Hereditary chorea - what else to consider when the Huntington's disease genetics test is negative?

Abstract

Chorea, cognitive, behavioural and psychiatric disturbance occur in varying combinations in Huntington's disease (HD). This is often easy to recognise particularly in the presence of an autosomal dominant history. Whilst HD may be the most common aetiology of such a presentation, several HD phenocopies should be considered if genetic testing for HD is negative. We searched PubMed and the Cochrane Database from January 1, 1946 up to January 1, 2016, combining the search terms: 'chorea', 'Huntington's disease', 'HDL' and 'phenocopies'. HD phenocopies frequently display additional movement disorders such as myoclonus, dystonia, parkinsonism and tics. Here, we discuss the phenotypes, and investigations of HD-like disorders where the combination of progressive chorea and cognitive impairment is obvious, but HD gene test result is negative. Conditions presenting with sudden onset chorea such as vascular, infectious and autoimmune causes are not the primary focus of our discussion, but we will make a passing reference to these as some of these conditions are potentially treatable. Hereditary forms of chorea are a heterogeneous group of conditions and this number is increasing. While most of these conditions are not curable, molecular genetic testing has enabled many of these disorders to be distinguished from HD. Getting a precise diagnosis may enable patients and their families to better understand the nature of their condition.

Myoclonic Disorders

“…In juvenile Huntington’s disease ( Table 2 ), cortical generators of myoclonus were identified by jerk-locked back-averaging, reduced intracortical inhibition and enhanced long-latency reflexes, but without giant SEPs [ 61 ]. Huntington’s disease phenocopies with myoclonus and sometimes dementia can be caused by C9orf72 hexanucleotide repeat expansions, dentatorubral-pallidoluysian atrophy (DRPLA) or mitochondrial disease [ 62 , 63 ].…”

Discrepancy in prevalence of Huntington's disease in two Swedish regions

“…1 Disease onset is usually between 30 and 50 years of age and related to the number of CAG repeats and other genetic factors. 4 The prevalence of HD is not equally distributed throughout the world. 3 The availability of genetic testing has improved the diagnostics.…”

“…3 The availability of genetic testing has improved the diagnostics. 4 The prevalence of HD is not equally distributed throughout the world. A systematic review and meta-analysis of 17 studies performed between 1990 and 2010 estimated the prevalence in Asia and Europe to be 0.4 and 5.7 per 100 000 residents, respectively.…”

Review of Hereditary and Acquired Rare Choreas

“…These HD phenocopies include neurodegenerative diseases caused by repeat expansions in the C9orf72 gene, spinocerebellar ataxia (SCA) 17, Huntington disease-like 2 (HDL2), dentatorubropallidoluysian atrophy (DRPLA), neuroferritinopathy, familial prion disease (e.g. Huntington disease-like 1 [HDL1]) [ 7 ]. Recently, mutations in new genes associated with HD phenocopy syndromes have been identified, including CACNA1A, VSP13A , and VCP [ 8 9 ].…”

“…A multisystem clinical presentation involving several organs, including peripheral and central nervous systems should prompt the clinician to consider a possible mitochondrial disorder. A clue to the diagnosis is the presence of other family members with myopathic disorders or ophthalmoplegia [ 7 ]. Movement disorders are common in mitochondrial diseases.…”