Huntington Disease-Like 2

Excerpt

Clinical characteristics: Huntington disease-like 2 (HDL2) typically presents in midlife with a relentless progressive triad of movement, emotional, and cognitive abnormalities that lead to death within ten to 20 years. HDL2 cannot be differentiated from Huntington disease (HD) clinically. Neurologic abnormalities include chorea, hypokinesia (rigidity, bradykinesia), dysarthria, abnormalities of eye movements and gait, and hyperreflexia in the later stages of the disease. There is a strong correlation between the duration of the disease and the progression of motor and cognitive signs and symptoms.

Diagnosis/testing: The diagnosis of HDL2 is established in a proband with characteristic clinical findings and heterozygous expansion of 40 or more CTG trinucleotide repeats in JPH3 identified by molecular genetic testing.

Management: Treatment of manifestations: Treatment is symptomatic and is presumably similar to that for HD and other neurodegenerative disorders – although this must be considered speculative pending objective data. Pharmacologic agents that may suppress abnormal movements include tetrabenazine and its derivatives or low-dose neuroleptic agents such as fluphenazine and haloperidol. Remove loose rugs and clutter from the individual's home and minimize or eliminate the need for stairs to help prevent falls and other injuries; physical therapy evaluation and treatment for mobility issues; speech therapy, communication devices, and environmental modifications for dysarthria; speech-language pathology and nutrition referrals for dysphagia; food should be prepared in such a manner as to prevent choking; feeding changes when needed to minimize risk of aspiration; driving may need to be curtailed or limited to prevent risk of accidents; planning for financial matters; environmental interventions for cognitive issues; antidepressants, antipsychotics, mood stabilizers (lithium, valproic acid, carbamazepine, and lamotrigine), electroconvulsive therapy, and occasionally stimulants may improve psychiatric manifestations. Education about the course of disease; social work and care coordination support.

Surveillance: Annual evaluation or more frequently as needed to assess motor skills including gait and abnormal movements; physical therapy assessment of mobility and appropriate strategies or devices to minimize falls; assess cognitive skills and driving safety to assure that affected individuals do not present a danger to themselves or others; assess weight, nutrition, swallowing, and risk of aspiration in order to implement feeding changes when necessary; assess for psychiatric manifestations, including mood, suicidality, anxiety, irritability, and apathy; assess sleep and sexual concerns; assess family needs; assess planning for future (financial, legal issues).

Agents/circumstances to avoid: Any agents that increase ataxia should be used with caution; begin psychoactive medicines at lower doses and increase doses carefully; minimize polypharmacy, which may increase the risk of delirium.

Genetic counseling: HDL2 is inherited in an autosomal dominant manner. Most individuals with HDL2 have an affected parent. At conception, each child of an individual with HDL2 has a 50% chance of inheriting the HDL2-causing allele. Offspring who inherit a pathogenic (full-penetrance) HDL2-causing allele (≥40 CTG repeats) are considered at risk of developing HDL2 in their lifetime; offspring who inherit an allele of questionable significance (29-39 CTG repeats) may or may not develop manifestations of HDL2. Testing of asymptomatic adults at risk for HDL2 is possible once a heterozygous expansion of a CTG repeat in JPH3 has been identified in an affected family member. Testing for the JPH3 CTG repeat expansion in the absence of definite manifestations of the disease is predictive testing. Prudence suggests following the same genetic testing guidelines used for HD, including counseling prior to testing, a confidant to serve as a social support, and availability of counseling following the disclosure of genetic results. If the presence of an HDL2-causing allele has been confirmed in the affected parent or in an affected relative of the at-risk parent, prenatal and preimplantation genetic testing are possible.