sphingolipidoses

Sphingolipidoses are a group of lysosomal storage disorders caused by inherited defects in the breakdown of sphingolipids, leading to the accumulation of sphingolipids within lysosomes. The diseases arise from deficiencies of specific hydrolytic enzymes or, less commonly, from defects in lipid transport within lysosomes. The accumulating substrates and the affected tissues vary, producing a range of symptoms that may involve the nervous system, liver and spleen, bone marrow, heart, and kidneys. Most sphingolipidoses are inherited in an autosomal recessive pattern; Fabry disease is X-linked recessive.

Key examples include:

- Gaucher disease: deficiency of glucocerebrosidase with accumulation of glucocerebroside in macrophages, causing hepatosplenomegaly, bone disease, and, in some types, neurologic involvement.

- Fabry disease: deficiency of alpha-galactosidase A with accumulation of globotriaosylceramide, leading to angiokeratomas, acroparesthesias, kidney and heart disease.

- Niemann-Pick disease (types A and B): acid sphingomyelinase deficiency resulting in sphingomyelin buildup, neurodegeneration, hepatosplenomegaly.

- Tay-Sachs and Sandhoff diseases: deficiency of hexosaminidases A and B, GM2 ganglioside accumulation with progressive neurodegeneration (Tay-Sachs) or more severe forms (Sandhoff).

- Krabbe disease: galactocerebrosidase deficiency causing accumulation of psychosine and galactocerebrosides with early demyelination.

- Metachromatic leukodystrophy: arylsulfatase A deficiency leading to cerebroside sulfate buildup and demyelination.

Diagnosis relies on clinical suspicion confirmed by enzymatic activity testing in leukocytes or fibroblasts and genetic testing; biomarkers can support specific diagnoses. Treatments include enzyme replacement therapy and, for some diseases, substrate reduction therapy, supplemented by supportive care. Research into gene therapy and other disease-modifying approaches is ongoing.