3-Methylglutaconic Aciduria With Cataracts, Neurologic Involvement, And Neutropenia

A number sign (#) is used with this entry because of evidence that 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MEGCANN), also referred to as 3-methylglutaconic aciduria type VII (MGCA7), is caused by homozygous or compound heterozygous mutation in the CLPB gene (616254) on chromosome 11q13.

Description

3-Methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MEGCANN) is an autosomal recessive inborn error of metabolism characterized primarily by increased levels of 3-methylglutaconic acid (3-MGA) associated with neurologic deterioration and neutropenia. The phenotype is highly variable: most patients have infantile onset of a progressive encephalopathy with various movement abnormalities and delayed psychomotor development, although rare patients with normal neurologic development have been reported. Other common, but variable, features include cataracts, seizures, and recurrent infections (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).

Clinical Features

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-MGA 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 MEGCANN. 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.

Inheritance

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

Molecular Genetics

In 14 individuals from 9 unrelated families with MEGCANN 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 MEGCANN, 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 MEGCANN, 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.

Animal Model

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.