A number sign (#) is used with this entry because of evidence that autosomal dominant 3-methylglutaconic aciduria type VIIA (MGCA7A) is caused by heterozygous dominant-negative mutation in the CLPB gene (616254) on chromosome 11q13.

Biallelic loss-of-function mutation in the CLPB gene causes an autosomal recessive form of the disorder (MGCA7B; 616271), which shows overlapping features.

3-Methylglutaconic aciduria (MGCA7) is an inborn error of metabolism characterized primarily by increased levels of 3-methylglutaconic acid (3-MGA) associated with variable neurologic deficits and neutropenia. The phenotype is highly variable: most patients have infantile onset of a severe progressive encephalopathy with various movement abnormalities and delayed psychomotor development. Other common variable features include seizures, recurrent infections due to neutropenia, anemia, and brain imaging abnormalities (Wortmann et al., 2021).

For a general phenotypic description and a discussion of genetic heterogeneity of 3-methylglutaconic aciduria, see MGCA1 (250950).

Wortmann et al. (2021) identified 6 unrelated patients, ranging in age from 19 months to 12.5 years, with neurologic deficits, 3-methylglutaconic aciduria, and neutropenia (in 5 patients) associated with de novo heterozygous missense mutations in the CLPB gene. The patients presented in early infancy with either seizures and developmental delay or recurrent infections and neutropenia. All eventually showed global developmental delay, although the severity was highly variable. Most patients had impaired intellectual development, poor or absent speech, axial hypotonia, limb spasticity, and difficulty walking or inability to walk. Five patients had variable types of seizures, and 3 showed developmental regression with loss of skills, suggesting neurodegeneration. All patients had brain imaging abnormalities, including cerebral atrophy, cerebellar atrophy, periventricular white matter alterations, thin corpus callosum, and delayed myelination. Four patients had secondary microcephaly. The least affected individual (P6) had mild speech delay and no seizures, whereas the most severely affected individual (P2) had early-onset seizures and essentially no development and died of respiratory failure at age 19 months. Cataracts were notably absent in all patients. All patients except P1 had neutropenia, and several had mild anemia. Two patients underwent hematopoietic stem cell transplant at age 15 months and 5 years, respectively. Wortmann et al. (2021) noted the phenotypic similarities to patients with MGCA7B who have biallelic mutations in the CLPB gene.

The heterozygous mutations in the CLPB gene that were identified in patients with MGCA7A by Wortmann et al. (2021) occurred de novo.

In 6 unrelated patients with MGCA7A manifest as neutropenia and neurologic dysfunction, Wortmann et al. (2021) identified 4 different de novo heterozygous missense variants in the CLPB gene (see, e.g., 616254.0011-616254.0013). The mutations, which were found by exome or genome sequencing, were not present in the gnomAD database. In vitro functional expression studies using a luciferase assay showed that the mutations caused a variable reduction in ATPase activity and impaired the renaturation and disaggregase activity of CLPB. When mixed with wildtype CLPB, the mutations demonstrated a dominant-negative effect. In control fibroblasts, HAX1 (605998) migrated predominantly as a monomer, whereas patient samples showed multiple HAX1 peaks comigrating at higher molecular masses with CLPB. These findings suggested a longer-lasting interaction between CLPB and HAX1; HAX1 is mutated in SCN3 (610738).