Hereditary benign chorea

Methods.

Family.

The family (figure) was ascertained and clinically evaluated in the Neurogenetics Clinics at the University of Washington Medical Center and the Veterans Affairs Puget Sound Health Care System. Under protocols approved by the Institutional Review Board of the University of Washington, subjects were examined and blood samples were obtained from five affected members, one unaffected member, and two spouses from three generations of this family.

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Figure. Pedigree of the family with benign hereditary chorea (BCH). Gray-filled symbols represent affected status and open symbols represent unaffected status. A slash line indicates deceased status. Some persons in generations I and II are indicated as affected based on family recollection and description. The 14 markers included in the genotype analysis and their map locations are shown in the inset at the lower left; D14S1064 was not genotyped. On this map, previously specified flanking markers1 are indicated by thin arrows and the new proximal border of the critical region is shown by a thick arrow. Haplotypes are shown below symbols for subjects from whom DNA was obtained. Brackets indicate inferred genotypes. Genotypes are shown between the chromosome pair for markers where the phase is not known. On the pedigree, the thin arrow indicates a microsatellite mutation. BCH appears to be segregating with the black chromosomal segment. The recombination event refining the proximal border of the critical region is indicated by the thick arrow. Because the markers were not fully informative, the breakpoint cannot be more specifically defined.

Results.

This family was originally reported as having essential nonprogressive chorea with an autosomal dominant inheritance pattern.18 The syndrome manifests as early childhood onset of sudden choreiform movements of small amplitude, generally involving the distal parts of the upper extremities, but also involving the feet, shoulders, head, and face. The movements are worsened by anxiety but not by voluntary movements, exercise, startle, caffeine, or alcohol. The adventitious movements increase in severity until early adolescence, when progression ceases, and the symptoms may improve in adulthood. Although the condition is not associated with dementia or a decrease in lifespan, it can be socially disabling. Some members of the family have educational and behavioral difficulties.

The pedigree demonstrates an autosomal dominant pattern, with evidence of male-to-male transmission, no evidence for decreased penetrance, but variable expressivity in terms of severity. The ages at onset range from 2 to 5 years, although one subject was unaware of her status until examined at age 21 (IV-3). There is no evidence of genetic anticipation.

Clinical evaluations of three affected members of this family are described in detail; the others are summarized in the table. Individual IV-2, a man with normal intellect, had onset in early childhood of choreic movements. Between ages 1 and 2 years he was noted to have jerky movements of the hands. When examined at age 6 years he had sudden, jerky movements of small amplitude involving the distal parts of the upper limbs. Similar movements were occasionally noted in the shoulder, feet, head, and face. Cranial nerve testing results were normal. He had mild difficulty hopping on one foot and was unable to skip. The rest of his coordination, gait, muscle strength, muscle tone, and sensation was normal. Deep tendon reflexes were hyperactive, but symmetric with flexor plantar responses. Wechsler Intelligence Scale for Children showed a verbal IQ of 106, performance IQ of 90, and full-scale IQ of 98. Over the intervening years he experienced many social problems associated with his movements. He left school after the ninth grade, had trouble maintaining employment, was turned down by the Navy, and has been inaccurately accused of being intoxicated. He has avoided drugs and medications. On examination at age 31, he had a normal mental status. He had brief, irregular movements of his arms, legs, trunk, and more frequently of his head. These were more evident when he was distracted and on turning or moving his head or body. Cranial nerves, muscle strength, muscle tone, and sensation were normal. His deep tendon reflexes were normal and symmetric with flexor plantar responses. His gait was steady and Romberg sign was negative. Blood ceruloplasmin level, EEG, and HD DNA test results were all normal.

Individual II-3, a woman with normal intellect, had onset of the disease in early childhood with improvement of her movements in adulthood. As an adult she noted occasional, sudden extension spasms of her neck lasting seconds. Examination at age 47 years showed moderate, choreiform movements of her distal upper and lower extremities and head. At age 71 years, she was living in a nursing home and had a history of the onset of moderate memory loss beginning in her mid 60s. Examination showed infrequent, brief jerks of her upper limbs and brief orolingual quivering. The movements were much less noticeable than at age 47. Her cranial nerves were normal. She had normal to brisk, symmetric, deep tendon reflexes and flexor plantar responses. She uses levothyroxine for hypothyroidism and hydrochlorothiazide for hypertension. She has used chlordiazepam, phenobarbital, and chlorazepate without improvement of her movements.

This woman’s mother (I-2) had medical records indicating the onset of adventitious movements before age 6 years and a diagnosis of St. Vitus dance (Sydenham chorea) at age 12 years. As an adult she was described as having grimacing, twisting, turning movements called choreiform. At age 63 years she had a pneumoencephalogram showing normal caudate shadows (reviewed by us) and was thought not to have HD. EEG and CSF examination findings were normal. She died at age 67 years of lung cancer prior to the current study, but her medical records indicate that she had the most severe movement disorder in this family.

Individual III-5, the daughter of II-3, had onset of adventitious movements at age 5 years. The movements did not increase in frequency or severity except transiently during pregnancy. Examination at age 18 years showed frequent mild choreiform movement of her hands, feet, arms, and face. The movements were increased by anxiety. The rest of the neurologic examination findings were normal. Examination at age 42 years showed a normal mental status. She had mild to moderate chorea of arms, legs, face, and trunk. Cranial nerve examination findings were normal. Strength, muscle tone, and sensation were normal. She had a mild fine tremor of her outstretched hands. Coordination and gait were normal. She had normal to brisk tendon reflexes with flexor plantar responses. Historically, phenobarbital was not beneficial, but she reported that 10 mg/day of diazepam caused mild improvement. She was not using medication at the time of examination. Her two daughters were found to be affected on examination at ages 21 and 14 years. Individual IV-4 was examined by three of the authors (M.F., H.L., and T.B.) and had clear adventitious movements that had been noted by her mother for many years, although a precise age at onset could not be determined.

Discussion.

We have described a second family with BCH localizing to 14q, refined the proximal border of the critical region, and narrowed the region to 6.93 KcM. Two of three previously suggested candidate genes, glial maturational factor beta and GCH1, lie within this region, but survival motor neuron (SMN) interacting protein is excluded by its location outside the narrowed region.1

The GCH1 gene is of special interest because it is responsible for dopa-responsive dystonia. Both BCH and dopa-responsive dystonia are movement disorders of early onset. Individuals I-2 and II-3 had brief sudden neck spasms that could represent dystonia. However, no mutations were found by direct sequencing of the coding region and the contiguous 32 nucleotides of the 5′ untranslated region. It remains possible that a mutation outside this region is responsible for disease in this family. It would be reasonable to perform sequence analysis in additional families whose disease localizes to chromosome 14. It is also interesting that the locus for a syndrome of basal ganglia calcification20 characterized by chorea, dystonia, parkinsonism, and tremors was recently mapped to this same genomic region; GCH1 lies outside the minimal region for familial calcification of the basal ganglia. Glial maturational factor beta remains a candidate gene for BCH.

The phenotype of BCH is most commonly confused with two other causes of chorea, namely HD and Sydenham chorea. BCH differs from HD in that it is nonprogressive, does not involve deteriorating cognitive or behavioral changes, does not have caudate atrophy on neuroimaging, and has a normal-sized CAG repeat in the HD gene. Although subjects in our family and in the previously described family1 have been thought to have Sydenham’s chorea, BCH is present for years or even decades, is not associated with rheumatic fever, and has a family history. Several of the children in our family have had difficulties in school, but it is unclear whether this is a direct consequence of the CNS disease or related to problems with social interaction. Several were unable to finish school and experienced serious social isolation. A single person in this family (II-3) has had mild late-onset dementia. This may be coincidental because no other person in this family or the previously described family1 has developed dementia.

Benign familial chorea is a heterogeneous syndrome that may have a variety of causes.7 Many families with this initial diagnosis prove to have other disorders when more thoroughly evaluated or followed up for long periods. This has even been the case with one of our other families initially thought to have BCH but now shown to have familial dyskinesia with myokymia.21 Nevertheless, previous findings1 combined with our current study demonstrate that there is a distinct genetic entity of early-onset, nonprogressive, uncomplicated chorea with a locus on 14q.