Peripheral neuropathy in metachromatic leukodystrophy: current status and future perspective

Abstract

Metachromatic leukodystrophy (MLD) is an autosomal recessively inherited metabolic disease characterized by deficient activity of the lysosomal enzyme arylsulfatase A. Its deficiency results in accumulation of sulfatides in neural and visceral tissues, and causes demyelination of the central and peripheral nervous system. This leads to a broad range of neurological symptoms and eventually premature death. In asymptomatic patients with juvenile and adult MLD, treatment with allogeneic hematopoietic stem cell transplantation (HCT) provides a symptomatic and survival benefit. However, this treatment mainly impacts brain white matter, whereas the peripheral neuropathy shows no or only limited response. Data about the impact of peripheral neuropathy in MLD patients are currently lacking, although in our experience peripheral neuropathy causes significant morbidity due to neuropathic pain, foot deformities and neurogenic bladder disturbances. Besides, the reasons for residual and often progressive peripheral neuropathy after HCT are not fully understood. Preliminary studies suggest that peripheral neuropathy might respond better to gene therapy due to higher enzyme levels achieved than with HCT. However, histopathological and clinical findings also suggest a role of neuroinflammation in the pathology of peripheral neuropathy in MLD. In this literature review, we discuss clinical aspects, pathological findings, distribution of mutations, and treatment approaches in MLD with particular emphasis on peripheral neuropathy. We believe that future therapies need more emphasis on the management of peripheral neuropathy, and additional research is needed to optimize care strategies.

Intravenous arylsulfatase A in metachromatic leukodystrophy: a phase 1/2 study

“…This is generally in line with previous findings that CNS pathology, as assessed by demyelination load, but not PNS pathology, as assessed by nerve conduction velocity, correlates with a decline in motor function in MLD 38 . However, some case reports of children with MLD have suggested that in some patients with initial abnormalities in motor function, peripheral neuropathy may precede apparent CNS pathology 39 . It therefore seems likely that both CNS and PNS damage may contribute to impaired motor function in MLD, and that it may be necessary for degradation of sulfatides to reach a critical threshold in both the CNS and PNS to achieve improvements in gross motor function.…”

Early clinical course after hematopoietic stem cell transplantation in children with juvenile metachromatic leukodystrophy

“…There was no influence on motor impairment or on outcome after HSCT. This is in line with other studies which demonstrated that, while HSCT had an impact on the CNS, the PNS remained relatively unchanged, or even deteriorated, while brain lesions improved [17,30,33,39]. The fact that peripheral neuropathy might respond better to gene therapy because of the higher enzyme levels that are achieved has been discussed previously [39].…”

Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

“…Glycosylsphingosin-sulfatide (lyso-Gb1-sulfatide) has been identified so far as a sensitive and specific biomarker. An overview for different therapeutic approaches is given in [121].…”