Al-Tahan et al. (1999) described a Saudi family with an autosomal recessive Huntington disease-like neurodegenerative disorder. Five of 10 sibs (three sisters and two brothers) from a first-cousin marriage presented with clinical and radiologic features simulating juvenile Huntington disease. The disorder manifested at an early age with mental deterioration, speech disturbance, dystonia, and other extrapyramidal and pyramidal features. Molecular studies excluded Huntington disease. The proband, an 18-year-old male, had normal early milestones, including motor and language development. At the age of 5 years his speech became progressively incoherent, hand movements became clumsy, and his gait unsteady. Shortly thereafter, he started having involuntary movements involving the limbs and trunk and causing deforming postures. By the age of 12 years, he became mute and wheelchair-bound and began to have attacks of tonic movements of the upper limbs with rolling up of both eyes.

A year later, Kambouris et al. (2000) presented further data on the same family. The 19-year-old brother and 24-year-old sister of the proband described by Al-Tahan et al. (1999) were shown to be bedridden and fully dependent. They had similar clinical picture, including the age of onset and the disease course. Another 14-year-old sister was affected, at the age of four years she started to show mobility and speech disturbances. Then when she was 8-year-old, she started to have seizures and frequent brief episodes of generalized tonic movements, with flexion, crossing of both upper limbs, and extension of lower limbs. Also a 12-year-old sister had a progressive deterioration of speech and mobility commencing at the age of 3-4 years. When she was nine years she became totally mute and incontinent, walked only with help, and needed assistance in feeding. She had poor facial expressions, but full eye movements. She was able to move all limbs voluntarily, but slowly, and with generalized rigidity. A novel, autosomal recessive, neurodegenerative Huntington-like disorder was identified in this family. The presence of only 4 recombinant events (theta of 0.2) between the disorder and the Huntington locus in 20 informative meioses suggested that the disease locus is localized to 4p. Linkage was initially achieved with marker D4S2366 at 4p15.3 (lod of 3.03). High-density mapping at the linked locus resulted 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. Heterozygosity at the distal D4S2366 and proximal D4S2983 markers defined the maximum localization interval as 7 cM. Among the known genes residing in the linked interval, the most likely candidate, DRD5, was excluded, since all five affected family members were heterozygous for an intragenic dinucleotide repeat. [CTGA Database Editor's note: Independent studies pointed to weaknesses in the evidence for linkage to chromosome 4].