A number sign (#) is used with this entry because of evidence that autosomal recessive 3-methylglutaconic aciduria type VIIB (MGCA7B) is caused by homozygous or compound heterozygous loss-of-function mutations in the CLPB gene (616254) on chromosome 11q13.

Heterozygous dominant-negative mutations in the CLPB gene cause autosomal dominant MGCA7A (619835), which shows similar 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, although rare patients with normal neurologic development have been reported. Other common variable features include cataracts, seizures, recurrent infections due to neutropenia, and brain imaging abnormalities (summary by Wortmann et al., 2015 and Saunders et al., 2015).

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

Wortmann et al. (2015) reported 14 individuals from 9 unrelated families with an inborn error of metabolism characterized by increased urinary excretion of 3-MGA. Additional features were highly variable, with some patients having no neurologic involvement or infections and others having neonatal or even prenatal onset of progressive neurologic symptoms and/or severe neutropenia with progression to leukemia and death in the first months of life. Common features included delayed psychomotor development/variable intellectual disability (12 patients), congenital neutropenia (10 patients), brain atrophy (7 patients), microcephaly (7 patients), movement disorder (7 patients), and cataracts (5 patients). The oldest living patient was 18 years old and the youngest was 2; 6 patients died between 24 days and 46 months of age. The least severely affected children were a pair of sibs ascertained due to neutropenia. One sib had congenital nuclear cataracts and the other had attention deficit-hyperactivity disorder, dyslexia, and dysgraphia; however, both showed normal overall growth and development at ages 8 and 10 years, respectively. Most of the other patients showed neonatal hypotonia that progressed to spasticity, suggesting pyramidal tract dysfunction. Patients with a moderate phenotype had hypotonia, feeding difficulties, microcephaly, delayed psychomotor development, ataxia, and dystonia. Four patients had the most severe phenotype, with onset in utero or at birth of increased muscle tension ('stiff babies'), lack of eye contact, complete absence of development, and death in the first months of life. Eleven patients had swallowing difficulties, and 4 had seizures. Results of brain imaging also varied significantly, and included normal findings, isolated cerebellar atrophy, cerebral atrophy, and abnormalities of the basal ganglia. Ten patients had neutropenia, but only some patients had recurrent severe infections. Two sibs developed acute myeloid leukemia and myelodysplastic syndrome, respectively. Less common features, occurring in only a few patients, included facial dysmorphism, cardiomyopathy or hypertrophy, and hypothyroidism. Studies of patient cells did not show defects in mitochondrial oxidative phosphorylation.

Saunders et al. (2015) reported 4 children, including 2 sibs, of Greenlandic descent, and an unrelated child of northern European and Asian descent, with 3-MGCA and neutropenia. The 4 children of Greenlandic origin showed regression of psychomotor development after a few months of normal early development; all died within the first years of life. The fifth child presented at birth with growth retardation, microcephaly, rigidity, contractures, and abnormal facial features, and died from respiratory failure on day 8 of life. Additional variable features among all patients included cataracts, hypotonia, extrapyramidal symptoms such as myoclonus, dystonia, choreoathetosis, opisthotonus, and seizures. Bone marrow biopsies showed maturational arrest of granulopoiesis. Brain imaging was either normal or showed cerebral atrophy; 1 patient had lesions in the basal ganglia.

Capo-Chichi et al. (2015) reported 4 sibs, born of consanguineous Cambodian parents, with a severe form of MGCA7. They did not move or breathe spontaneously at birth. Appendicular tone was increased, and they showed sustained clonic movements induced by minimal tactile stimulation. EEG showed burst suppression. Brain imaging in 1 patient showed gyral simplification. All were ventilator-dependent and died in the first week of life after removal of respiratory support. Laboratory studies showed increased serum lactate, increased urinary 3-methylglutaconic acid and methylglutaric acid, neutropenia, and coagulation defects. Neuropathologic examination showed neuronal loss in several brain regions, diffuse gliosis, and microvacuolization, which are nonspecific changes consistent with a defect in energy metabolism.

Rivalta et al. (2022) reported a 5-year-old girl who was found to have severe neutropenia in the setting of respiratory distress and fever at 1 year of age. She had severe, persistent neutropenia, and a bone marrow examination showed selective maturation arrest of neutrophil precursors. Laboratory testing showed hypergammaglobulinemia with normal IgA, IgM, and IgE as well as normal response to vaccines. She had increased excretion of urine 3-methylglutaconic acid and 3-methylglutaric acid.

The transmission pattern of MGCA7B in the families reported by Wortmann et al. (2015) and Saunders et al. (2015) was consistent with autosomal recessive inheritance.

In 14 individuals from 9 unrelated families with MGCA7B, Wortmann et al. (2015) identified 14 different homozygous or compound heterozygous mutations in the CLPB gene (see, e.g., 616254.0001-616254.0007). Mutations in the first 2 unrelated patients were found by exome sequencing; mutations in subsequent patients were found by direct sequencing of the CLPB gene in 16 additional individuals with a similar phenotype. There was no clear correlation between the severity of the disorder and the position and nature of the specific missense mutations, although patients with a more severe phenotype tended to carry mutations resulting in complete absence of the functional protein. Fibroblasts from affected individuals did not show defects in mitochondrial oxidative phosphorylation or phospholipid metabolism. In vitro functional expression studies performed on 1 of the mutations (R408G; 616254.0006) showed that the mutant protein had decreased ATPase activity at 26% of wildtype. Four missense variants were unable to rescue morpholino knockdown of the clpb ortholog in zebrafish, suggesting that these variants had little or no residual activity.

In 4 patients, including 2 sibs, of Greenlandic descent with MGCA7B, Saunders et al. (2015) identified a homozygous missense mutation in the CLPB gene (T268M; 616254.0008). The mutation was found by homozygosity mapping and candidate gene sequencing. Exome sequencing of an unrelated patient with a similar disorder identified compound heterozygous truncating mutations in the CLPB gene (616254.0007 and 616254.0009). Immunoblot analysis of patient fibroblasts showed absence of the CLPB protein.

In 4 sibs, born of consanguineous Cambodian parents, with MGCA7B, Capo-Chichi et al. (2015) identified a homozygous truncating mutation in the CLPB gene (616254.0010) that segregated with the disorder in the family. The mutation was found by a combination of homozygosity mapping and exome sequencing and confirmed by Sanger sequencing.

In a patient with MGCA7B, Rivalta et al. (2022) identified compound heterozygous mutations in the CLPB gene (616254.0018-616254.0019). The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. Each parent was heterozygous for one of the mutations. Rivalta et al. (2022) concluded that biallelic mutations in CLPB can cause a mild phenotype with isolated severe congenital neutropenia.

Wortmann et al. (2015) found that morpholino knockdown of the clpb ortholog in zebrafish embryos resulted in dose-dependent cerebellar defects, microcephaly, and reduction of the size of the optic tectum.