Benign hereditary chorea?Entity or syndrome?

Abstract

The existence of “benign hereditary chorea” (BHC), a rare disorder of childhood‐onset familial chorea without other neurologic features or progression, has increasingly been questioned, because many patients with this disorder were subsequently diagnosed with different conditions. We therefore analyzed all published reports of families with BHC and contacted their authors to obtain follow‐up information. In addition, we reviewed all patients in whom at least one of the authors had at some stage considered a possible diagnosis of BHC. Of 42 families reported to have BHC in the literature, we obtained follow‐up information on 11 families, three of which had been seen by us. An additional seven new, unreported families and four sporadic cases, in which this diagnosis was suspected by at least one of us at one point, were reviewed and videotaped. On reviewing the videotapes of the 11 families in the literature, the diagnosis of BHC was changed in nine. In the remaining two families, atypical features suggesting different diagnoses were present in the original reports. In none of our own previously unreported patients (seven familial and four sporadic) was BHC diagnosed unequivocally by all evaluators after review of their video recordings. In three of these families and all four sporadic patients the diagnosis was changed; in one family multifocal myoclonus could not be differentiated from chorea by any author, and in the remaining three families no consensus between the raters was found. Apart from the 11 families in whom we obtained follow‐up information, analysis of the remaining 31 reports on families with BHC also revealed atypical features in the majority. We conclude that BHC is not a diagnosis, but a syndrome that requires further investigation. Whether there is a distinct entity “BHC” with a single gene abnormality remains to be proven.

Nonsense mutation in TITF1 in a Portuguese family with benign hereditary chorea

“…The clinical presentation of the patients in this family overlaps with that of the reported cases in the literature. The variability of the neurological signs found in one or both of our patients (e.g., spasticity, dysarthria, mental retardation, and falls) is in accordance with the heterogeneity of the published cases of BHC [2,9]. Some of these features, such as pes cavus and hammer toes, seen in patient 1, were shared by the patient's father, and are therefore most likely not due to the TITF1 mutation.…”

“…Heterogeneity of clinical presentation exists within and among BHC families. Besides chorea, many of the published cases of BHC include atypical clinical features such as dystonia, myoclonic jerks, mild dysarthria or gait disturbances, and low-average intelligence [2].…”

“…Until recently, doubts existed concerning the definition of BHC as a separate and well-defined clinical entity [2]. However, the mapping and cloning of its causative gene on chromosome 14q [3], the gene encoding thyroid transcription factor 1 (TITF1), also known as NKX2-1, was even-tually reported in 2002 [4].…”

“…In adult human tissues, TITF1 is exclusively expressed in the thyroid and in the lung [7]. However, during human development, the gene is expressed: (1) strongly in the ventral diencephalon (hypothalamic area and infundibulum) and in the telencephalon, more precisely, in the developing basal ganglia region (striatum and paleostriatum); (2) in the lung bud, firstly in the primary bronchi epithelia and at 9 weeks of gestation in the alveolar primordial epithelium; and (3) weakly in the thyroid primordium [8]. Mutations in this gene have been found in five independent BHC families of Dutch, North American, Welsh, Italian, and Canadian origin [4,[9][10][11][12], as well as in patients with a combination of choreoathetosis, hypothyroidism, and pulmonary symptoms of different origins [7,[13][14][15][16][17][18] (see Table 1 for review).…”

A novel nonsense mutation in the TITF-1 gene in a Japanese family with benign hereditary chorea

“…In addition to chorea, some patients exhibit other neurological features, such as dystonia, myoclonic jerks, intentional tremor, dysarthria, and gait disturbance [7].…”