Huntington's Disease and Huntington's Disease-like Syndromes

An Overview

Felix Gövert and Susanne A. Schneider


Curr Opin Neurol. 2013;26(4):420-427. 

In This Article

Huntington's Disease-like Syndromes

About 1% of suspected Huntington's disease cases emerge as phenocopy syndromes.[5] These include the HDL syndromes, which will be discussed in the below ( Table 1 ).

Huntington's Disease-like 1

HDL-1 is a rare familial prion disease, first described in 2001.[6] The progressive autosomal dominant neurodegenerative disorder is caused by additional octapeptide repeats in the prion protein (PrP) gene (PRNP). Mean onset age is in early adulthood between 20 and 45 years.[7] Disease course is progressive, with a mean survival time of 1–10 years after onset.[8] Clinical symptoms of HDL-1 are often quite similar to Huntington's disease with prominent personality change, psychiatric symptoms and cognitive decline, chorea, rigidity and dysarthria. Furthermore, limb and truncal ataxia as well as seizures have been observed.[9,10]

Neuropathological examination in HDL-1 showed atrophy and prion deposition within basal ganglia, frontal and temporal lobes and cerebellar cortex. In comparison to other prion diseases, spongiosis is not prominent.[9,10]

Huntington's Disease-like 2

HDL-2, also inherited in an autosomal dominant manner, takes a progressive course and may show remarkable similarities to Huntington's disease. Genetically it is caused by a CTG-CAG triplet repeat expansion in the junctophilin 3 (JPH3) gene on chromosome 16q24.3.[11] Normal alleles range from six to 28 triplets, whereas pathological repeat expansions range from 40 to 59 triplets.[12] The impact of triplets in between remains unclear.[13] Penetrance is high. Similar to Huntington's disease, there is a negative correlation between age of onset and repeat length.[14] In contrast to Huntington's disease, the anticipation phenomenon is more likely when the disease is maternally inherited and the repeat expansions are more unstable.[8] HDL-2 is overall rare, accounting for about 0.7% of Huntington's disease phenocopies; however, it is quite frequent in black South Africans of sub-Saharan descent.[15–17] In this ethnic group, HDL-2 is responsible for about 24-50% of patients with an HDL presentation.[18,19] With the exception of one Brazilian family of Spanish/Portuguese ancestry, the disease so far has only been described in patients with African descent, consistent with haplotype studies.[8,20]

Clinically, the classic form of HDL-2 may be indistinguishable from Huntington's disease with similar cognitive, psychiatric and motor features. However, adult-onset cases with a progressive akinetic–rigid syndrome but clinically insignificant chorea have been reported.[14,21] Mean age of onset is in the third or fourth decade of a patient's life, although juvenile-onset variants are described with absence of seizures and mostly normal eye movements in contrast to juvenile Huntington's disease.[22] The disease leads to death within 10–20 years.[13]

The neuropathologic features of HDL-2 are also very similar to Huntington's disease. Both diseases show a marked cortical and striatal neurodegeneration and neuronal protein aggregates staining positive for antiubiquitin antibodies and expanded polyglutamine tracts. However, there may be more brainstem involvement in Huntington's disease but more selectivity of cortical involvement (with prominent occipital atrophy) in HDL-2.[21,23] The molecular mechanisms underlying HDL-2 remain ill-understood. The gene product serves to stabilize junctional membrane complexes and regulates neuronal calcium flux. Therefore, the loss of JPH3 protein expression may lead to cellular vulnerability due to disruption of calcium flux or endoplasmic reticulum dysregulation. However, a multifactorial pathogenic mechanism is suggested with a toxic effect caused by both a toxic loss of JPH3 expression and additional toxic gain of function of JPH3 RNA.[24,25]

Huntington's Disease-like 3

HDL-3 is an autosomal recessive HDL neurodegenerative disorder, which was so far only described in two Saudi-Arabian families. The clinical phenotype was complex, somewhat resembling juvenile Huntington's disease with early onset mental deterioration, speech disturbance, dystonia, chorea and other extrapyramidal but also pyramidal features. The mean age of onset was 3–4 years. MRI showed progressive atrophy of the caudates bilaterally and the frontal cortex. The causative gene still remains unclear, but the disease locus initially was mapped to chromosome 4p15.3.[26]

Considering the early onset and the pattern of inheritance, HDL-3 clearly differs from the other HDL syndromes and the report is to be read critically.

Huntington's Disease-like 4

Triplet repeat expansions in the TATA box-binding protein (TBP) gene located on chromosome 6q27 cause HDL-4, also classified as spinocerebellar ataxia type 17 (SCA17). HDL-4 is autosomal dominantly inherited and represents the most frequently identified Huntington's disease phenocopy syndrome in whites, although chorea only occurs in 20% of SCA17 patients.[20]

The CAG/CAA expansion leads to an abnormal expansion of a polyglutamine stretch in the corresponding TBP protein, which is a fundamental general transcription initiation factor.[27] This is of interest because transcriptional dysregulation seems to play an important pathogenic mechanism in Huntington's disease as well.[28] The normal allele size ranges from 25 to 40 CAG/CAA repeats, whereas 41 to 48 CAG/CAA repeats lead to reduced penetrance and 49 and greater repeats to full penetrance.[29] Similar to Huntington's disease, a negative correlation between the size of repeat expansion and the age of onset and intergenerational instability with anticipation have been recognized.[30,31]

The clinical phenotype is markedly heterogeneous and the age at onset is extremely variable, ranging from age 3 to 75 years.[32] Cerebellar ataxia is the most common clinical feature (95%) but extrapyramidal signs (73%), in particular dystonia and chorea, and dementia (76%) are also quite frequent. Furthermore, pyramidal signs, epilepsy and psychiatric disturbances are common.[33] However, a Huntington-like presentation occurs only in a subset of SCA17 cases.[34,5] Reflecting the broad clinical spectrum, neuropathological findings may vary with a wide participation of the central nervous system involving the cerebellum, cerebral neocortex, basal ganglia (in particular the caudate nucleus) and hippocampus. Neuronal intranuclear inclusions containing the abnormal protein TBP and other proteins are widely distributed throughout the brain grey matter.[35] MR imaging demonstrated atrophy of the cerebellum and the caudate nucleus. Rim enhancement of the putamen has also been described[36,37] but is not specific to HDL-4/SCA17 as it may also occur in HDL-2[14] and other disorders.

Notably, other forms of SCAs may also present with chorea and should be kept in mind in patients with an ataxic HDL phenotype, in particular SCA 1,2 and 3.[38]