Microcephaly, Cataracts, Impaired Intellectual Development, And Dystonia With Abnormal Striatum

A number sign (#) is used with this entry because of evidence that microcephaly, cataracts, impaired intellectual development, and dystonia with abnormal striatum (MCIDDS) is caused by homozygous mutation in the KCNA4 gene (176266) on chromosome 11p14. One such family has been reported.

Description

The MCIDDS syndrome is characterized by microcephaly and growth retardation, congenital cataracts, impaired intellectual development with attention deficit-hyperactivity disorder, and dystonia, with striatal thinning seen on MRI (Al-Owain et al., 2013).

Clinical Features

Al-Owain et al. (2013) reported 4 sibs from a consanguineous Saudi family who all exhibited microcephaly, growth retardation, mild delay in gross motor skills, and bilateral congenital cataract. The sibs had impaired cognitive function, with IQs ranging from 77 to 89, and showed moderate attention deficit-hyperactivity disorder with marked linguistic delay and dysarthric speech. Neurologic examination showed brisk deep tendon reflexes with clonus, positive Babinski response, cogwheel rigidity, dystonic posturing, and spastic gait. Brain MRI in all patients showed an unusual pattern of thinning of the lentiform nucleus, predominantly involving the putamen, as well as swelling in the caudate heads bilaterally. PET scan showed moderate to severe hypometabolism of the putamina bilaterally.

Mapping

In a consanguineous Saudi family with microcephaly, cataracts, impaired intellectual development, and dystonia with abnormal striatum, Al-Owain et al. (2013) performed genomewide linkage analysis using SNP-based chip arrays and obtained a maximum lod score of 4.2353 at a 45.9-Mb region on chromosome 11 (chr11:23,348,262-69,261,956).

Kaya et al. (2016) restudied the consanguineous Saudi family with MCIDDS, originally reported by Al-Owain et al. (2013), and obtained a lod score of 4.0896 on chromosome 11 between rs11602300 and rs7118193.

Molecular Genetics

In the proband of a consanguineous Saudi family with microcephaly, cataracts, impaired intellectual development, and dystonia with abnormal striatum, originally reported by Al-Owain et al. (2013) and negative for mutation in 266 cataract-associated genes, Kaya et al. (2016) performed exome sequencing and identified homozygosity for a missense mutation in the KCNA4 gene (R89Q; 176266.0001). The mutation segregated fully with disease in the family and was not found in 428 controls, but was present twice in heterozygous state in the ExAC database. Functional analysis demonstrated a decrease in whole-cell current with mutant channels compared to wildtype KCNA4.

Exclusion Studies

In a consanguineous Saudi family with MCIDDS, Al-Owain et al. (2013) analyzed the mitochondrial genome but identified no likely pathogenic changes. In addition, they detected no pathogenic CNVs within the linkage interval on chromosome 11 or elsewhere in the genome.