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. In vitro functional studies showed that 1 of the variants (lys276del 612256.0002) increased MAST1 binding to microtubules compared to controls. 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). The mutations were found by exome sequencing and confirmed by Sanger sequencing. In 6 unrelated patients with MCCCHCM, 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. 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. More variable features included gait instability, hypotonia, esotropia, dysmorphic features, and seizures. 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. Two of the patients had autism spectrum disorder and 2 had mild microcephaly. (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. Through the GeneMatcher program, Tripathy et al. Less common features included seizures (in 2 patients), short stature, strabismus, and oculomotor apraxia. The patients had hypotonia and unsteady gait or only the ability to sit.
The patients had variable motor and cognitive impairment, ranging from intellectual disability to severe encephalopathy 5 were nonverbal. Four patients had gyral simplification, 3 had dysplastic longitudinal gyri, and 1 had periventricular white matter nodules. (2018) reported 6 unrelated children with characteristic brain malformations, including enlargement of the corpus callosum, enlarged ventricles, and cerebellar and brainstem hypoplasia. Periventricular nodular formations (in some patients) Seizures (in some patients) Įnlarged corpus callosum Įnlarged ventricles Ĭerebellar hypoplasia īrainstem hypoplasia
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