Microcephaly, Progressive, With Seizures And Cerebral And Cerebellar Atrophy

A number sign (#) is used with this entry because progressive microcephaly with seizures and cerebral and cerebellar atrophy (MSCCA) is caused by compound heterozygous mutation in the QARS gene (QARS1; 603727) on chromosome 3p21.

Description

Progressive microcephaly with seizures and cerebral and cerebellar atrophy is a severe autosomal recessive neurodevelopmental and neurodegenerative disorder with onset in the first days or months of life. Patients are born with microcephaly and soon develop intractable seizures, resulting in profoundly delayed development and hypotonia (summary by Zhang et al., 2014).

Clinical Features

Zhang et al. (2014) reported 4 children from 2 unrelated families who presented at birth with sloping forehead and microcephaly. All showed profound developmental delay and progressive microcephaly (in 1 patient, -10 SD) in the first years of life. Three patients developed severe intractable seizures in the first days of life, including status epilepticus in 1 patient and migrating partial seizures in another. The fourth patient developed recurrent intractable seizures at age 1 month. In 1 family, 2 brothers had episodes of agitation associated with pneumonia and rhabdomyolysis. Other more variable features included cortical visual impairment, lack of visual contact, loss of visual contact after onset of seizures, hypotonia, and hyperreflexia. Dysmorphic features were also variable and included bitemporal narrowing, epicanthal folds, broad flat nasal bridge, hypotelorism, and low-set, posteriorly rotated ears. Brain imaging showed apparent neurodegeneration, hypomyelination or delayed myelination, thin corpus callosum, enlarged cerebral ventricles, and small cerebellar vermis. Two brothers, who had more severe microcephaly, also had a simplified gyral pattern on brain imaging.

Inheritance

The transmission pattern of MSCCA in the family reported by Zhang et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 patients from 2 unrelated families with MSCCA, Zhang et al. (2014) identified compound heterozygous mutations in the QARS gene (603727.0001-603727.0004). The mutations were found by whole-exome sequencing. Studies in patient cells and expression of recombinant variants in E. coli showed that all 4 mutations caused a severe loss of QARS catalytic activity, consistent with a loss-of-function effect. Homozygous loss of qars in zebrafish caused decreased brain and eye size and extensive cell death in the brain. The results suggested that QARS is essential for normal brain development.