We report a unique neurodegenerative disorder characterized by early-onset epilepsy, ataxia, progressive cognitive decline and retinitis pigmentosa (RP) in a highly consanguineous family of Pakistani origin. Affected members are three siblings including a 28-year-old male, 23-year-old female, and 15-year-old male, as well as their 30-year-old female cousin, clearly suggesting an autosomal recessive disorder. All affected individuals experienced a highly similar clinical course characterized by juvenile-onset seizures, retinitis pigmentosa and cognitive decline. Cerebellar signs manifesting as progressive ataxia and dysarthria appeared early and progressively increased, leading to severe impairment and confinement to wheelchair by early adulthood. Additionally, the older sibling experienced first-degree heart block and underwent pacemaker placement. Brain MRI of all affected individuals revealed severe cerebellar atrophy in the absence of cerebral atrophy or other structural brain abnormalities. Neuronal ceroid-lipofuscinosis (NCL) was suspected and investigated by histopathologic examination and electron microscopy (EM) studies of biopsied tissues, enzymatic analysis of PPT1 and TPP1 in white blood cells and molecular studies for the commonly implicated genes in NCL, which were negative. Hisopathologic examination and EM of rectal biopsy tissue revealed focal accumulation of lipofuscin bodies in ganglion cells and Schwann cells but no curvilinear or fingerprint bodies or excess accumulation of unstructured secondary lysosomes characteristic of NCL. Given these pathologic findings, the diagnosis of NCL was ruled out. Additionally, investigations for spinocerebellar ataxia, mitochondrial disorders, and congenital disorders of glycosylation have been negative to date.

In order to determine the molecular basis of the disorder in this family, whole genome sequencing has been initiated in conjunction with genetic linkage and homozygosity mapping.  Four affected individuals and three obligate carriers were used for the analysis.  Homozygosity mapping identified a single consensus region of homozygosity of ~6 MB mapping to chromosome 8 and containing 8 known RefSeq genes. Parametric linkage analysis revealed a maximum LOD score of 4.4615 (highly suggestive of linkage) within the region of homozygosity. Analysis and evaluation of the genes in this region is currently being performed, and these results, together with results of whole genome sequencing in this family will be presented.

This poster (#331) will be presented at the ACMG Annual Meeting by Ghayda Mirzaa, our molecular fellow, Thursday March 29: 10:30-11:30am. Stop by and learn more