Urine valine level above the normal range.

Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.

Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.

Abnormal feeling of sleepiness or difficulty staying awake.

Motor hyperactivity with excessive movement of muscles of the body as a whole.

Reduced strength of muscles.

Valinemia is an inborn error of metabolism characterized clinically by vomiting, feeding difficulties, hypotonia, and developmental delay, and biochemically by high concentrations of valine in serum and urine (Wada, 1965).

Valinemia is an inborn error of metabolism characterized clinically by vomiting, feeding difficulties, hypotonia, and developmental delay, and biochemically by high concentrations of valine in serum and urine (Wada, 1965).

The major clinical features of maple syrup urine disease (MSUD) are mental and physical retardation, feeding problems, and a maple syrup odor to the urine. The keto acids of the branched-chain amino acids (BCAA) are present in the urine, resulting from a block in oxidative decarboxylation. There are 4 clinical subtypes of MSUD1B: the classic neonatal severe form, an intermediate form, an intermittent form, and a thiamine-responsive form (Chuang and Shih, 2001). The classic form is manifested within the first 2 weeks of life with poor feeding, lethargy, seizures, coma, and death if untreated. Intermediate MSUD is associated with elevated BCAAs and BCKA, with progressive mental retardation and developmental delay without a history of catastrophic illness. The diagnosis is usually delayed for many months. An intermittent form of MSUD may have normal levels of BCAAs, normal intelligence and development until a stress, e.g., infection, precipitates decompensation with ketoacidosis and neurologic symptoms, which are usually reversed with dietary treatment. Thiamine-responsive MSUD is similar to the intermediate phenotype but responds to pharmacologic doses of thiamine with normalization of BCAAs (Chuang et al., 1995). For general phenotypic information and a discussion of genetic heterogeneity of MSUD, see MSUD1A (248600).

Myopathy with extrapyramidal signs is an autosomal recessive disorder characterized by early childhood onset of proximal muscle weakness and learning disabilities. While the muscle weakness is static, most patients develop progressive extrapyramidal signs that may become disabling (summary by Logan et al., 2014). Brain MRI in 1 patient showed congenital malformations, including polymicrogyria and cerebellar dysplasia (Wilton et al., 2020).

Hypervalinemia and hyperleucine-isoleucinemia (HVLI) is a branched-chain amino acid metabolic disorder characterized by highly elevated plasma valine and leucine concentrations. The patient presented in adulthood with headache and mild memory impairment, and had abnormal symmetric white matter signals on brain MRI (Wang et al., 2015).

Hypermetabolism due to uncoupled mitochondrial oxidative phosphorylation-2 (HUMOP2) is characterized by failure to thrive apparent in infancy despite adequate caloric intake. Affected individuals show normal thyroid function, hyperphagia, tachypnea, increased basal temperature, and increased sweating. Biochemical studies demonstrate increased mitochondrial oxygen consumption with inefficient production of ATP in the final steps of oxidative phosphorylation due to an uncoupling defect (Ganetzky et al., 2022). Genetic Heterogeneity of Hypermetabolism due to Uncoupled Mitochondrial Oxidative Phosphorylation See also HUMOP1 (238800).