Huntington Disease-Like 2

A number sign (#) is used with this entry because of evidence that Huntington disease-like-2 (HDL2) is caused by a heterozygous expanded CAG/CTG repeat in the junctophilin-3 gene (JPH3; 605268) on chromosome 16q24.

Normal alleles contain 6 to 28 repeats, whereas pathogenic alleles contain over 41 repeats (Todd and Paulson, 2010).

Clinical Features

Margolis et al. (2001) described a large kindred with an autosomal dominant disorder that is clinically similar to Huntington disease (143100) but arose from a CAG expansion in a different gene. The disorder is characterized by onset in the fourth decade, involuntary movements and abnormalities of voluntary movements, psychiatric symptoms, weight loss, dementia, and relentless course with death about 20 years after disease onset. Brain magnetic resonance imaging scans and an autopsy revealed marked striatal atrophy and moderate cortical atrophy, with striatal neurodegeneration in a dorsal-to-ventral gradient and occasional intranuclear inclusions. This family was of African American ethnicity, and the parents of the first known affected individual were from a semirural region of the southeastern United States. The disorder in this family, designated family W, fell well within the spectrum of HD. Other than a lower frequency of eye movement findings and the absence of seizures, the disease was similar to juvenile-onset HD (van Dijk et al., 1986) and the 'Westphal' variant of HD observed in some adult cases. Unlike the HDL1 (603218), seizures did not occur in affected members of pedigree W. However, in both pedigrees, rigidity was more prominent than chorea.

Walker et al. (2002) reported a family in which 3 individuals were affected with what the authors thought was an autosomal dominant form of chorea-acanthocytosis (200150), but which was later found by Walker et al. (2003) to be HDL2. The proband was a 56-year-old man who had initially been diagnosed with Huntington disease. At age 34 years, he developed a slowly progressive deterioration in memory and personality, with involuntary movements of the face and hands. By age 54 years, he was unable to stand, had no spontaneous speech, and showed continuous choreiform movements. Postmortem examination of the brain showed severe, diffuse cortical atrophy and severe atrophy of the caudate and putamen, as well as ubiquitinated intranuclear inclusions with immunoreactivity for expanded polyglutamine repeats throughout the brain. His son, who had fragile X syndrome (300624), developed gait abnormalities, chorea, and dystonia in his late twenties. Head CT scan showed generalized cerebral and caudate atrophy. Walker et al. (2002) suspected that the fragile X was unrelated to the neurologic disorder. The third patient, the nephew of the proband, developed personality changes, primitive reflexes, hyperreflexia, and mild parkinsonism beginning at age 28 years. All 3 patients had 30 to 35% acanthocytosis on peripheral blood smear.

Pathogenesis

Rudnicki et al. (2007) detected RNA foci within frontal lobe neurons of 4 patients with HDL2 using riboprobes specific for expanded CUG tracts and with riboprobes specific for JPH3 intron 1, exon 2A, or exon 2B. The RNA foci resembled those detected in DM1 (160900) in terms of size, restriction to nuclei, and colocalization with MBNL1 (606516). Approximately 30% of neurons contained foci, and most neurons contained more than 1 focus. Similar foci were also observed in the striatum. There was also a significant decrease in general MBNL1 expression compared to controls. No foci were detected in control brains or HD frontal cortex used as control. Overexpression of JPH3 transcripts containing an expanded CUG repeat expansion were toxic to HEK293 and HT22 cells, suggesting that the RNA transcripts play an important role in the pathogenesis of HDL2 via a toxic RNA gain-of-function effect.

Molecular Genetics

Margolis et al. (2001) found that in family W all tested affected individuals, and no tested unaffected individuals, had a CAG/CTG trinucleotide repeat expansion of 50 to 60 triplets, as determined by the repeat expansion detection assay. Tests for the HD expansion, for all other then-known CAG expansion mutations, and for linkage to chromosomes 20p and 4p were negative, indicating that this mutation was novel.

Holmes et al. (2001) demonstrated that the expanded CAG/CTG repeat in the original pedigree was located in an alternatively spliced exon of the JPH3 gene (605268.0001). This exon has multiple splice acceptor sites. They found the same mutation in the JPH3 gene in other African American patients with a Huntington disease-like neurologic disorder.

Among 74 patients with an HD-like phenotype but without CAG repeat expansions in the IT15 gene (HTT; 613004.0001), Stevanin et al. (2002) identified 1 patient with a pure uninterrupted 50 CAG/CTG repeat in the JPH3 gene. The patient was a 44-year-old Moroccan woman with subcortical dementia, mild choreic movements, and atrophy of the cerebral cortex. In the study by Stevanin et al. (2002), the HDL2 locus accounted for only 2% of typical HD cases not caused by expansion in the IT15 gene, suggesting further genetic heterogeneity.

In the family reported by Walker et al. (2002) as having choreoacanthocytosis, Walker et al. (2003) identified trinucleotide repeat expansions of 51, 58, and 57 triplets in the junctophilin-3 gene, confirming Huntington disease-like-2. Walker et al. (2003) also reported a Mexican family with HDL2, characterized by dementia, depression, chorea, and parkinsonism, in which affected members had 46, 49, and 46 triplet repeats. One of the patients also had acanthocytosis. Another unrelated affected African American patient, who did not have acanthocytosis, had 44 triplet repeats. The findings indicated that some, but not all, patients with the HDL2 mutation may develop acanthocytosis, and Walker et al. (2003) suggested that there may be reduced penetrance of this feature or that the acanthocytosis may vary over the course of the disease.

Population Genetics

In 9 independent series of patients referred for HD testing in North America (538 patients) or Japan (44 patients), Margolis et al. (2004) found an HDL2 frequency of approximately 1% in North America and 0% in Japan. HDL2 was identified predominantly in patients of African ancestry. One affected Mexican pedigree originated from a region of Mexico colonized by Africans. Repeat expansions in the junctophilin-3 gene ranged from 44 to 57 triplets, and a younger age at onset was correlated with a longer repeat length.

Rudnicki et al. (2007) stated that at least 25 HDL2 pedigrees had been identified; all with known ancestry are of definite or probable African origin.

Santos et al. (2008) reported a 48-year-old Brazilian man of European ancestry who presented with a phenotype very suggestive of HD with onset of symptoms at age 44 years. His deceased father was reportedly similarly affected from age 50 years. Genetic analysis in the proband identified a 47 CTG repeat expansion in the JPH3 gene. Although the family did not refer to any African ancestry, the haplotype with the repeat expansion has only been identified in individuals of African ancestry (16.3%), suggesting that there was remote African ancestry in this family.

Rodrigues et al. (2008) reported 4 unrelated Brazilian patients with HDL2 associated with heterozygous expanded repeat expansions of 47, 59, 46, and 48, respectively, in the JPH3 gene. Age at onset ranged from 22 to 60 years and was inversely correlated to the size of the repeat expansion. Three patients were black, consistent with African descent, and the fourth patient, who was white, was found to have a 'dark-skinned' grandmother, suggesting African ancestry. Rodrigues et al. (2008) noted that approximately 44.6% of the Brazilian population is of African descent.

Nomenclature

Margolis et al. (2001) stated that consistent with the recommendation of the Nomenclature Committee of HUGO, the disorder that maps to 20p is designated Huntington disease-like-1 (HDL1; 603218). They concluded that the family from Saudi Arabia that had been described as 'HD-like-3' is sufficiently distinct, based primarily on autosomal recessive inheritance and in part on presentation (onset age 3 to 4 years, prominent seizures, rapid course), to be classified separately. Since about 1% of all cases of clinically or pathologically defined HD do not carry the HD mutation, it was considered likely that the basis for other rare 'HD-like' disorders will be identified.