Localization of the gene for a novel autosomal recessive neurodegenerativeHuntington-like disorder to 4p15.3

A consanguineous family affected by an autosomal recessive, progressive neu rodegenerative Huntington-like disorder, was tested to rule out juvenile-on set Huntington disease (JHD). The disease manifests at similar to 3-4 years and is characterized by both pyramidal and extrapyramidal abnormalities, i ncluding chorea, dystonia, ataxia, gait instability, spasticity, seizures, mutism, and intellectual impairment. Brain magnetic resonance imaging (MRI) findings include progressive frontal cortical atrophy and bilateral caudat e atrophy. Huntington CAG trinucleotide-repeat analyses ruled out JHD, sinc e all affected individuals had repeat numbers within the normal range. The presence of only four recombinant events (theta = .2) between the disease a nd the Huntington locus in 20 informative meioses suggested that the diseas e localized to chromosome 4. Linkage was initially achieved with marker D4S 2366 at 4p15.3 (LOD 3.03). High-density mapping at the linked locus resulte d in homozygosity for markers D4S431 and D4S394, which span a 3-cM region. A maximum LOD score of 4.71 in the homozygous interval was obtained. Hetero zygosity at the distal D4S2366 and proximal D4S2983 markers defines the max imum localization interval (7 cM). Multiple brain-related expressed sequenc e tags (ESTs) with no known disease association exist in the linkage interv al. Among the three known genes residing in the linked interval (ACOX3, DRD 5, QDPR), the most likely candidate, DRD5, encoding the dopamine receptor D 5, was excluded, since all five affected family members were heterozygous f or an intragenic dinucleotide repeat. The inheritance pattern and unique lo calization to 4p15.3 are consistent with the identification of a novel, aut osomal recessive, neurodegenerative Huntington-like disorder.