Benign Hereditary Chorea of Early Onset Maps to Chromosome 14q

Abstract

Benign hereditary chorea (BHC) is an autosomal dominant disorder characterized by an early-onset nonprogressive chorea. The early onset and the benign course distinguishes BHC from the more common Huntington disease (HD). Previous studies on families with BHC have shown that BHC and HD are not allelic. We studied a large Dutch kindred with BHC and obtained strong evidence for linkage between the disorder and markers on chromosome 14q (maximum LOD score 6.32 at recombination fraction 0). The BHC locus in this family was located between markers D14S49 and D14S1064, a region spanning approximately 20.6 cM that contains several interesting candidate genes involved in the development and/or maintenance of the CNS: glia maturation factor-beta, GTP cyclohydrolase 1 and the survival of motor neurons (SMN)-interacting protein 1. The mapping of the BHC locus to 14q is a first step toward identification of the gene involved, which might, subsequently, shed light on the pathogenesis of this and other choreatic disorders.

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

“…The Dutch BHC family, carrying a R243S mutation in TITF1 [4], presented cerebellar and pyramidal signs, but the patients' MRIs revealed no alterations [3]. The cortical cerebral and cortical/subcortical cerebellar atrophy seen in patient 2 can possibly correlate with the observation that Nkx2.1 knockout mice have reduced numbers of cortical migrating cells expressing gamma-aminobutyric acid (GABA), DLX2, and calbindin produced in the pallidum [23].…”

“…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]. TITF1 is a member of the NK2 family homeodomain-containing transcription factors [5,6].…”

Benign hereditary chorea: more than meets the eye

“…Despite this, a relatively small number of cases have been described with persistent motor impairments and features of additional movement disorders such as ataxia, dystonia, myoclonus, and spasticity. 2 The phenotype of BHC has since been expanded with the identification of coexistent hypothyroidism and respiratory disease under the alternative name 'brain-lung-thyroid' syndrome, reflecting the implications on broader organogenesis. 3 Peall et al have continued this work in further describing the BHC picture in a larger cohort.…”

“…1 The renaissance in functional neurosurgery came with increasing recognition of the limitations of medical therapies for Parkinson disease, and, in particular, the on-off dyskinesia seen with levodopa. 2 The report by Laitinen et al in 1992 3 of a series of 46 patients undergoing pallidotomy in the management of Parkinson disease marked the start of a surge of papers on the beneficial effects of pallidotomy, including in the management of dystonia.…”

“…Functional neurosurgeons increasingly moved towards deep brain stimulation (DBS) of the subthalamic nucleus, GPi, and other targets in the management of movement disorders. 2 As a non-destructive lesioning technique, DBS offers the perceived benefit of reversibility over pallidotomy but is not without complications, most notably the infection of implanted neurostimulator systems. Whilst DBS of the GPi has undoubtedly improved the lives of many patients with Parkinson disease and dystonia, has pallidotomy been prematurely abandoned?…”