Huntington Disease: The Orphan Enigma

Rigidity and dystonia in Huntington disease (HD) are associated with atrophy of the caudate nucleus and putamen (B). Extensive neuronal loss and gliosis in the cerebral cortex (A,C) in both HD and Alzheimer disease (AD) are responsible for varying degrees of cognitive impairment (however, neurofibrillary tangles and senile plaques are seen only in AD). Understanding a rare genetic disorder can lead to treatments for more common conditions. The one-in-a-million children with familial hypercholesterolemia, for example, spearheaded development of the blockbuster statins. In neurology, study of rare familial variants of Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis (ALS), and even prion disorders revealed molecular targets for drug discovery. For HD, however, the genes-as-a-guidepost strategy fails, because HD has no common counterpart. It is a disorder of information overload--a gene too long, a complex cellular derangement with many entangled and interacting components. "Parkinson disease is a deficiency of 1 chemical that can be replaced--we can increase availability of dopamine or mimic its effects. HD isn't that simple," said Kathleen M. Shannon, MD, director of the Huntington's Disease Center of Excellence at Rush University Medical Center in Chicago. HD stands out even among the single-gene disorders in its strangeness. Unlike the others, homozygotes for the HD mutation are no worse off than the more common heterozygotes. Also highly unusual, penetrance approaches 100%--if you inherit the gene and live long enough, you get the disease. Yet its rarity stymies progress. "There's no easy answer, at least for now, to the question of why HD has been so difficult to understand and treat," said Allan J. Tobin, PhD, professor of neurology at University of California, Los Angeles, and senior scientific advisor to the High Q Foundation, a New York City-based private philanthropic organization that coordinates academic, industrial, government, and private efforts to develop treatments for HD. "High Q" refers to the high numbers of glutamine (symbolized as "Q") repeats in the abnormal huntingtin (htt) protein in HD (Table 1 lists polyQ diseases.) "The question is whether there's a single pathogenic cascade, or many parallel, interacting ones," Tobin added. CURRENT MANAGEMENT APPROACHES The goal of disentangling the mechanistic threads that weave the fabric of HD is to identify drug targets--and that's already happening. Two drugs are in clinical trials: tetrabenazine (marketed in Canada and Europe as Nitoman by Prestwick Pharmaceuticals) and ethyl-eicosapentaenoate (ethyl-EPA; Miraxion, Amarin Neuroscience). Two are commonly used to manage symptoms: haloperidol and clonazepam. A project called Systematic Evaluation of Treatments for Huntington's Disease (SET-HD) has identified 40 initial candidates from the existing pharmacopeia and has evaluated 24 (see www. huntingtonproject.org and Table 2). And the European Rare Diseases Therapeutic Initiative (ERDITI; www.erditi.org) is seeking new treatments among drug candidates for common disorders that never made it to market. With 10 research institutions and 4 large pharmaceutical companies on board, ERDITI is matching basic researchers with big pharma's stockpile. Meanwhile, the role of the neurologist in treating HD isn't restricted to the prescription pad. A neurologist can do "a lot," said Karl Kieburtz, MD, MPH, professor of neurology and community and preventive medicine at the University of Rochester in New York. Information can help, such as stressing the variability of the disease. "Some people see their parents and think that they will suffer in the same exact way. Explain that, between members of a family, the disease can look very different," he added. In one family, age at onset across 3 generations varied by 50 years. Also within