Dentatorubropallidoluysian atrophy (DRPLA), sometimes mistaken clinically for Huntington chorea, was described in European families by Warner and associates and is discussed further on. The extrapyramidal manifestations include chorea, myoclonus, and rigidity. Adult-onset chorea and dementia has been described with propionic acidemia; propionic acid is elevated in the plasma, urine, and CSF. This disorder must be added to other metabolic diseases described in Chap. 36 as causes of childhood chorea and dyskinesia—such as glutaric acidemia, keratin sulfaturia, calcification of basal ganglia, phenylketonuria, and PANK disease.
Other problems in differential diagnosis include prion disease, Wilson disease (see Chap. 36), acquired hepatocerebral degeneration (see Chap. 39), paraneoplastic chorea (see Chap. 30), and most often and especially, tardive dyskinesia (see Chap. 41). Many drugs in addition to the toxic effects of l-dopa and antipsychotic medications occasionally cause chorea (amphetamines, cocaine, tricyclic antidepressants, lithium, isoniazid, linezolid). The hyperglycemic–hyperosmolar state is known for producing a variety of generalized or local movement disorders, prominent among them being chorea.
The dopamine antagonist haloperidol, in daily doses of 2 to 10 mg, is effective partially in suppressing the movement disorder. Because of the danger of superimposing tardive dyskinesia on the chronic disorder, the chorea should be treated only if it is functionally disabling, using the smallest possible dosages. Haloperidol may also help alleviate abnormalities of behavior or emotional lability, but it does not alter the progress of the disease. The authors have not been impressed with the therapeutic effectiveness of other currently available drugs. Levodopa and other dopamine agonists make the chorea worse and, in the rigid form of the disease, evoke chorea. Drugs that deplete dopamine or block dopamine receptors—such as reserpine, clozapine, and particularly tetrabenazine, which is an inhibitor of vesicular monoamine oxidase transporter 2 (VMAT2) and has been validated in a controlled study (Huntington Study Group)—suppress the chorea to some degree, but their side effects (drowsiness, akathisia, and tardive dyskinesia) usually outweigh their desired effects. Deutetrabenazine is a newer VMAT2 inhibitor, which has been approved for use in HD. Both tetrabenazine and deutrabenazine are contraindicated in patients with active suicidality or inadequately treated depression. The juvenile (rigid) form of the disease is probably best treated with antiparkinsonian drugs. Preliminary studies of the transplantation of fetal ganglionic tissue into the striatum have achieved mixed results. The psychologic and social consequences of the disease require supportive therapy, and genetic counseling is essential. Antidepression drugs are widely implemented because of the high incidence of depression and suicidality but their efficacy is not clear. Huntington disease pursues a steadily progressive course and death occurs as mentioned, on average 15 to 20 years after onset, sometimes much earlier or later.
Novel therapeutic agents in the form of antisense oligonucleotides are currently being tested. These agents are introduced intrathecally and bind to huntingtin mRNA in the central nervous system. In early stage in-human safety and tolerability studies lead to dose-dependent reduction in huntingtin mRNA and protein. This approach is comparable to what has been accomplished in spinal muscular atrophy (discussed later in this chapter).