Cerebellar Atrophy, Visual Impairment, And Psychomotor Retardation

A number sign (#) is used with this entry because of evidence that cerebellar atrophy, visual impairment, and psychomotor retardation (CAVIPMR) is caused by homozygous mutation in the EMC1 gene (616846) on chromosome 1p36.

Clinical Features

Harel et al. (2016) reported 6 children from 3 unrelated families of different ethnic origin with a severe neurodegenerative disorder apparent since birth. The children, ranging in age from 3 to 14 years, had global developmental delay, speech delay, and hypotonia associated with cerebellar atrophy and a short or atrophic corpus callosum. Four patients from 2 families had a more severe disorder, with profound intellectual disability, progressive microcephaly (up to -4 SD), increased tone in the extremities, hyporeflexia, dystonic posturing, scoliosis, and cerebral atrophy. All patients had some variable dysmorphic features, including deep-set eyes, gingival hyperplasia, retrognathia, and short philtrum. Ophthalmologic abnormalities were also present, and included cortical visual impairment, abnormal visual evoked potentials (VEP) and electroretinograms (ERG), esotropia, strabismus, and astigmatism. Only 1 patient had evidence of subclinical seizures. The families were of European, Turkish, and Saudi Arabian origin; 2 of the families were consanguineous.

Inheritance

The transmission pattern of CAVIPMR in the families reported by Harel et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In affected children from 3 unrelated families with CAVIPMR, Harel et al. (2016) identified homozygous mutations in the EMC1 gene (616846.0002-616846.0004). One of the mutations was a truncating mutation; the other 2 were missense mutations. The mutations were found by whole-exome sequencing. Functional studies of the variants and studies of patient cells were not performed. A 12-year-old boy from a fourth family with overlapping features was found to carry a de novo heterozygous missense variant in the EMC1 gene (G471R). A second hit in the EMC1 gene was not found in this patient, and functional studies of the G471R variant were not performed. This patient also carried compound heterozygous variants in other genes, including URB1 (608865). However, Harel et al. (2016) suggested that the EMC1 variant contributed to the phenotype.