Trinucleotide repeat length and clinical progression in Huntington's disease

Abstract

We examined the relationship between length of the trinucleotide (CAG) repeat at IT-15 and clinical progression of Huntington's disease in 46 mildly to moderately affected patients over a 2-year interval. Patients were divided into those with short mutations (37 to 46 repeats; n = 25) and those with long mutations (> or = 47 repeats; n = 21). Patients with long repeat lengths had earlier age at onset and were younger and less functionally impaired than those with short repeats at the initial visit, but the groups did not differ in severity of neurologic or cognitive impairment. However, the long-repeat group displayed significantly greater decline in both neurologic and cognitive functioning over the 2-year follow-up period. The length of the CAG repeat correlated highly with age at onset (r = -0.72, p < 0.001) and was a strong predictor of decline in both neurologic and cognitive function. The mechanism of gene action, and the means by which longer expansions result in a more malignant disease process, remain to be elucidated.

Genetic background of Huntington disease in Croatia: Molecular analysis of CAG, CCG, and ?2642 (E2642del) polymorphisms

“…Analysis of the CAG repeat region among 44 HD patients (39-66 CAGs) and 51 normal individuals (9-34 CAGs) showed that the range of the repeat size was similar to previous reports in other populations (Andrew et al, 1993;Huntington's Disease Collaborative Research Group, 1993;Andrew and Hayden, 1995;Brandt et al, 1996;Pramanik et al, 2000). In addition, the mean CAG size of 102 normal chromosomes of Croatian origin (18.5 ± 3.5) was found to resemble that for a Western European populations (18.4 ± 3.7) and was considerably higher than the mean CAG lengths found on Black, Chinese, Japanese and Finnish normal chromosomes (16.5 ± 1.7) (Squitieri et al, 1994).…”

“…HD alleles have 36 CAGs in the HD gene (also called IT15), while normal individuals have between 10-35 CAG units (Huntington's Disease Collaborative Research Group, 1993). The severity and age at onset of HD inversely correlates with CAG repeat length; longer repeats cause an earlier age of onset (Andrew et al, 1993;Brandt et al, 1996;Brinkman et al, 1997). HD is characterized by uncontrolled movements (chorea), accompanied with cognitive and/or psychiatric distrurbances (Andrew et al, 1993;Cummings, 1993;Brandt et al, 1996).…”

“…The severity and age at onset of HD inversely correlates with CAG repeat length; longer repeats cause an earlier age of onset (Andrew et al, 1993;Brandt et al, 1996;Brinkman et al, 1997). HD is characterized by uncontrolled movements (chorea), accompanied with cognitive and/or psychiatric distrurbances (Andrew et al, 1993;Cummings, 1993;Brandt et al, 1996). Since the first symptoms usually present between 35 and 45 years of age, when most families already have their children, genetic counseling has been an important but delicate issue.…”

Rosiglitazone Treatment Prevents Mitochondrial Dysfunction in Mutant Huntingtin-expressing Cells

“…In addition, PPAR␥ activation by rosiglitazone up-regulates the Bcl-2 protective pathway and prevents neuronal degeneration induced by both oxidative stress and treatment with A␤ fibrils, with a concomitant increase in mitochondrial viability (22). Recent studies have also provided evidence that the expression of PGC-1␣, a potent co-activator of PPAR␥, is repressed by mutant huntingtin expression, and when PGC-1␣ knock-out (KO) mice are crossed with HD knockin mice, this resulted in increased neurodegeneration of striatal neurons and motor abnormalities in the HD mice (2). At the same time, there is evidence suggesting that PPAR␥ agonists are neuroprotective and increase mitochondrial function (23,24).…”

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“…3 The probability that the gene is inheritable transimissible is 50%. 4,5 We present the case of a person with Major Neurocognitive Disorder and Huntington's Disease with a rapid progression in the neuropsychological domains.…”