A category of disorders, termed “phenocopies” of Huntington disease but without an excessive number of trinucleotide repeats in the HD gene, has been found to be due to hexanucleotide repeats within C9orf 72, the same gene implicated in some cases of ALS. The clinical features included chorea and mental deterioration but also many other features such as myoclonus. In a cohort of 514 such patients reported by Hensman Moss et al, 2 percent of cases had the C9orf 72 expansion.
Once the disease has been observed in its fully developed form, its recognition requires no great clinical acumen. The main difficulty arises in patients who lack a family history but who display progressive chorea, emotional disturbance, and dementia. This problem has been largely overcome since the mutation was identified. It is now possible to confirm or exclude the diagnosis by analysis of DNA from a blood sample. The presence of 36 of CAG repeats confers a risk of developing clinical manifestations at some time. Those with 36 to 40 repeats may not manifest the disease, particularly if the patient does not live long enough to express the illness. Most individuals with 40 or more repeats will demonstrate the disorder in middle life. Therefore, the length of the repeat segment indicates the likelihood of developing clinical manifestations, and the likely age of onset. However, from large multigenerational kindreds in Venezuela, it has been estimated that approximately 40 percent of the variability in age of onset is accounted for by genetic factors other than the triplet length and by environmental aspects (see Wexler et al).
Chorea that begins in late life with only mild or questionable intellectual impairment and without a family history of similar disease is a source of diagnostic difficulty. A few cases are the result of the earlier mentioned HDL2 mutation and others derive from alternative degenerative conditions discussed below. Referring to the problem as “senile chorea” does not solve the problem. Indeed, senile chorea has many causes. We have seen it appear with infections, hyperglycemia, drug therapy, strokes, and thyrotoxicosis, only to disappear after a few weeks. A few times we have been confronted with the problem of an older patient who displays orolingual dyskinesias that are most characteristic of exposure to neuroleptic drugs but in whom there was no such history of exposures; testing usually disclosed Huntington disease.
Chorea in early adult life always raises the question of a late form of Sydenham chorea, of lupus erythematosus with antiphospholipid antibodies, or of cocaine use, but neither familial occurrence nor mental deterioration is part of these processes. A “benign inherited chorea,” transmitted as an autosomal dominant trait without prolongation of a triplet sequence, has been traced to chromosome 14q. It is differentiated from Huntington disease by onset before age 5 years, progressing little, and having no associated mental deterioration (Breedveld et al). Other progressive neurologic disorders inherited as autosomal dominant traits and beginning in adolescence or adult life (e.g., polymyoclonus with or without ataxia, acanthocytosis with progressive chorea, and dentatorubropallidoluysian degeneration) can closely mimic Huntington disease, as described further on; sometimes only the genetic and pathologic findings settle the matter. A midlife progressive chorea without dementia (after more than 25 years of followup) that does not display the Huntington genotype has been reported. In at least one family in which this clinical picture is dominantly inherited, the fundamental defect is a mutation in the gene encoding the light chain of ferritin (Curtis). Affected individuals have axonal changes in the pallidum with swollen, ubiquitinand tau- positive aggregates; serum ferritin levels may be depressed. The implication of this mutation is that perturbations of iron metabolism may be toxic to neurons, a feature that also characterizes Hallervorden-Spatz disease, now called PANK disease, mentioned below.