Chorea, Benign Hereditary

A number sign (#) is used with this entry because some patients with benign hereditary chorea (BHC or BCH) have mutations in the NKX2-1 gene (600635) encoding thyroid transcription factor-1 (TITF1).

See also choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress (610978), an allelic disorder with a more severe phenotype.

Clinical Features

Pincus and Chutorian (1967) and Haerer et al. (1967) described an early-onset, nonprogressive form of chorea not associated with intellectual deterioration.

Bird et al. (1976) pointed out that hereditary benign chorea is a socially embarrassing condition and, perhaps for that reason, may be associated with behavioral problems and learning difficulties. For purposes of genetic counseling and prognostication, it is important to distinguish BCH from Huntington disease (HD; 143100).

Robinson and Thornett (1985) reported a 10-year-old boy with this disorder whose father was the only other affected person known in the family. Corticosteroids given in multiple courses for asthma invariably were associated with an abrupt improvement in frequency and amplitude of his chorea. The authors suggested that the improvement resulted from modulation of neurotransmitter function by the agent. Schady and Meara (1988) described a family in which chorea began in childhood and affected predominantly the head, face, and arms. Dysarthria appeared later, followed in 2 family members by elements of an axial dystonia. There was no intellectual impairment. Unlike previously described families, symptoms progressed steadily up to the eighth decade, causing considerable physical disability.

Kleiner-Fisman et al. (2003) reported a family in which 5 members over 4 generations had typical features of BHC. Delayed motor development and chorea began in early childhood and followed a slowly progressive course. Neuropathologic examination of 1 patient showed mild frontal-parietal-temporal atrophy, but no other abnormalities, including normal striatum and pigmented substantia nigra. Other regions of the brain showed nonspecific astrocytosis without noticeable neuronal loss.

Inheritance

Possible dominant inheritance of BHC was demonstrated in 2 families by Chun et al. (1973). Harper (1978) favored autosomal dominant inheritance with reduced penetrance in females. He pointed out that male-to-male transmission occurred in the families of Pincus and Chutorian (1967) and possibly in the family of Sadjadpour and Amato (1973), excluding X-linked inheritance. Furthermore, X-linked inheritance appears to be excluded by the apparent transmission through an unaffected male in the family of Pincus and Chutorian (1967). Both a dominant and a recessive form (215450) may exist.

Mapping

Exclusion Linkage

In a study of 5 families with BCH, Quarrell et al. (1988) found that the disorder was not closely linked to the D4S10 marker, thus excluding the possibility that benign hereditary chorea is allelic with Huntington disease. Furthermore, when the expanded repeat sequence was discovered as the basis of Huntington disease, these families were restudied by MacMillan et al. (1993). In 4 of the families, the (CAG)n repeat was not found; in 1 family, expanded repeats were found. Because of the small size of the family and the uninformativeness of typing, this linkage to 4p16 could not be excluded in the original study of this family. Yapijakis et al. (1995) likewise excluded linkage to the HD locus in an affected Greek family.

Linkage to 14q

In a large Dutch kindred with BHC, de Vries et al. (2000) found strong evidence for linkage between the disorder and markers on 14q (maximum lod score of 6.32 at recombination fraction 0.0). The BHC locus in this family was located between markers D14S49 and D14S1064, a region spanning approximately 20.6 cM and containing several candidate genes involved in the development and/or maintenance of the central nervous system, including glia maturation factor-beta (GMFB; 601713), GTP cyclohydrolase I (GCH1; 600225), and SMN-interacting protein-1 (SIP1; 602595).

Fernandez et al. (2001) reported a 4-generation family with BCH showing linkage to 14q. Haplotype analysis defined a 6.93-cM critical region between D14S1068 and D14S1064, excluding SIP1 as a candidate gene. Direct sequencing of the GCH1 gene in this family revealed no mutations.

Genetic Heterogeneity

Breedveld et al. (2002) reported clinical and genetic heterogeneity in 6 families with BHC and the large Dutch family reported by de Vries et al. (2000). Three of the 7 families showed linkage to chromosome 14 between markers D14S49 and D14S278, and haplotype analysis narrowed the critical interval for the BHC locus to 8.4 cM. In the remaining 4 families, linkage to 14q was excluded. The 3 families with linkage to 14q had a similar clinical phenotype including onset in infancy and childhood, chorea, and absence of mental deterioration. Other variable features in these families included gait difficulties, pyramidal signs, slow saccades, and abnormal reflexes. The 4 unlinked families had a slightly later age at onset and other signs besides chorea, including myoclonic jerks, dystonia, tremor, and tics.

Molecular Genetics

Breedveld et al. (2002) reported a small BHC family with a de novo deletion of 1.2 Mb, including the TITF1 gene (600635.0001). They also described 3 other multigenerational families with BHC who had heterozygous point mutations in the TITF1 gene (600635.0002-600635.0004).

In a family with BHC, Kleiner-Fisman et al. (2003) identified a heterozygous mutation in the TITF1 gene (600635.0007).

Nomenclature

Schady and Meara (1988) discussed the use of the label 'benign' and concurred with Behan and Bone (1977) that the most accurate term was 'hereditary chorea without dementia.'