Infantylna gangliosydoza GM1 z padaczką spowodowana tym samym kodonym wariantem genu GLB1 (c.808T>G/c.808T>C)
Infantile GM1 Gangliosidosis with Epilepsy Associated with a Same-Codon GLB1 Variant (c.808T>G/c.808T>C)
W skrócie
W badaniu opisano dziecko z rzadką chorobą genetyczną - gangliosydozą GM1, u którego znaleziono dwa mutacje w tym samym miejscu genu GLB1, co nigdy wcześniej nie zostało opisane. Mutacje te uszkadzają pracę enzymu, który powinien rozkładać określone substancje w organizmie, co prowadzi do szybko postępującej choroby ze znacznym upośledzeniem neurologicznym. Wyniki badania potwierdzają, że to konkretne miejsce genu jest szczególnie ważne dla prawidłowego działania enzymu i jego uszkodzenie powoduje poważną chorobę już u niemowląt.
Oryginalny abstract (angielski)
GM1 gangliosidosis is an autosomal recessive lysosomal storage disorder caused by a deficiency of β-galactosidase due to pathogenic variants in the gene. Almost 300 pathogenic or likely pathogenic variants have been identified, associated with a phenotypic spectrum ranging from GM1 gangliosidosis to mucopolysaccharidosis type IVB. Disease severity is largely determined by the extent to which specific variants impair enzymatic catalytic activity, particularly through disruption of substrate recognition and binding within the active site. We report a patient with GM1 gangliosidosis type I harboring two pathogenic missense variants, c.808T>G (p.Tyr270Asp) and c.808T>C (p.Tyr270His), in a compound heterozygous state. To the best of our knowledge, this specific allelic combination has not been previously described. Both variants affect the same codon, resulting in distinct amino acid substitutions at position 270, a residue critically involved in maintaining the structural and functional integrity of the catalytic domain of β-galactosidase. Disruption at this site is expected to severely compromise enzymatic activity. Comparative analysis with previously reported cases carrying variants at the same residue, in either homozygous or compound heterozygous states, demonstrates a possible consistent association with the infantile form of GM1 gangliosidosis, characterized by a rapidly progressive neurodegenerative course and multisystem involvement. Collectively, these findings provide additional support for the hypothesis that codon 270 can be regarded as a critical functional hotspot within , where even distinct amino acid substitutions can result in profound enzymatic dysfunction and a severe early-onset phenotype.