Huntington Disease-Like 3

Clinical Features

Al-Tahan et al. (1999) described a Saudi family with an autosomal recessive Huntington disease (143100)-like neurodegenerative disorder. Five of 10 sibs, 3 sisters and 2 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.

Kambouris et al. (2000) studied a consanguineous family affected by an autosomal recessive, progressive neurodegenerative Huntington-like disorder. The disorder manifested at approximately 3 to 4 years and was characterized by both pyramidal and extrapyramidal abnormalities, including chorea, dystonia, ataxia, gait instability, spasticity, seizures, mutism, and intellectual impairment. Brain magnetic resonance imaging (MRI) showed progressive frontal cortical atrophy and bilateral caudate atrophy. Huntington disease CAG trinucleotide-repeat analyses ruled out juvenile-onset Huntington disease, since all affected individuals had repeat numbers within the normal range.

Mapping

In the consanguineous family with an autosomal recessive, progressive neurodegenerative Huntington-like disorder reported by Kambouris et al. (2000),, 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 (126453), was excluded, since all 5 affected family members were heterozygous for an intragenic dinucleotide repeat.

Lesperance and Burmeister (2000) pointed to weaknesses in the evidence for linkage to chromosome 4 reported by Kambouris et al. (2000).

Nomenclature

After consultation with the Nomenclature Committee of HUGO, Margolis et al. (2001) proposed that the disorder that maps to 20p should be designated Huntington disease-like-1 (HDL1; 603218); that the disorder they described, which is linked to neither 20p nor 4p, should be designated Huntington disease-like 2 (HDL2; 606438); and that the disorder described here should be designated Huntington disease-like 3 (HDL3).