Microcephaly, Postnatal Progressive, With Seizures And Brain Atrophy

A number sign (#) is used with this entry because the phenotype, which is characterized by postnatal progressive microcephaly, seizures, and brain atrophy, is caused by homozygous mutation in the MED17 gene (603810) on chromosome 11.

Clinical Features

Kaufmann et al. (2010) reported 5 infants from 4 Jewish families from the Caucasus region with postnatal progressive microcephaly and severe developmental retardation associated with cerebral and cerebellar atrophy. One of the families was consanguineous. All pregnancies were uneventful, and the infants were born at term with normal head circumference. Ultrasound performed at 22 weeks' gestation in 1 affected infant showed normal brain structure. At 4 to 9 weeks of age, all developed swallowing difficulties leading to failure to thrive, jitteriness, poor visual fixation and lack of tracking, truncal arching, and seizures. Physical examination at that time showed microcephaly, increased muscle tone, clonus, and hyperreflexia. None showed further developmental progression; features included marked spasticity and profound retardation. Progressive microcephaly was evident, with a head circumference of -6 SD at 9 months of age. Dysmorphic features were not noted. At the time of the report, all patients were alive, ranging in age from 5 months to 15 years. EEG abnormalities were progressive, and included dysmature background with multifocal spike and wave activity, hypsarrhythmia, and a diffuse slowing of background with bilateral slow, sharp frontotemporal activity at an older age. Brain MRI revealed severe diffuse cerebral and cerebellar atrophy, small thalami, thin brainstem, and poor myelination. Routine laboratory investigations were normal.

Mapping

By homozygosity mapping of Caucasus Jewish patients with postnatal microcephaly, seizures, and brain atrophy, Kaufmann et al. (2010) identified a 2.28-Mb region of homozygosity on chromosome 11 between rs12363947 and rs333027.

Molecular Genetics

By candidate gene sequencing of 5 patients from 4 families with postnatal progressive microcephaly, seizures, and brain atrophy, Kaufmann et al. (2010) identified a homozygous mutation in the MED17 gene (L371P; 603810.0001). Screening of additional patients with a similar disorder identified the same homozygous mutation in 4 more patients. All affected individuals were of Caucasus Jewish origin, indicating a founder effect. The L371P mutation was found in the heterozygous state in 4 of 76 unaffected individuals in this population. The mutation was not found in 110 individuals of Ashkenazi Jewish origin or in 113 individuals of Arab Moslem origin.

Population Genetics

All patients with infantile postnatal microcephaly, seizures, and brain atrophy, Kaufmann et al. (2010) were of Caucasus Jewish origin and were found to have the same homozygous mutation (L371P; 603810.0001) in the MED17 gene, suggesting a founder effect. The Jewish community in the Caucasus region is believed to have originated from the area of today's (2010) southern Iran. The Caucasus Jews were genetically isolated for more than 2,500 years by their language and religious practice, and most members of this community immigrated to Israel between 1970 and 1990.