Metachromatic leukodystrophy caused by a partial cerebroside sulfatase defect

Abstract

A patient with neuropathy and myopathy since infancy but whose neuropathy had been stable for a number of years showed a profound deficiency of arylsulfatase A in leukocytes and urine. Urine contained material that stained metachromatically and cochromatographed with cerebroside sulfate. In contrast, cultured fibroblasts contained about 10–20 % of normal arylsulfatase A with properties identical to properties of normal fibroblast enzyme, except that it showed no cerebroside sulfatase activity. Growing fibroblasts in the cerebroside sulfate loading test had an attenuated rate of sulfatide hydrolysis. A reexamination of the cerebroside sulfatase reaction revealed that while only limited hydrolysis occurred with low concentrations of taurodeoxycholate or chelate (type I activation), significant hydrolysis of the natural substrate did take place with high concentrations of cholate (type II activation). This suggests that there is a partial cerebroside sulfatase defect in this atypical form of metachromatic leukodystrophy.

Arylsulphatase A (ASA) activity in parkinsonism and symptomatic essential tremor

“…In the typical subgroup (PD and ET) no patient showed a reduced ASA activity, while in the atypical subgroup (PS and SET) 15 patients presented decreased values (12 with PS and 3 with SET). This frequency difference was statistically significant (X2 = 13.86 p<O.OI) ( Table 2).…”

“…Leukocytes were utilized as a source of reliable enzymatic activity estimation since a good correspondence between ASA values estimated on leu-kocytes and on fibroblasts was demonstrated (19) and the method is currently utilized (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20).…”

“…Partially reduced ASA activity is generally considered a non pathological condition, but has been described in patients with neurological diseases or symptoms, always different from the classical M L D pictures: delayed psychomotor development and mental retardation (2)(3), seizures with or without mental retardation (4)(5), myoclonic epilepsy of Lafora (6), retinal pigment epithelial degeneration (7), multiple sclerosis (8) as well as psychiatric diseases (9). In a few cases, partial ASA deficiency was also found associated with movement disorders: dystonia (10-19, dys or bradydiadocokinesia (12)(13)(14)(15)(16), choreiform (14), choreoathetosic (13), athetosic movements and orofacial dyskynesia (10). To investigate the relationship between ASA deficit and movement disorders we assayed ASA activity in a large series of patients.…”

A variant form of metachromatic leucodystrophy in a patient suffering from another congenital degenerative neurological disease

“…The low CS-activity observed in fibroblasts is slightly higher than seen in typical MLD-patients and might be high enough to enable the fibroblasts an almost normal sulfatide uptake and degradation. To our knowledge, only 2 patients with similar biochemical findings have ever been reported (9,17). None of these patients, however, showed progressive neurological deficits.…”

Identification of a missense ARSA mutation in metachromatic leukodystrophy and its potential pathogenic mechanism

“…Metachromatic leukodystrophy (MLD) is an inherited lysosomal disorder caused by recessive gene mutations in ARSA and PSAP. [1][2][3][4] It is recognized that there are 5 allelic forms of MLD (MIM ID: 250100), including late-infantile, juvenile, adult, partial cerebroside sulfate deficiency, and pseudoarylsulfatase A deficiency; [3][4] and 2 nonallelic forms, including metachromatic leukodystrophy due to saposin B deficiency (MIM ID: 249900) and multiple sulfatase deficiency or juvenile sulfatidosis (MIM ID: 272200), a disorder that combines features of a mucopolysaccharidosis with those of metachromatic leukodystrophy. MLD is a rare disorder with an estimated birth prevalence of 1.4 to 1.8 per 100,000; there are also reports of 1/40,000 to 1/170,000.…”