Late‐Onset Tay‐Sachs Disease in an Irish Family

Abstract

Background Background: Late-onset Tay-Sachs disease (LOTS) is an autosomal-recessive lysosomal storage disease caused by deficient β-hexosaminidase A activity. LOTS is rare in the Ashkenazi Jews, but even rarer in the non-Jewish population. Cases Cases: We report an Irish family expanding the LOTS phenotype (ataxia, diffuse muscle wasting, dystonia, chorea, belly dancer's dyskinesia, and neuropsychiatric features) associated with the known HEXA variant 1073 + 1G > A and a novel variant c.459 + 24G > C. Conclusions Conclusions: LOTS should be considered in patients with similar symptoms and cerebellar atrophy on brain imaging. Late-onset Tay-Sachs disease (LOTS) is an autosomal-recessive disorder attributed to HEXA mutations causing reduced β-hexosaminidase A activity and subsequent CNS ganglioside accumulation. Affected individuals can present from late childhood with slowly progressive and heterogenous clinical manifestations such as cerebellar dysfunction, anterior horn cell pathology mimicking spinal muscular atrophy, and extrapyramidal and psychiatric features. 1 LOTS is rare in the Ashkenazi Jewish (1:135,000). 1 In the non-Jewish, LOTS is much scarcer and associated with extreme mutation heterogeneity, often with private or unique alleles. 2 We report an Irish family with LOTS, harboring a novel HEXA variant, and present videos of 3 siblings demonstrating heterogenous clinical manifestations including extrapyramidal, spinocerebellar, and neuropsychiatric involvement. Case Series A family pedigree showing genotypes are illustrated in Figure 1. Clinical, biochemical, and MRIbrain characteristics for patients II.4, II.5, II.6, and II.9 are illustrated in Table 1. Genetic Analysis Molecular analysis of the HEXA gene was performed at the Department of Clinical Genetics Amsterdam, the Netherlands. All coding sequences of the HEXA gene, including the flanking intron sequences, were analyzed by direct sequencing. Large deletions or insertions were excluded using Multiplex Ligation Dependent Probe Amplification analysis P199 from MRC Holland (www.mrc-holland.com). HEXA gene DNA analysis detected a previously reported heterozygous mutation c. 1073 + 1G > A and a previously unpublished c.459 + 24G > C variant in all 4 affected siblings (II.4. II.5, II.6, and II.9). The mother (I.2) was heterozygous for c. 1073 + 1G > A. An unaffected sister (II.10) tested negative for both variants. The rest of the family members were not available for testing (Fig. 1A). The variant c.459 + 24G > C has not been described before, and as splicing prediction modules (Alamut Visual 2.7.1) did not predict splicing defects, it is classified as class 3 (pathogenicity unclear). Case 1 (II.4 Proband) This 56-year-old man, born to nonconsanguineous parents of non-Jewish European ancestry, presented with a 10-year history

Pontocerebellar atrophy is the hallmark neuroradiological finding in late-onset Tay-Sachs disease

“…Notably, none of these patients had cognitive impairment. Marked frontal atrophy that was previously reported [23] was not seen in any of our patients. Supratentorial abnormalities of signal intensity were seen only in two patients, which suggests that this finding may not be related to LOTS and is rather coincidental.…”

“…With regard to clinical phenotype in our group of patients, dystonia was present in 19% of patients that is more frequent than in previous studies. [8,23] Psychiatric manifestation can be the initial manifestation in some patients and overall occurs in 30 to 50% of patients with LOTS [33,34]. The prevalence of psychiatric manifestation was 68%, which may be explained by the long disease duration in our patient's group.…”

Late‐onset Tay−Sachs disease presenting with a neuromuscular phenotype—a case series

“…Previous phenotypic studies of LOTS describe cerebellar, extrapyramidal and neuropsychiatric features occurring in addition to neuromuscular weakness. Whilst some cases may present with a neuromuscular predominant phenotype, additional features such as tandem gait ataxia are typically seen on examination [3–5]. Cerebellar atrophy on MRI, which is almost always seen, was not a feature in this case series.…”

Letter response: Intra-familial phenotype variability in Late-Onset Tay-Sachs disease

“…predominant cerebellar or stuttering phenotype at presentation) but the age of onset within different individuals in the same family and the progression of the symptoms was different [3,8]. Other authors described, instead, a significant intra-familial variability in the reported cases, both in terms of clinical presentation and timeline of symptom onset [2,3,[9][10][11][12][13].…”