Tayova-Sachsova choroba je raritné autozomálne recesívne podmienené ochorenie zapríčinené deficitom enzýmu β-hexozaminidázy A (HexA). Dochádza k akumulácii GM2 gangliozidov v lyzozómoch neurónov, čo potenciuje ich toxický účinok a navodzuje tak postupnú neurodegeneráciu. Presný mechanizmus spustenia zániku neurónov je stále neznámy. Pre zachovanú reziduálnu aktivitu enzýmu HexA má adultná forma ochorenia zvyčajne miernejší priebeh ako infantilná forma. Klinický obraz je nešpecifický, preto je ochorenie výrazne poddiagnostikované. V našej videokazuistike prezentujeme prípad 49-ročného pacienta s geneticky potvrdenou adultnou formou Tayovej-Sachsovej choroby.
Tay-Sachs disease is a rare autosomal recessive disorder caused by β-hexosaminidase A (HexA) enzyme deficiency. There is accumulation of GM2 gangliosides in neuronal lysosomes, which potentiates their toxic effect, thus inducing gradual neurodegeneration. The exact mechanism triggering neuronal death is still unknown. Due to the preserved residual HexA enzyme activity, the adult form of the disease tends to have a milder course than the infantile form. The clinical presentation is non-specific; hence, the disease is significantly underdiagnosed. Our video case report presents a 49-year-old patient with a genetically confirmed diagnosis of adult Tay-Sachs disease.
- MeSH
- cerebelární ataxie MeSH
- lidé středního věku MeSH
- lidé MeSH
- Tay-Sachsova nemoc * diagnóza terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
BACKGROUND: Pathogenic variants in the ATAD3A gene lead to a heterogenous clinical picture and severity ranging from recessive neonatal-lethal pontocerebellar hypoplasia through milder dominant Harel-Yoon syndrome up to, again, neonatal-lethal but dominant cardiomyopathy. The genetic diagnostics of ATAD3A-related disorders is also challenging due to three paralogous genes in the ATAD3 locus, making it a difficult target for both sequencing and CNV analyses. RESULTS: Here we report four individuals from two families with compound heterozygous p.Leu77Val and exon 3-4 deletion in the ATAD3A gene. One of these patients was characterized as having combined OXPHOS deficiency based on decreased complex IV activities, decreased complex IV, I, and V holoenzyme content, as well as decreased levels of COX2 and ATP5A subunits and decreased rate of mitochondrial proteosynthesis. All four reported patients shared a strikingly similar clinical picture to a previously reported patient with the p.Leu77Val variant in combination with a null allele. They presented with a less severe course of the disease and a longer lifespan than in the case of biallelic loss-of-function variants. This consistency of the phenotype in otherwise clinically heterogenous disorder led us to the hypothesis that the severity of the phenotype could depend on the severity of variant impact. To follow this rationale, we reviewed the published cases and sorted the recessive variants according to their impact predicted by their type and the severity of the disease in the patients. CONCLUSION: The clinical picture and severity of ATAD3A-related disorders are homogenous in patients sharing the same combinations of variants. This knowledge enables deduction of variant impact severity based on known cases and allows more accurate prognosis estimation, as well as a better understanding of the ATAD3A function.
