Benign hereditary chorea: dopaminergic brain imaging in patients with a novel intronic NKX2.1 gene mutation

Abstract

Mutations in the NKX2.1 gene, which is essential for the development, differentiation and organization of the basal ganglia, cause benign hereditary chorea (BHC) characterized by childhood-onset non-progressive chorea. We herein report the clinical features of six patients from a single family with a novel intronic mutation and present the dopaminergic neuronal imaging by using positron emission tomography (PET) imaging to assess the integrity of the striatal dopaminergic system using [(11)C]-CFT for the presynaptic dopamine transporter function and [(11)C]-raclopride for the postsynaptic D2 receptor function. The patients showed mild generalized chorea without either congenital hypothyroidism or a history of pulmonary infection and some of the patients had goiter. Genetic analyses of NKX2.1 gene showed a novel heterozygous c.464-9C>A mutation that created a new acceptor splice site resulting in the production of an aberrant transcript with a 7-bp insertion identical to a intronic sequence of genomic DNA. Oral levodopa failed to improve the involuntary movement, while haloperidol, a dopamine D2 receptor blocking agent, exacerbated the choric movement in a single patient. The dopaminergic PET studies in the two patients revealed decreased raclopride binding in the striatum, while the CFT binding was not altered. The impairment of D2 receptor function in the basal ganglia may result in exacerbation of the chorea induced by haloperidol. The molecular brain imaging and therapeutic response may help elucidate the pathophysiological mechanism of the motor control in the BHC-associated NKX2.1 mutation.

Recurrent drop attacks in early childhood as presenting symptom of benign hereditary chorea caused by TITF1 gene mutations

“…Previous reports showed the efficacy of levodopa for treating choreic movements in BHC, supporting the hypothesis that the dopaminergic neuronal system in the striatum is involved in its pathogenesis . We observed that levodopa/carbidopa also resulted in rapid improvement of both choreic movements and related drop attacks episodes in patient 1, while in patient 2 choreic movements and falls became less frequent over time without any treatment.…”

Benign hereditary chorea related to NKX2.1: expansion of the genotypic and phenotypic spectrum

“…Finally, the individuals in our series have been treated with a variety of oral therapies, none of which has provided significant improvement in their chorea. Previous studies have reported improvement with levodopa, ropinirole, and tetrabenazine, a partial response to propranolol, and worsening of symptoms with haloperidol . The lack of response in our cohort may be explained by the use of lower doses because of the development of intolerable side‐effects.…”

Functional neuroimaging and chorea: a systematic review

“…Additionally, a report of two related patients with BHC with an NKX2.1 mutation demonstrated reduced relative [ 11 C]-raclopride binding in the striatum with normal relative binding of 11-carbon-2 carbomethoxy-3-(4-[ 18 F]-fluorophenyl)tropane ([ 11 C]-CFT), a radioligand used to evaluate presynaptic dopamine transporter function [32]. This is rather surprising, as this disorder is not characterized by neurodegeneration affecting the neurons that bear dopaminergic receptors, but only of various interneurons [33].…”