Isolated Peripheral Neuropathy in Atypical Metachromatic Leukodystrophy: A Recurrent Mutation

Abstract

Abstract:Background:Metachromatic leukodystrophy (MLD) is a genetic neurodegenerative disorder resulting from a deficiency of arylsulfatase A. Late onset forms are relatively rare. Central nervous system (CNS) involvement is characteristic at all ages.Methods:A patient in her late 40s with peripheral neuropathy was assessed by EEG, evoked potentials, CTand nerve conduction studies. Nerve and muscle biopsy samples were investigated by electron microscopy. Arylsulfatase A activity in leukocytes and excreted cerebroside sulfate were determined. The arylsulfatase A gene was investigated for mutations using polymerase chain reaction (PCR) and DNAsequencing. The identified mutation was expressed transiently in African green monkey kidney (COS) cells to determine the effect of the mutation on arylsulfatase A activity.Results:Central nervous system functions were normal. Nerve conduction velocities were decreased. Sural nerve biopsy showed inclusions typical of MLD. Arylsulfatase A was less than 5% of normal. A homozygous mutation thr286pro was identified in the arylsulfatase A gene and demonstrated to be deleterious through transient expression studies.Conclusions:Our patient has a progressive peripheral neuropathy but has apparently intact CNS function at her present age of 57 years. Biochemical, physiological and pathological findings are consistent with a diagnosis of MLD. A homozygous mutation, thr286pro, found in her arylsulfatase A gene, decreased enzyme activity to a level consistent with a late onset form of MLD.

A spontaneously immortalized Schwann cell line to study the molecular aspects of metachromatic leukodystrophy

“…Weakness of lower limbs with characteristic lamellar inclusions in Schwann cells and macrophages was observed in MLD patients (Bindu et al, 2005;Fressinaud et al, 1992). Similar reports with peripheral neuropathy in MLD patients were published by different groups (Coulter-Mackie et al, 2002;Hansen et al, 1994;Martinez et al, 1975). In addition, ASA-deficient mice older than 18 months show degeneration of up to 20% of fibers in peripheral nerves (Gieselmann, 2003).…”

Peripheral neuropathy in metachromatic leukodystrophy: current status and future perspective

“…A few studies also suggest an association between genotype and the presence of peripheral neuropathy in adult MLD, although the number of patients included is low. Two variants in the ARSA gene are thought to be associated with adult MLD with solely PNS involvement: these are: c.862A > C (p.Thr288Pro, homozygous) [29, 30] and c.1223C3 > T (p.Thr408Ile) [28]. Three other variants in the ARSA gene are thought to be associated with adult MLD without PNS involvement: c.661 T > G (p.Phe221Val; homozygous) [25], c.878G > A (p.Arg293Gln) and c.1465 T > G (p.Cys489Gly) [24].…”

Isolated Cranial Nerve Enhancement in Metachromatic Leukodystrophy

“…It has been proposed that cranial nerve enhancement may be due to disruption of the myelin sheath and accumulation of the metachromatic lipid material, affecting the cranial nerves in a manner similar to the peripheral nerves [7,8]. Isolated peripheral nerve enhancement on MRI early in the course of the disease has been seen in Krabbe’s [10] and striking peripheral nerve enhancement is also known to occur in MLD [11,12]. In this patient, the eye findings were due to cranial nerve involvement, and the upper motor signs of the leg suggested subcortical involvement, although not evident on imaging.…”