RESUMEN
Spinocerebellar ataxias (SCA) are highly heterogenous group of neurodegenerative diseases causing progressive cerebellar dysfunction. We report the first description of relative frequencies of the common SCA mutations and of phenotypic characteristics of SCA3 patients among Malaysians. Pooled data from adult Malaysian patients who had undergone genetic testing for SCA 1,2,3,6 and 7 at UKM Medical Centre and Institute for Medical Research from 2017 to 2020 were analysed. Fifteen patients with SCA 3 had detailed clinical phenotype evaluation using Inventory for Non -Ataxia Signs (INAS) and Ataxia Severity evaluation using the Scale for Assessment and Rating of Ataxia (SARA). Out of 152 adults patients who were tested for common SCA mutations, 64(42.1%) patients were tested positive for either SCA 1,2,3,6 or 7. Of the 64 positive cases, 44 (68.9%) patients were diagnosed with SCA 3 followed by SCA 2 in 13(20.3%) patients and SCA 1 in 5 (7.8%) patients. Our findings suggest that Malay race had the highest frequency of SCA (n = 34, 50%), followed by the Chinese (n = 16, 23.5%) and approximately 60 (93.8%) SCA patients had first degree family history. In conclusion, SCA 3 is the commonest SCA in Malaysia, followed by SCA 2 and SCA 1. It is important to develop a proper registry of SCA patients to further understand the true prevalence and local impact of the disease in Malaysia.
RESUMEN
Mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1 are thought to cause the excessive autonomous aldosterone secretion of aldosterone-producing adenomas (APAs). The histopathology of KCNJ5 mutant APAs, the most common and largest, has been thoroughly investigated and shown to have a zona fasciculata-like composition. This study aims to characterize the histopathologic spectrum of the other genotypes and document the proliferation rate of the different sized APAs. Adrenals from 39 primary aldosteronism patients were immunohistochemically stained for CYP11B2 to confirm diagnosis of an APA. Twenty-eight adenomas had sufficient material for further analysis and were target sequenced at hot spots in the 5 causal genes. Ten adenomas had a KCNJ5 mutation (35.7%), 7 adenomas had an ATP1A1 mutation (25%), and 4 adenomas had a CACNA1D mutation (14.3%). One novel mutation in exon 28 of CACNA1D (V1153G) was identified. The mutation caused a hyperpolarizing shift of the voltage-dependent activation and inactivation and slowed the channel's inactivation kinetics. Immunohistochemical stainings of CYP17A1 as a zona fasciculata cell marker and Ki67 as a proliferation marker were used. KCNJ5 mutant adenomas showed a strong expression of CYP17A1, whereas ATP1A1/CACNA1D mutant adenomas had a predominantly negative expression (P value =1.20×10-4). ATP1A1/CACNA1D mutant adenomas had twice the nuclei with intense staining of Ki67 than KCNJ5 mutant adenomas (0.7% [0.5%-1.9%] versus 0.4% [0.3%-0.7%]; P value =0.04). Further, 3 adenomas with either an ATP1A1 mutation or a CACNA1D mutation had >30% nuclei with moderate Ki67 staining. In summary, similar to KCNJ5 mutant APAs, ATP1A1 and CACNA1D mutant adenomas have a seemingly specific histopathologic phenotype.
