Mega-Corpus-Callosum Syndrome With Cerebellar Hypoplasia And Cortical Malformations

A number sign (#) is used with this entry because of evidence that mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (MCCCHCM) is caused by heterozygous mutation in the MAST1 gene (612256) on chromosome 19p13.

Description

MCCCHCM is an autosomal dominant neurodevelopmental disorder characterized by global developmental delay, impaired intellectual development, and characteristic brain abnormalities on brain imaging. Affected individuals have enlargement of the corpus callosum, enlarged ventricles, and cerebellar and brainstem hypoplasia. Other features may include lack of speech development, gait instability, and seizures. Some patients with MAST1 mutations may have impaired intellectual development and/or autism spectrum disorder without significant findings on brain imaging (summary by Tripathy et al., 2018).

Clinical Features

Tripathy et al. (2018) reported 6 unrelated children with characteristic brain malformations, including enlargement of the corpus callosum, enlarged ventricles, and cerebellar and brainstem hypoplasia. Four patients had gyral simplification, 3 had dysplastic longitudinal gyri, and 1 had periventricular white matter nodules. The patients had variable motor and cognitive impairment, ranging from intellectual disability to severe encephalopathy; 5 were nonverbal. The patients had hypotonia and unsteady gait or only the ability to sit. Less common features included seizures (in 2 patients), short stature, strabismus, and oculomotor apraxia.

Clinical Variability

Through the GeneMatcher program, Tripathy et al. (2018) identified 4 additional unrelated children with developmental delay and impaired intellectual development and poor or absent speech associated with de novo missense variants in the MAST1 gene. Two of the patients had autism spectrum disorder and 2 had mild microcephaly. Brain imaging showed a small brainstem, cerebellum, and enlarged ventricles in 1 patient and dorsal hypoplasia of the corpus callosum in another patient, but the other 2 patients had normal brain imaging. More variable features included gait instability, hypotonia, esotropia, dysmorphic features, and seizures. Functional studies of the variants and studies of patient cells were not performed, but the variants were not found in the dbSNP, 1000 Genomes Project, or ExAC databases, Tripathy et al. (2018) speculated that these variants had a deleterious effect on protein function and may contribute to a phenotypic spectrum of neurodevelopmental disorders.

Molecular Genetics

In 6 unrelated patients with MCCCHCM, Tripathy et al. (2018) identified de novo heterozygous mutations in the MAST1 gene (612256.0001-612256.0004). The mutations were found by exome sequencing and confirmed by Sanger sequencing. Three unrelated patients carried in-frame deletions of single residues in a hydrophobic core of a 4-helix bundle in the domain of unknown function (DUF1908), and 3 unrelated patients carried the same missense variant in the kinase domain (G517S; 612256.0004). In vitro functional studies showed that 1 of the variants (lys276del; 612256.0002) increased MAST1 binding to microtubules compared to controls. Mutant mice heterozygous for a Mast1 leu278del allele (612256.0003) showed a thicker corpus callosum compared to wildtype, which was due to an increase in the number of myelinated axons crossing the midline. Mutant mice also had an overall reduction in cortical volume and thickness and decreased cerebellar volume and number of granule and Purkinje cells due to increased apoptosis compared to controls.

Animal Model

Tripathy et al. (2018) used CRISPR-Cas9 genome editing to generate a mutant Mast1 mouse strain with heterozygous expression of a leu278del allele, to recapitulate the mutation identified in a patient with MCCCHCM (612256.0003). Mutant mice showed a thicker corpus callosum compared to wildtype, which was due to an increase in the number of myelinated axons crossing the midline. Mutant mice also had an overall reduction in cortical volume and thickness and decreased cerebellar volume and number of granule and Purkinje cells due to increased apoptosis compared to controls. The deletion of leu278 was associated with decreased levels of other MAST protein family members, whereas complete loss of Mast1 was associated with increased levels of other MAST proteins, likely a compensatory effect. These findings suggested that the leu278 allele acts in a dominant-negative manner. There was no evidence of abnormal activation of the AKT3 (611223)/mTOR (see 601231) pathway.