Periventricular Heterotopia With Microcephaly, Autosomal Recessive

A number sign (#) is used with this entry because autosomal recessive periventricular nodular heterotopia with microcephaly (ARPHM) is caused by homozygous mutation in the ARFGEF2 gene (605371) on chromosome 20q13.

For a phenotypic description and a discussion of genetic heterogeneity of periventricular heterotopia, see 300049.

Clinical Features

Sheen et al. (2003) described 2 consanguineous pedigrees with periventricular heterotopia suggesting an autosomal recessive inheritance pattern. Magnetic resonance imaging (MRI) of the brains of affected individuals revealed periventricular nodules of cerebral gray matter intensity, typical of the disorder. One of the families was Turkish with a 2.5-year-old boy and 16-month-old girl affected. The other family was Israeli of Yemenite ethnicity with a much less severe neurologic phenotype. In this family, a 41-year-old man and his 60-year-old sister had histories of seizures but were otherwise in good health. Another sib had a history of seizures but refused MRI and was considered probably affected. Microsatellite analysis of the pedigrees suggested no linkage to the FLNA (300017) or FLNB (603381) genes. Sheen et al. (2003) noted the difference in severity between the 2 families and suggested that it may be due to genetic heterogeneity.

Sheen et al. (2004) noted that severe developmental delay and recurrent infections are clinical features of ARPHM. No anomalies extrinsic to the CNS, such as dysmorphic features or grossly abnormal endocrine or other conditions, are associated. MRI of the brains of affected individuals shows notable periventricular heterotopia, resulting from a failure of neurons to migrate normally from the lateral ventricular proliferative zone, where they are formed, to the cerebral cortex. Abnormal MRI signals in subcortical white matter and elsewhere also suggest a delay in the normal myelination by glial cells.

Banne et al. (2013) reported 5 patients from a consanguineous Palestinian family who developed infantile spasms accompanied by hypsarrhythmia between ages 3 and 9 months. The patients had severely delayed psychomotor development even before onset of seizures, and all eventually showed severe mental retardation. The features were consistent with a clinical diagnosis of West syndrome. Other features included progressive microcephaly (-3 to -5 SD) and severe hypotonia. Brain MRI showed diffuse periventricular heterotopia with a thin corpus callosum. No other organ systems were affected.

Mapping

By an initial genomewide screen at 10-cM intervals in 2 Turkish families with ARPHM, Sheen et al. (2004) identified shared homozygosity at a single locus on 20q11.21-q13.2, which they refined by further marker analysis.

Molecular Genetics

In affected members of 2 Turkish families with ARPHM, including 1 reported by Sheen et al. (2003), Sheen et al. (2004) identified homozygous mutations in the ARFGEF2 gene (605371.0001 and 605371.0002).

In 5 members of a consanguineous Palestinian family with periventricular heterotopia with microcephaly, Banne et al. (2013) identified a homozygous mutation in the ARFGEF2 gene (605371.0003). The mutation was found by homozygosity mapping combined with whole-exome sequencing.