Table 1.

Disorders of the branched chain amino acid metabolic pathway. Clinical presentation, outcomes and therapeutic approaches

Disorder	Clinical presentation	Outcome	Treatment
Maple syrup urine disease	Classic: Lethargy/irritability, progressive encephalopathy, opisthotonus, coma	Intellectual disability depending on age at diagnosis and metabolic control	Leucine restriction, high-caloric BCAA-free formulas
	Intermediate: Metabolic encephalopathy with stress, anorexia, growth failure	ADHD, anxiety, depression	Valine and isoleucine, glutamine/alanine supplementation (as needed)
	Intermittent: Normal early development, episodic crises associated with stress	Transient encephalopathy,	Thiamine (according to genotype)
	Thiamine responsive: similar to intermediate, improved biochemical profile with thiamine	hyperactivity, focal dystonia, choreoathetosis, ataxia	Multivitamin, minerals
	Type III, E3 deficient: Leigh-type encephalopathy, lactic acidosis, often lethal	Amino acid or other nutritional deficiencies	Liver transplantation (classic patients)
Osteoporosis
Isovaleric acidemia	Acute presentation:	Failure to thrive	Leucine restriction
	Metabolic ketoacidosis	Pancytopenia with acidotic episodes	Glycine supplementation
	Hyperammonemia	Myeloproliferative syndrome	L-Carnitine
	Bone marrow failure	Pancreatitis	Multivitamin, minerals
	Poor feeding, vomiting	Fanconi syndrome
	Encephalopathy	Cardiac arrhythmias
	“Sweaty feet” odor	Intellectual disability
	Chronic intermittent presentation:
	Exacerbations during periods of stress
	Asymptomatic, common missense mutation 932C>T (A282V), with only partial reduction in IVD activity
3-Methylcrotonyl-CoA carboxylase deficiency	Acute hypoglycemia, episodic metabolic acidosis, severe neurological symptoms in neonates (seizures, hypotonia, coma, developmental delay)	Completely asymptomatic adults (i.e. affected mothers detected through newborn screening)	Fasting avoidance
			L-Carnitine
3-Methylglutaconic aciduria type I	Intellectual disability, seizures, hepatomegaly, hypotonia	Optic atrophy, dysarthria, ataxia,	Leucine restriction
		adult onset progressive leukoencephalopathy	L-Carnitine
3-Methylglutaconic aciduria type II:	X-linked dilated cardiomyopathy, cyclic neutropenia, skeletal myopathy, and mitochondrial respiratory chain dysfunction	Growth retardation
Barth syndrome
3-Methylglutaconic aciduria type III:	Infantile optic atrophy, extrapyramidal signs, spasticity, ataxia, dysarthria,
Costeff optic atrophy
3-Methylglutaconic aciduria type IV: “unclassified”	Encephalomyopathic, hepatocerebral, cardiomyopathic, myopathic forms with mitochondrial respiratory chain dysfunction	Cataracts, cardiomyopathy, deafness, lactic acidosis
		Facial dysmorphism
		Intellectual disability
3-Hydroxy-3- methylglutaryl-CoA lyase deficiency	Non-ketotic hypoglycemia, metabolic acidosis	Hepatomegaly	Leucine and fat restriction
	Sensitivity to dietary leucine	Early death	L-Carnitine
2-methyl-3-hydroxyisobutyric aciduria	Static or progressive encephalopathy,	Seizures, optic atrophy, retinopathy, deafness, ataxia, di or tetraplegia, cardiomyopathy, facial dysmorphism	Isoleucine restriction
	Few cases with acute metabolic decompensation		Antioxidant therapy
	Milder phenotype in female patients
Methylbutyryl-CoA dehydrogenase def.	Acute neonatal acidosis, MRI abnormalities	Intellectual disability, seizures in few symptomatic patients	Protein restriction
	Hmong decent: transient hypotonia, or mostly completely asymptomatic		L-Carnitine
			No treatment for Hmong patients
Mitochondrial acetoacetyl-CoA thiolase deficiency	Acute intermittent ketoacidosis,	Intellectual disability (small percent of patients)	Protein restriction
	vomiting, coma	Mostly excellent outcome with dietary restriction
Isobutyryl-CoA dehydrogenase deficiency	Anemia	Dilated cardiomyopathy	L-Carnitine
3-Hydroxyisobutyryl- CoA deacylase deficiency	Congenital malformations, failure to thrive, developmental delay	Failure to thrive	Protein restriction
			L-Carnitine
3-Hydroxyisobutyric aciduria	Brain dysgenesis, multiple congenital malformations, acute ketoacidosis	Failure to thrive,	Protein restriction
		Intellectual disability	L-Carnitine
Methylmalonic semialdehyde dehydrogenase deficiency	Mild clinical symptoms	Asymptomatic	Protein restriction
			L-Carnitine
Propionic acidemia	Recurrent ketoacidosis	Cardiomyopathy	Protein restriction
	Hyperglycinemia, Hyperammonemia, Coma	Seizures	Valine, isoleucine, methionine, threonine free formula
	Neutropenia, thrombocytopenia	Osteoporosis	L-Carnitine, (biotin)
	Hypotonia	Pancreatitis	Bicarbonate or citrate replacement
		Intellectual disability	Reduction of propiogenic gut flora (metronidazole or neomycin)
			Liver transplantation
Methylmalonic acidemia	Recurrent ketoacidosis	Chronic renal failure	Protein restriction
	Anorexia, failure to thrive	Renal tubular acidosis	Valine, isoleucine, methionine, threonine free formula
	Hepatomegaly	Recurrent pancreatitis	L-Carnitine
	Hyperglycinemia, Hyperammonemia, Coma	Osteoporosis	Bicarbonate or citrate replacement
	Pancytopenia	Metabolic stroke of the globus pallidus, spastic quadriparesis, choreoathetosis, dystonia	Reduction of propiogenic gut flora (metronidazole or neomycin)
	Hypotonia	Intellectual disability	OHCbl (cblA, mut- responsive patients)
		Bulls’ eye maculopathy and blindness (CblC disease)	Liver and/or kidney transplant (selected patients)
		Seizures, intellectual disability	OHCbl and betaine (in cblC disease)