Examination of Huntington’s disease with atypical clinical features in a Bangladeshi family tree
A disorder appeared in a family in Northern Bangladesh nearly 130 years ago in one of two siblings. Over five generations the disease was passed down. When the family was discovered by a team of scientists from ideSHi in 2014, already eight living members of the family were affected by the disease.
The disease is characterized by mild jerky movement of fingers and slow movement of eyes as the first detectable clinical symptoms. The age of onset had decreased from 65 over five generations to 20 years. Suprovath Kumar Sarker, one of the leading members of the team says, “we had suspected Huntington’s Disease, but the clinical features were quite atypical. All eight patients appeared normal with regards to their thinking ability because there was no significant dementia as manifested by mini‐mental state examination. Additionally, none of the patients did show any psychiatric disturbances. Although three cases showed characteristic features of anxiety, there was no tendency of committing suicide. It is mentionable here that one patient had severe chorea characterized by balanced trouble, clumsiness, tremor, significant weight loss, fidgeting, facial grimaces, increased appetite, less control over handwriting, rigidity, speech difficulties, grunting and abnormal speech patterns, inability to control speed and force of movement, general weakness, and impairment of superficial sensation. However, the clinical symptoms, as manifested by brain imaging and mini‐mental state examination, were not typical of Huntington's disease (HD) or any other choreatic movement‐associated neurodegenerative diseases including HD‐like disorders or Wilson's disease. We went on to analyse blood parameters like total bilirubin, ALT, and ceruloplasmin as well as Kayser–Fleischer (K‐F) ring test, but none showed any abnormal results, excluding the possibility of Wilson's disease. MRI examination of the patient's brain did not reveal pathology typical of Huntington's disease. Putamen and Caudate are the primary sites to be affected for the structural changes in Huntington's disease. No changes were evident in the caudate nucleus and striatum regions like putamen and globus pallidus, although mild cerebellar atrophy was observed.
Puzzled by these atypical clinical symptoms, the team resorted to genetic testing using DNA specimens to identify the disease. They first used PCR‐based method to check the length of the HTT allele 3. All unaffected subjects tested had typical HD allele length of 80–85 bp, while all affected individuals were heterozygous, with one normal HD allele and one expanded allele.
They then used Sanger DNA sequencing to show that the normal allele had 20 CAG repeats, within the previously reported range of 6–35. The expanded allele had either 53 or 70 CAG repeats, confirming the diagnosis of Huntington's disease. The patient with the longer CAG repeat was just 20 years of age and thus was diagnosed as juvenile. The team found no mutations in three genes (PRNP, JPH3, and TBP) associated with HD‐like diseases HDL 1, HDL 2, and HDL 4, respectively.
Major clinical characteristic of typical Huntington's disease (HD) is manifested by progressive dementia. However, HD chorea without dementia and absence of observable atrophy of either cortex or basal ganglia have been reported.
The findings of the study has been published on November 11, 2016 in Clinical Case Reports
According to the team, this is the first study on diagnosis of a neurodegenerative disease using a sequencing‐based approach in Bangladesh, paving the way for expansion of facilities for diagnosis of other genetic disorders. Furthermore, the atypical manifestation of HD in this Bangladeshi family could inform ongoing research into HD genetic modifiers not present in the primarily European populations studied to date. This work demonstrates that expanding HD genetic testing into under‐resourced healthcare settings can benefit both local communities and ongoing research into HD disease etiology and new therapies.
Al-Mamun MM, Sarker SK, Qadri SK, Shirin T, Mohammad QD, LaRocque R et al. Examination of Huntington's disease with atypical clinical features in a Bangladeshi family tree. Clinical Case Reports. 2016;4(12):1191-1194.