Sphingolipidoses and Related Disorders

The role of Sphingolipids in myelination and myelin stability and their involvement in childhood and adult demyelinating disorders

“…This could at least in part explain why GALC represents a major risk locus for MS. As outlined, Krabbe's disease manifests when two copies of mutated alleles are inherited, an event that occurs with an incidence of 1:100,000-200,000 births. The carrier frequency is 1:150 (Laquerriere et al, 2018). GALC ± animals have been demonstrated to be clinically similar to WT animals at 3 months of age, exhibiting no accumulation of psychosine.…”

“…In any case, GALC deficiency impairs psychosine catabolism provoking its accumulation that is deeply toxic for oligodendrocytes and also for neurons. Over 100 mutations affecting GALC, that spans 60.2 kb, have been discovered; in Europe, the most common is a 30 kb deletion mapped from 11th to 17th exon (502T/del) (Laquerriere et al, 2018). Different mutations affect GALC functionality in different way: by impairing the conformation of the catalytic site, by altering the enzyme folding, processing or localization, or by distorting its ability to associate with coactivators (Spratley et al, 2016).…”

“…In the nervous system, sulphatides are particularly produced by oligodendrocytes (and by Schwann cells in the periphery) and are constituents of myelin (Takahashi & Suzuki, 2012). Genetic mutations of ARSA or of saposin B, that acts as coactivator, leading to ASA deficiency are well recognized as the causal mechanism of metachromatic leukodystrophy, a frequently fatal disease, prevalently with an infantile onset, characterized by a progressive and diffuse demyelination of CNS and peripheral nervous system (PNS) (Laquerriere et al, 2018). Strangely, polymorphisms leading to ASA deficiency has been found also in healthy subjects, without symptoms of leukodystrophy.…”

Neurodegenerative Disorder Risk in Krabbe Disease Carriers

“…Despite the very low incidence of KD [1:100,000 live births in the United States and Europe, with a pick of incidence recorded in Sweden (1:39,000)] [ 19 , 20 ], heterozygous carriers are estimated to be frequent in Caucasians (1:150) [ 21 ] and are suggested to carry a risk for neurological disorder onset [ 5 ]. In fact, despite carriers of recessive disorders not being clinically ill, they may present non-physiological biochemical and molecular traits that may predispose them to develop a disease state [ 16 ].…”