Helena Jahnová1, Helena Poupětová1, Jitka Jirečková1, Hana Vlášková1, Eva Košťálová1, Radim Mazanec2, Alena Zumrová3, Petr Mečíř4, Zuzana Mušová5, Martin Magner6. 1. Department of Paediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 2, 120 00, Prague 2, Czech Republic. 2. Department of Neurology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic. 3. Department of Paediatric Neurology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic. 4. Department of Neurology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic. 5. Department of Biology and Medical Genetics, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic. 6. Department of Paediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 2, 120 00, Prague 2, Czech Republic. martin.magner@vfn.cz.
Abstract
BACKGROUND: Tay-Sachs disease (TSD) is an inherited neurodegenerative disorder caused by a lysosomal β-hexosaminidase A deficiency due to mutations in the HEXA gene. The late-onset form of disease (LOTS) is considered rare, and only a limited number of cases have been reported. The clinical course of LOTS differs substantially from classic infantile TSD. METHODS: Comprehensive data from 14 Czech patients with LOTS were collated, including results of enzyme assays and genetic analyses. RESULTS: 14 patients (9 females, 5 males) with LOTS were diagnosed between 2002 and 2018 in the Czech Republic (a calculated birth prevalence of 1 per 325,175 live births). The median age of first symptoms was 21 years (range 10-33 years), and the median diagnostic delay was 10.5 years (range 0-29 years). The main clinical symptoms at the time of manifestation were stammering or slurred speech, proximal weakness of the lower extremities due to anterior horn cell neuronopathy, signs of neo- and paleocerebellar dysfunction and/or psychiatric disorders. Cerebellar atrophy detected through brain MRI was a common finding. Residual enzyme activity was 1.8-4.1% of controls. All patients carried the typical LOTS-associated c.805G>A (p.Gly269Ser) mutation on at least one allele, while a novel point mutation, c.754C>T (p.Arg252Cys) was found in two siblings. CONCLUSION: LOTS seems to be an underdiagnosed cause of progressive distal motor neuron disease, with variably expressed cerebellar impairment and psychiatric symptomatology in our group of adolescent and adult patients. The enzyme assay of β-hexosaminidase A in serum/plasma is a rapid and reliable tool to verify clinical suspicions.
BACKGROUND:Tay-Sachs disease (TSD) is an inherited neurodegenerative disorder caused by a lysosomal β-hexosaminidase A deficiency due to mutations in the HEXA gene. The late-onset form of disease (LOTS) is considered rare, and only a limited number of cases have been reported. The clinical course of LOTS differs substantially from classic infantile TSD. METHODS: Comprehensive data from 14 Czech patients with LOTS were collated, including results of enzyme assays and genetic analyses. RESULTS: 14 patients (9 females, 5 males) with LOTS were diagnosed between 2002 and 2018 in the Czech Republic (a calculated birth prevalence of 1 per 325,175 live births). The median age of first symptoms was 21 years (range 10-33 years), and the median diagnostic delay was 10.5 years (range 0-29 years). The main clinical symptoms at the time of manifestation were stammering or slurred speech, proximal weakness of the lower extremities due to anterior horn cell neuronopathy, signs of neo- and paleocerebellar dysfunction and/or psychiatric disorders. Cerebellar atrophy detected through brain MRI was a common finding. Residual enzyme activity was 1.8-4.1% of controls. All patients carried the typical LOTS-associated c.805G>A (p.Gly269Ser) mutation on at least one allele, while a novel point mutation, c.754C>T (p.Arg252Cys) was found in two siblings. CONCLUSION: LOTS seems to be an underdiagnosed cause of progressive distal motor neuron disease, with variably expressed cerebellar impairment and psychiatric symptomatology in our group of adolescent and adult patients. The enzyme assay of β-hexosaminidase A in serum/plasma is a rapid and reliable tool to verify clinical suspicions.
Entities:
Keywords:
Ataxia; Cerebellum; GM2 gangliosidosis; Late-onset Tay–Sachs disease; Proximal weakness of lower extremities; β-Hexosaminidase A
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