Galactosialidosis: nueva mutación de novo en el gen CTSA en un paciente afecto de la forma infantil tardía / Galactosialidosis: a new "de novo" mutation in CTSA gene in a patient with late infantile galactosialidosis

La galactosialidosis (OMIM #256540) es una enfermedad metabólica lisosomal causada por mutaciones en el gen CTSA, que codifica la proteína protectora catepsina A. La pérdida de función de dicha proteína causa, secundariamente, un déficit combinado de dos enzimas, beta-galactosidasa y neuraminidasa. Se expone el caso de un paciente que presentó manifestaciones clínicas compatibles con el subtipo infantil tardío de galactosialidosis. El análisis bioquímico mostró déficits de las dos enzimas implicadas, mientras que el estudio molecular reveló dos mutaciones: una nueva mutación nunca antes descrita, p.His475Pro (c.1424 A>C), y una mutación previamente reportada, p.Arg441Cys (c.1321C>T), localizadas en los exones 15 y 14, respectivamente.

Galactosialidosis (OMIM #256540) is an autosomal recessive lysosomal storage disorder caused by mutations in the CTSAgene, which encodes the protective protein cathepsin A. The loss of function of this protein causes a secondarily deficiency of beta-galactosidase and N-acetyl-α-neuraminidase enzymes activities. We describe the clinical, biochemical and molecular analysis of a case report with a phenotype compatible with the late infantile form. The biochemical analysis reveled deficiencies of beta-galactosidase and neuraminidase activities in dried blood spot and fibroblasts and the molecular study showed two missense mutations in the CTSA gene: a previously reported mutation, p.Arg441Cys (c.1321C>T), and a novel mutation, p.His475Pro (c.1424 A>C), located in exons 14 and 15, respectively.

A Galactosialidosis Mimicking GM1-gangliosidosis Type I / 대한소아신경학회지

Galactosialidosis is a lysosomal storage disease associated with a combined deficiency of beta-galactosidase and alpha-neuraminidase, secondary to a defect of another lysosomal protective protein. It is a neurodegenerative disorder clinically characterized by psychomotor deterioration, cerebellar ataxia, coarse facies, generalized bony deformity and organomegaly. Three phenotypic subtype are recognized:early infantile, late infantile and juvenile/adult type. We report a 13 months old boy with a late infantile galactosialidosis. He was presented with progressive mental regression and motor disturbance and observed cherry red spot, hearing loss, moderate dysostosis multiplex and vacuolated lymphocytes in peripheral blood. He showed only beta-galactosidase deficiency in the lymphocytes and was diagnosed as GM1-gangliosidosis type 1. However, further studies revealed the possible defect of alpha-neuraminidase suggesting that he was a case of galactosialidosis which was mimicking GM1-gangliosidosis type 1.

Morphological and Functional Alterations of Ear in Lysosomal Protective Protein/Cathepsin A Gene Knock Out Mouse / 听力学及言语疾病杂志

Objective Galactosialidosis(GS) is an autosomal recessive lysosomal storage disease caused by a combined deficiency of lysosomal ?-galactosidase and neuraminidase as a result of a primary defect in the protective protein/cathepsin A(PPCA).Mouse model of GS has been generated by targeted deletion of PPCA gene and closely resembled the phenotypes in human conditions.However,it remains to be determined whether hearing loss observed in human also occurs in the mouse model.In this study,we observed their alterations of the auditory function and morphology of the ear,and explored pathophysiological mechanisms of hearing impairment.Methods PPCA homozygous(PPCA-/-) mice at 1 and 2 months of age,and their wildtype littermates(PPCA+/+) were examined for auditory thresholds through auditory brainstem responses(ABR) to click,tone pips 8,16,and 32 kHz stimuli.Morphological analyses in ears were performed by series temporal bone section and light microscopy.Results PPCA-/-mice at 1 month of age showed a normal threshold and the morphology of ears.Up to 2months of age,their thresholds were elevated 40～45 dB SPL above those of PPCA+/+ mice.There were distinct pathological changes of middle and inner ear in PPCA-/-mice of 2 months old.The severe otitis media and the vacuolation associated with lysosomal storage were observed within ossicles and cochlear bone cells,stria vascularis cells,spiral ganglion neurons,spiral limbus,Reissner's membrane cells,and the mesothelial cells of the perilymphatic scala and basilar membrane,but not within the organ of Corti.Vestibular organ did not show vacuolation.Conclusion The deficiency of lysosomal protective protein/cathepsin A may result in hearing loss and morphological alterations of ear.The otitis media and ossicle changes,and the defects in lysosomal storage of neurons,stria vascularis,spiral limbus,Reissner's membrane and basilar membrane cells may contribute to the conductive and sensorineural hearing loss respectively.