Pontocerebellar hypoplasia type III (CLAM): extended phenotype and novel molecular findings

Abstract

Pontocerebellar hypoplasia (PCH) is a heterogeneous group of disorders characterized by abnormally small cerebellum and brainstem. Recently a rare, novel form of PCH has been reported called cerebellar atrophy with progressive microcephaly (CLAM). Here we report a second family of CLAM with additional phenotypic features and novel molecular findings. Three-year old index patient had severe developmental delay and presented with short stature and microcephaly. Her cranial magnetic resonance imaging revealed hypoplasia of the cerebellum, brainstem and cerebrum associated with hypoplasia of the corpus callosum. Brainstem auditory evoked potentials revealed hearing loss and visual evoked potentials confirmed the optic atrophy. She also had seizures with two posterior epileptic foci on electroencephalogram. Molecular analysis revealed a homozygous haplotype between the markers D7S802 and D7S630 within the originally linked region, narrowing the critical region from 20 Mb to 7 Mb. Two highly relevant candidate genes, CROT and SLC25A40 located in this region were sequenced, but no causative mutations identified. Our case provides additional clinical characteristics on the previously described features of this new entity, and reducing the critical region will now allow systematic positional cloning efforts to identify the causative gene.