Differential Diagnosis of Huntington's Disease-like Syndromes

Differential Diagnosis of Huntington's Disease-like Syndromes

Abstract and Introduction

Abstract

A growing number of progressive heredodegenerative conditions mimic the presentation of Huntington's disease (HD). Differentiating among these HD-like syndromes is necessary when a patient with a combination of movement disorders, cognitive decline, behavioural abnormalities and progressive disease course proves negative to the genetic testing for HD causative mutations, that is, IT15 gene trinucleotide-repeat expansion. The differential diagnosis of HD-like syndromes is complex and may lead to unnecessary and costly investigations. We propose here a guide to this differential diagnosis focusing on a limited number of clinical features ('red flags') that can be identified through accurate clinical examination, collection of historical data and a few routine ancillary investigations. These features include the ethnic background of the patient, the involvement of the facio-bucco-lingual and cervical district by the movement disorder, the co-occurrence of cerebellar features and seizures, the presence of peculiar gait patterns and eye movement abnormalities, and an atypical progression of illness. Additional help may derive from the cognitive–behavioural presentation of the patient, as well as by a restricted number of ancillary investigations, mainly MRI and routine blood tests. These red flags should be constantly updated as the phenotypic characterisation and identification of more reliable diagnostic markers for HD-like syndromes progress over the following years.

Introduction

Huntington's disease (HD) is the most common hereditary neurodegenerative illness with onset before mid-life and a distinct phenotype characterised by movement disorders (mainly chorea, dystonia and Parkinsonism), incoordination, cognitive deterioration and behavioural changes. Progressive neural cell loss within cortico-striato-thalamo-cortical circuits, predominantly in the neostriatum (caudate and putamen), leads to this clinical presentation.

HD is a trinucleotide-repeat disorder with autosomal dominant mode of inheritance. The causative mutation is a prolongation (above 35 repeats) of a trinucleotide (CAG) stretch within the IT15 gene, associated with full penetrance when this exceeds 40 and incomplete penetrance between 36 and 39. As in several other trinucleotide-repeat disorders, there is a strong association between repeat length and age at disease onset, with higher repeat length leading to earlier onset. Paternal transmission facilitates this anticipation phenomenon. Age at onset is strongly linked to the clinical expression of both motor and cognitive features of the disease. Juvenile HD (ie, with onset before age 20) is dominated by a hypokinetic-rigid syndrome (Westphal variant) and a more rapid course, whereas adult-onset HD classically presents with a choreatic syndrome and a less severe progression of motor and non-motor features.

An increasing number of progressive heredodegenerative illnesses may mimic the presentation of HD. It has been estimated that between 1% and 7% of subjects with a HD-like syndrome do not have HD. Given the relationship between motor phenotype and age at onset in HD, these HD-like syndromes are, with some exceptions, either diseases manifesting with a predominantly choreatic syndrome and onset in adulthood (online supplementary table 1a) or diseases presenting with predominant dystonia and Parkinsonism and onset in the first 2 decades (online supplementary table 1b). The comprehensive understanding of the phenomenology and diagnosis of progressive HD-like syndromes is crucial for an efficient and cost-effective diagnostic work-up and guides further genetic testing once the diagnosis of HD has been genetically excluded. This work-up may include thorough clinical examination, neuropsychological and neuropsychiatric assessment, metabolic screening, imaging and electrophysiology.

To date, progressive hereditary HD-like syndromes were classified mainly according to their mode of inheritance. Although this criterion can be very helpful in the presence of a well-established family history, it may not be practically useful in the numerous cases in which family history is unavailable or inaccurate. In this review, we discuss the differential diagnosis of HD focusing on a restricted number of clinical features ('red flags') that might help clinicians to narrow the spectrum of working diagnoses and improve efficiency and cost-effectiveness of the diagnostic process.