Huntington's disease has a gradual onset usually between age 30 and 50 of chorea and dementia with a family history for the disorder.  It is usually fatal within 15-20 years.  The first symptoms are often irritability, moodiness, antisocial behavior, or other psychiatric difficulty.  The chorea often starts as fidgetiness.  There is progressive stiffness after the chorea with eventual akinesia.  Cerebral atrophy is seen on CT scan. There is no cure.

It is autosomal dominant, occurring in all ethnic groups, and with a prevalence of about 5 per 100,000.  The abnormal gene is on chromosome 4 with an expanded and unstable CAG trinucleotide repeat.

Dopaminergic receptors are lost in striatum, cortex, and hypothalamus. Anti-psychotics may control the dyskinesia. Reduced muscle mass, depressive mood, and cognitive impairment are often present.

Huntington's Dementia: Huntington's disease (HD) is a devastating neuropsychiatric disorder for which therapeutic interventions have been rather fruitless to date, except in a slight symptomatic relief. Even the discovery of the gene related to HD in 1993 has not effectively advanced treatments. Unfortunately, HD research has tended to concentrate on the motor aspects of the disorder, whereas the major problems are behavioral (e.g. dementia, depression, psychosis), and the chorea is often least relevant in terms of management. Based on data of open-label studies, or even case reports, the authors recommend riluzole, olanzapine and amantadine for the treatment of the movement disorders associated with HD, selective serotonin reuptake inhibitors and mirtazapine for the treatment of depression, and atypical antipsychotic drugs for HD psychosis and behavioral problems. Some cellular mechanisms are discussed because they are essential for future neuroprotective modalities, such as minocycline, unsaturated fatty acids or riluzole. Huntington's disease: present treatments and future therapeutic modalities. Bonelli RM, Wenning GK, Kapfhammer HP. University Clinic of Psychiatry, Karl-Franzens University Graz, Graz; University Clinic of Neurology, University of Innsbruck. Int Clin Psychopharmacol. 2004 Mar;19(2):51-6. Ed: Open trials are highly prone to error. 

Testosterone Deficiency Common: Testosterone and LH levels of the 42 patients were significantly lower compared to the levels of 44 age-matched (mean age 49) healthy men. Severity of illness was negatively related to plasma testosterone levels. Low testosterone levels were associated with dementia but not with depression or psychotic features. Clinical studies with selected HD patients are needed to evaluate possible beneficial effects of androgen substitution therapy on cognitive functions, depression, muscle mass and strength, general well-being, and, eventually, neuroprotective effects. Plasma testosterone in male patients with Huntington's disease: Relations to severity of illness and dementia. Markianos M, Panas M, et al. Athens University, Greece. Ann Neurol 2005;57:520-525.

Due to Polyglutamine Folding: When genetic repeats of glutamine get over 40 peptides long, abnormal toxic folding results. Hsp-70 (Heat shock protein) repeatedly binds and unbinds as a chaperone attempting to prevent binding of other proteins and minimize damage. Morimoto, Northwestern, Nature Cell Biology 10/1/02

Minocycline for Huntington’s: Harvard research with mice finds helps. NPAS2 protein assoc with long-term memory in mice in University of Texas study in Science 6/29/00.

HUFAs Helps in DB: 17 patients in a randomized, placebo-controlled, double blind study of treatment of Huntington's disease with unsaturated fatty acids found omega-3 fatty acids in fish oil helps. Vaddadi KS, Soosai E, Chiu E, Dingjan P. Neuroreport 2002 Jan 21;13(1):29-33

Huntingtin Protein Deposits Might Be Able to Be Blocked: The hallmarks of Huntington disease (HD) are cortical and striatal perinuclear cytoplasmic aggregates and intranuclear inclusions of mutant huntingtin protein. Transglutaminase 2 cross-links N-terminal fragments of mutant huntingtin (htt-N63-148Q-myc) in cells in culture. There is a significant increase in transglutaminase 2 mRNA in HD cortex (225% of controls) and striatum (399% of controls). Expression of the short transglutaminase 2 mRNA splice variant was not detectable in HD, although previous studies demonstrated upregulation in Alzheimer disease and progressive supranuclear palsy. Treatment of cells with cystamine, a chemical inhibitor of transglutaminase, decreased aggregated and cross-linked huntingtin and increased viability of cells that were transfected with transglutaminase 2 and htt-N63-148Q-myc. Inhibiting transglutaminase should be explored as a potential treatment strategy for HD. Mutant huntingtin protein: a substrate for transglutaminase 1, 2, and 3. Zainelli GM, Dudek NL, et al. Maywood, IL. J Neuropathol Exp Neurol. 2005 Jan;64(1):58-65.

Thomas E. Radecki, M.D., J.D.

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