Methylmalonate Semialdehyde Dehydrogenase Deficiency

A number sign (#) is used with this entry because of evidence that methylmalonate semialdehyde dehydrogenase deficiency (MMSDHD) is caused by homozygous or compound heterozygous mutation in the ALDH6A1 gene (603178) on chromosome 14q24.

Description

Methylmalonate semialdehyde dehydrogenase deficiency is a rare autosomal recessive inborn error of metabolism with a highly variable phenotype. Some patients may be asymptomatic, whereas others show global developmental delay, nonspecific dysmorphic features, and delayed myelination on brain imaging. Laboratory studies typically show increased urinary 3-hydroxyisobutyric acid, although additional metabolic abnormalities may also be observed (summary by Marcadier et al., 2013).

Clinical Features

Pollitt et al. (1985) and Gray et al. (1987) reported a male child with methylmalonate semialdehyde dehydrogenase deficiency characterized by elevated beta-alanine, 3-hydroxypropionic acid, and both isomers of 3-amino and 3-hydroxyisobutyric acids in urine organic acids. The child, who was asymptomatic, was identified through newborn screening.

Shield et al. (2001) reported a girl, born of consanguineous Pakistani parents, with significant hypotonia in infancy, poor feeding, and dysmorphic facial features, including narrowed, downslanting palpebral fissures, short convex nose with depressed nasal bridge, microphthalmia, cataracts, and adducted thumbs. She had severe developmental delay and marked postnatal microcephaly. Brain imaging showed delayed myelination and thinning of the corpus callosum. Laboratory studies showed 3-hydroxyisobutyric aciduria and mild lactic acidosis. Family studies identified a brother with 3-hydroxyisobutyric aciduria, microcephaly, and moderate learning difficulties. However, an unaffected brother also had microcephaly, indicating that microcephaly did not segregate with 3-hydroxyisobutyric aciduria in this family. Shield et al. (2001) concluded that the phenotype in the proband was consistent with Warburg Micro syndrome (see, e.g., WARBM1, 600118), but also suggested that the phenotype of the biochemical abnormality may show intrafamilial variability.

Sass et al. (2012) reported a boy, born of related parents of European origin, with MMSDHD. The child was first seen at age 12 months for mildly delayed development, microcephaly, and mild dysmorphic features, such as bulbous nose with hypoplastic nasal alae and long philtrum. Laboratory studies showed increased urinary 3-hydroxyisobutyric acid. He made significant progress on a low-protein, valine-restricted diet and showed normal age-appropriate development at age 25 months. He then developed a febrile illness and showed acute metabolic decompensation, resulting in death from hepatoencephalopathy secondary to liver failure. Of note, the patient had been treated with acetaminophen, and liver samples showed toxic liver injury, although acetaminophen levels were not increased in postmortem tissue. Postmortem examination also showed calcifications in the frontal cortex.

Marcadier et al. (2013) reported a 3-year-old girl with MMSDHD who presented in infancy with global developmental delay, hypotonia, and poor visual fixation. Dysmorphic features included high forehead, sparse hair, epicanthal folds, hypertelorism, short anteverted nose, tented mouth, and high-arched palate. Deep tendon reflexes were brisk, coordination was abnormal, and movements were dystonic. She also showed poor head growth. Laboratory studies over time showed transient and/or variable elevations of lactate, methylmalonic acid, 3-hydroxyisobutyric acid, and 3-aminoisobutyric acid.

Inheritance

The transmission pattern of MMSDHD in the families reported by Sass et al. (2012) was consistent with autosomal recessive inheritance.

Molecular Genetics

In the patient with methylmalonate semialdehyde dehydrogenase deficiency described by Pollitt et al. (1985) and Gray et al. (1987), Chambliss et al. (2000) identified a homozygous 1336G-A transition in the MMSDH gene, resulting in a gly446-to-arg (G446R; 603178.0001) substitution. The mother was heterozygous for the mutation, but the father was not available for testing. The patient was likely the product of a consanguineous union.

In 2 unrelated patients with MMSDHD, one of whom was previously reported by Shield et al. (2001), Sass et al. (2012) identified homozygous missense mutations in the ALDH6A1 gene (S262Y, 603178.0002 and P62S, 603178.0003). Functional studies of the variants were not performed.

In a patient with MMSDHD, Marcadier et al. (2013) identified compound heterozygous missense mutations in the ALDH6A1 gene (Y172H, 603178.0004 and R535C, 603178.0005). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Patient fibroblasts showed reduced ALDH6A1 activity compared to controls, but direct functional studies of the variants were not performed.