: 631–641. Testai FD, Gorelick PB (2010a). Inherited metabolic disorders and stroke, part 2: homocystinuria, organic acidurias, and urea cycle disorders. Arch Neurol 67: 148–153. Testai FD, Gorelick PB (2010b). Inherited metabolic disorders and stroke, part 1: Fabry disease and mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. Arch Neurol 67: 19–24.