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Abstract  1. Metabolism of the Branched Chain Organic Acids

Abstract  Catabolism of the essential branched chain amino acids, leucine, isoleucine, and valine begins with transamination to their 2-oxo branched chain organic acids, then oxidative decarboxylation to form branched chain acyl coenzyme A (CoA) products. The branched chain amino acid and organic acid disorder maple syrup urine disease, caused by a deficiency of branched chain α-ketoacid dehydrogenase, is described in Chap. 87. Isovaleryl-CoA derived from leucine, 2-methylbutyryl-CoA derived from isoleucine, and isobutyryl-CoA derived from valine are metabolized by separate pathways to intermediates which enter general metabolism. Defects in these pathways cause 13 known metabolic disorders termed branched chain organic acidurias. Several other disorders characterized by branched chain organic aciduria unrelated to branched chain amino acid metabolism are also reviewed in this chapter (Table 93-1).

Abstract  Propionic acidemia and methylmalonic acidemia are disorders of propionic acid degradation derived in part from the catabolism of isoleucine and valine, but are described separately in Chapter 94. Deficiency of the branched chain keto acid dehydrogenase is responsible for the disorder maple syrup urine disease and is described in Chapter 87. Inherited deficiencies of the remaining four enzymes of the catabolism of isovaleryl-CoA derived from leucine are known: isovaleric acidemia (isovaleryl-CoA dehydrogenase deficiency), isolated biotin-unresponsive 3-methylcrotonyl-CoA carboxylase deficiency, 3-methylglutaconic aciduria (3-methylglutaconyl-CoA hydratase deficiency), and 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. Mevalonic aciduria, due to a defect in the biosynthesis of cholesterol and isoprenoids from 3-hydroxy-3-methylglutaryl-CoA, is also considered a branched chain organic aciduria in this chapter. Three inherited disorders of the catabolism of 2-methylbutyryl-CoA derived from isoleucine are known: short/branched chain acyl-CoA dehydrogenase, 2-methyl- 3-hydroxybutyryl-CoA dehydrogenase, and mitochondrial acetoacetyl-CoA thiolase deficiency. Five disorders of the catabolism of isobutyryl-CoA derived from valine are known: isobutyryl-CoA dehydrogenase deficiency, 3-hydroxyisobutyryl-CoA deacylase deficiency, 3-hydroxyisobutyric aciduria; methylmalonic semialdehyde dehydrogenase deficiency with combined 3-hydroxyisobutyric, 3-aminoisobutyric, 3-hydroxypropionic, β-alanine, and 2-ethyl-3-hydroxybutyric aciduria; and a new form of mild methylmalonic aciduria related to methylmalonic semialdehyde metabolism. A new disorder, ethylmalonic encephalopathy, with increased excretion of ethylmalonic acid, isobutyrylglycine, and 2-methylbutyrylglycine is due to deficiency of a mitochondrial sulfur dioxygenase. Although not a branched chain organic aciduria, malonic aciduria due to malonyl-CoA decarboxylase deficiency is described.

Abstract  2. Isovaleric Acidemia (IVA Isovaleryl-CoA Dehydrogenase Deficiency, MIM 243500)

Abstract  Isovaleric acidemia was the first condition to be recognized as an organic acidemia when the odor of sweaty feet that surrounded an infant with episodic encephalopathy was shown to be due to isovaleric acid. The disorder in leucine degradation is due to deficiency of isovaleryl-CoA dehydrogenase, the mitochondrial enzyme that oxidizes the first irreversible step in this pathway, isovaleryl-CoA to 3-methylcrotonyl-CoA. Early literature on IVA, an autosomal recessive disorder, emphasized two apparent phenotypes. The first was an acute, neonatal presentation with patients becoming symptomatic within the first two weeks of life. 16 Patients appeared initially well, then developed vomiting and lethargy, progressing to coma. The second group presented with relatively non-specific failure to thrive and/or developmental delay (chronic intermittent presentation). In reality it is now apparent that patients can fall anywhere on the spectrum of acute to chronic presentation and that there is probably little predictive value to the initial presentation. Moreover, with the application of tandem mass spectrometry (MS/MS) in newborn screening, potentially asymptomatic patients with one recurring IVD gene mutation and a mild biochemical phenotype are being identified in increasing numbers, representing an additional phenotype of IVA. There are three goals for therapy of almost any organic acidemia, including IVA. The first is prevention of metabolic decompensation by careful clinical observation of the patient. The second goal is long term reduction of the production of toxic metabolites from general catabolism through dietary manipulation. The third goal of therapy is to prevent the accumulation of toxic metabolites by enhancing alternative metabolic pathways that produce non-toxic compounds that are readily excreted.

Abstract  3. Isolated 3-Methylcrotonyl-CoA Carboxylase Deficiency (MIM 210200)

Abstract  3-Methylcrotonyl-CoA carboxylase (3MCC) deficiency can be caused by a defect in the gene for this enzyme or as part of a multiple carboxylase deficiency (see Chapter 56). Isolated deficiency, manifesting as isolated 3-methylcrotonylglycinuria was first described in 1970 in a female infant with feeding problems, developmental delay, severe hypotonia, and an odor like that of cat’s urine. The disorder is due to deficiency of 3-methylcrotonyl-CoA carboxylase, a biotin-containing enzyme that converts its substrate, an intermediate in leucine oxidation, to 3-methylglutaconyl-CoA. Initial reports on patients with this condition reported episodes of vomiting, hypoglycemia, hepatomegaly, hyperammonemic encephalopathy, metabolic stroke, and hypotonia with developmental delay. Numerous affected babies have now been identified through newborn screening, and most, if not all, have remained well. Elevated metabolites characteristic of 3MCC deficiency have been identified through newborn screening in infants born to asymptomatic mothers with MCC deficiency. In conjunction with the identification of asymptomatic siblings of severely affected patients, the clinical relevance of the biochemical abnormalities related to this deficiency must be reevaluated.

Abstract  4. 3-Methylglutaconic Aciduria

Abstract  Elevation of 3-methylglutaconic acid in the urine is seen in a heterogeneous group of disorders. Highest concentrations, along with elevations of urinary 3-methylglutaric and 3-hydroxyisovaleric acids, are seen in 3-methylglutaconyl-CoA hydratase deficiency (MGA type I, MGA1; MIM 250950). This condition is associated with a slowly progressive leukoencephalopathy with clinical presentation in adolescence or adulthood; clinical features in childhood are variable and non-specific. Pathogenesis is poorly understood, and it is unknown whether treatment with carnitine supplementation and modest leucine restriction is of any benefit. Other forms of MGA have lower urinary concentrations of 3-methylglutaconic acid and are caused by mutations in various genes mostly required for mitochondrial functions. Barth syndrome (MGA type 2, MIM 302060) is X-linked and presents with dilated cardiomyopathy, neutropenia, and growth retardation. It is caused by mutations in the tafazzin gene. Costeff syndrome (MGA Type III; MIM 258501) is characterized by optic atrophy, choreoathetosis, spastic paraparesis, cerebellar ataxia, and nystagmus; it is caused by mutations in the OPA3 gene. More recently the combination of MGA with cardiomyopathy, conduction defects and cerebellar ataxia, due to mutations in the DNAJC19 gene, has been denoted MGA type V (MIM 610198). Apart from these rare conditions there are a large number of patients with various organ involvement and mostly progressive neurological impairment in whom (intermittent) 3-methylglutaconic aciduria is associated with biochemical features of dysfunctional oxidative phosphorylation. This is referred to as MGA type 4 (MIM 250951) and can be caused by mutations in a growing number of different genes.

Abstract  5. 3-Hydroxy-3-methylglutaryl-CoA Lyase Deficiency (MIM 246450)

Abstract  One-third of the patients present in the neonatal period and two-thirds present between 3 and 11 months of age with severe hypoglycemia and metabolic acidosis (but with little or no ketosis), hyperammonemia, vomiting, and hypotonia, which may progress to coma and death. The symptoms resemble Reye syndrome. Treatment by restriction of leucine and fat, avoidance of fasting, and carnitine supplementation generally leads to normal development. 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency is a disorder of branched chain amino acid (leucine) metabolism, and the diagnosis from the major abnormal metabolites, 3-hydroxy-3-methylglutaric, 3-methylglutaconic and 3-hydroxyisovaleric acids in urine is described in this chapter. But this disorder is also one of ketone body metabolism and therefore clinical, biochemical and molecular aspects are described in detail in Chapter 102, “Inborn errors of ketone body metabolism”.

Abstract  6. Mevalonic Aciduria (Mevalonate Kinase Deficiency (MIM 251170))

Abstract  Patients with the severe form of mevalonic aciduria present in the neonatal period with dysmorphic features, anemia, hepatosplenomegaly, gastroenteropathy, failure to thrive, and severe developmental delay. Patients with a milder form show poor muscle development, hypotonia, ataxia, and elevated creatine kinase. There is no metabolic acidosis, and although the defect is in cholesterol biosynthesis, blood cholesterol may be normal. A characteristic pattern of periodic fever with hyperimmunoglobulin D can also be seen. The only abnormal metabolite is an extremely elevated amount of mevalonic acid in urine and plasma. No effective therapy is yet available.

Abstract  7. Short/Branched Chain Acyl-CoA Dehydrogenase Deficiency (MIM 600301 and MIM 610006).

Abstract  This enzyme was originally named 2-methyl-branched chain acyl-CoA dehydrogenase based on the substrate specificity of an enzyme purified from rat liver. SBCAD deficiency was first described in two patients with rather significant neurologic symptoms. However, it was soon noted to be present in high frequency in the Hmong Chinese population in the United States due to a common founder mutation. These individuals, largely identified through newborn screening and family studies, appear to be asymptomatic. Other studies on affected, non-Hmong individuals, again largely identified through newborn screen, corroborate the absence of symptomatology. Currently, it seems appropriate to consider SBCAD deficiency a biochemical phenotype rather than a clinical disease though long term follow up studies are necessary to define any risks later in life. The major clinical concern is related to the characteristic metabolite (“C5 carnitine”) identified in babies by newborn screening with MS/MS. Since 2-methylbutyrylcarnitine and isovalerylcarnitine are isobaric, identification of a five carbon species by MS-MS can suggest either SBCAD or IVD deficiency. Urine organic acid analysis can readily distinguish the two disorders.

Abstract  8. 2-Methyl-3-Hydroxybutyric Aciduria / HSD10 disease (MIM 300256)

Abstract  The third step in the beta-oxidation of short 2-methylated acyl-CoA compounds is catalyzed by a multifunctional protein correctly classified as 17-beta-hydroxysterorid dehydrogenase type 10 (HSD10). It is coded by the X-chromosomal HSD17B10 gene. Most patients are males with a progressive neurodegenerative disease course comprising loss of cognitive and motor functions, epilepsy, blindness, and cardiomyopathy, often becoming evident in the second year of life (infantile form of HSD10 disease). Most of these patients are hemizygous for the same missense mutation p.Q130R. A severe neonatal form with little neurological development and severe cardiomyopathy, as well as a juvenile form of HSD10 disease, have been characterized. Patients usually show increased urinary excretion of 2-methyl-3 hydroxybutyrate and tiglylglycine without 2-methylacetoacetic acid, due to reduced 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) function of the HSD10 protein. Heterozygous females often show non-progressive intellectual disability. In one family it was shown that complete loss of enzyme function is compatible with normal neurological development and it appears that clinical features of HSD10 disease are unrelated to the dehydrogenase function. The exact pathogenesis remains to be clarified, but it is noteworthy that HSD10 is also a component of the mitochondrial RNase P required for the processing of mtDNA transcripts.

Abstract  9. Mitochondrial Acetoacetyl-CoA Thiolase Deficiency (MIM 203750)

Abstract  In patients with mitochondrial acetoacetyl-CoA thiolase deficiency, intermittent episodes of severe metabolic acidosis and ketosis begin during the first 2 years of life. These are accompanied by vomiting, often with hematemesis, diarrhea, and coma, which may progress to death. Deficiency of this thiolase is a disorder of branched chain amino acid (isoleucine) metabolism, and the diagnosis from the major abnormal metabolites 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid and tiglylglycine in urine is described in this chapter. But this disorder is also one of ketone body metabolism and therefore clinical, biochemical and molecular aspects are described in detail in Chapter 102, “Inborn errors of ketone body metabolism”.

Abstract  10. Isobutyryl-CoA Dehydrogenase Deficiency (IBDH; MIM 611283)

Abstract  The first patient with IBDH deficiency presented with carnitine deficiency and cardiomyopathy at one year of age. The child responded to carnitine supplementation and had no recurrence of cardiac disease or episodes of metabolic decompensation. Since identification of the index case, at least 15 additional patients have been reported, all identified through newborn screening. All but one has remained asymptomatic. Isobutyrylcarnitine elevation in blood can be documented by tandem mass spectroscopy including newborn screening. Since MS-MS does not distinguish between butyryl- and isobutyrylcarnitine, follow up testing is necessary. Identification of isobutyrylglycine (as opposed to butyrylglycine) in urine differentiates the two disorders, and the diagnosis is then best confirmed by molecular analysis.

Abstract  11. 3-Hydroxyisobutyryl-CoA Deacylase Deficiency (MIM 250620)

Abstract  The first patient with 3-hydroxyisobutyryl-CoA deacylase deficiency presented with vertebral malformations and tetralogy of Fallot along with dysmorphic features. There was little growth or development and he died at age 3 months. Agenesis of the cingulate gyrus and corpus callosum was found on autopsy. Enzyme assay confirmed the diagnosis. The second patient appeared well at birth but exhibited neurodegeneration beginning at age 4 months. MRI of the brain at that time demonstrated abnormalities in the globus pallidus and the midbrain, with asymmetrical involvement of the cerebral peduncles, though no structural abnormalities were noted. In the first patient, the alternative metabolites S-(2-carboxypropyl) cysteamine and S-(2-carboxypropyl) cysteine were seen. These compounds weren’t reported in the second patient but a hydroxy-C4-carnitine species was elevated. Both patients were shown to have enzymatic deficiency of 3-hydroxyisobutyryl-CoA deacylase on fibroblast assay, but the second patient also had partial deficiencies of respiratory chain complexes I and IV in muscle. Because of the complicated metabolite picture in these patients, it is likely that 3-hydroxybutyryl-CoA deacylase is under diagnosed and the full clinical spectrum remains to be described.

Abstract  12. Methylmalonic Semialdehyde Dehydrogenase Deficiency (MIM 603178)

Abstract  Several reports in the literature have described patients with metabolite accumulation thought to be consistent with methylmalonate semialdehyde dehydrogenase (MMSDH) deficiency, but only one has subsequently been shown to have mutations in the gene for this enzyme. Additional metabolic evaluation in the biochemically defined individuals reported thus far revealed high levels of urinary 3-hydroxyisobutyric acid and lesser elevations of 2-ethylhydracrylic acid, 3-aminoisobutyric acid, beta-alanine and 3-hydroxypropionic acid. The single patient with known gene mutations was identified on newborn screening for the unrelated finding of hypermethioninemia. A mutation in the MMSDH gene was ultimately identified. The patient was last reported to be well at age 4 years, so the clinical relevance of the biochemical phenotype is unknown. In that same study, three other patients previously suspected as having methylmalonate semialdehyde dehydrogenase deficiency did not have MMSDH gene mutations pointing to lack of specificity of the metabolic findings.

Abstract  13. 3-Hydroxyisobutyric Aciduria (MIM 236795)

Abstract  A number of patients have been reported with increased excretion of 3-hydroxyisobutyric acid, suggesting deficient activity of 3-hydroxyisobutyric acid dehydrogenase or methylmalonic semialdehyde dehydrogenase in the valine pathway. However, the clinical phenotype has been variable and no defects in 3-hydroxyisobutyrate dehydrogenase or methylmalonate-semialdehyde dehydrogenase have been identified. Thus, the etiology of this biochemical phenotype remains unknown.

Abstract  14. Methylmalonic Semialdehyde Dehydrogenase Deficiency with Combined 3-Hydroxypropionic, β-alanine, 3-hydroxyisobutyric and 3-aminoisobutyric aciduria

Abstract  In one individual with no clinical symptoms and another with mild symptoms, a deficiency of an uncharacterized semialdehyde dehydrogenase acting on both methylmalonic semialdehyde and malonic semialdehyde led to elevated excretions of 3-hydroxyisobutyric, 3-aminoisobutyric, 2-ethyl-3-hydroxybutyric and 3-hydroxypropionic acids together with β-alanine. The etiology of this biochemical phenotype and its relationship to clinical disease remains unknown

Abstract  15. Ethylmalonic aciduria encephalopathy (MIM 602473)

Abstract  Deficiency of a mitochondrial sulfur dioxygenase leads to a characteristic phenotype known as ethylmalonic encephalopathy. Previously thought to be a disorder in branched chain amino acid metabolism, the defect leads to the accumulation of sulfides within mitochondria, which in turn impairs mitochondrial energy metabolism. Ethylmalonic encephalopathy is characterized by neurodevelopmental delay and regression, prominent pyramidal and extrapyramidal signs, recurrent petechiae, orthostatic acrocyanosis, and chronic diarrhea. Pyramidal signs, hypotonia, microcephaly, failure to thrive, seizures, and episodic encephalopathy are common. Ethylmalonic acid accumulation in urine is the hallmark of ethylmalonic encephalopathy, but it is non-specific and can be intermittent in milder cases. Identification of the enzymatic cause of ethylmalonic encephalopathy has led to new therapeutic options in this previously untreatable disorder. In a single study, metronidazole, or N-acetylcysteine (a precursor of sulfide-buffering glutathione) substantially prolonged the lifespan of ETH1-deficient mice, with the combined treatment being cumulative. The same dual treatment caused marked clinical improvement in five affected children, with no reported adverse side effects. Additional studies will be needed to confirm the efficacy of this promising therapeutic regimen.

Abstract  16. Malonic aciduria (malonyl-CoA decarboxylase deficiency, MIM 248360))

Abstract  Although malonic aciduria due to malonyl-CoA decarboxylase (MCD) deficiency is not a disorder of branched chain amino acid metabolism, it is included in this chapter because of the methylmalonic aciduria derived from the catabolism of isoleucine and valine. MCD catalyzes the conversion of malonyl-CoA to acetyl-CoA and has been identified in both prokaryotes and eukaryotes. The cellular function of mammalian MCD is not known, though it may play a role in the regulation of fatty acid synthesis and oxidation via the potent inhibition of mammalian carnitine palmitoyl transferase I (CPT1) by malonyl-CoA. At least 24 patients have been reported with malonic aciduria, generally accompanied by lesser excretions of methylmalonic acid. The clinical features are variable but most patients have had developmental delay in early childhood. Other clinical symptoms variably present in 10-40% of the cases include seizures, hypotonia, diarrhea, vomiting, metabolic acidosis, hypoglycemia, ketosis and lactic acidemia, brain malformations, and hypertrophic cardiomyopathy. The diagnosis is confirmed by enzyme and/or molecular analysis.

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