Peripheral Neuropathy in Late-onset Krabbe Disease

Abstract & Commentary

By Michael Rubin, MD, Professor of Clinical Neurology, Weill Cornell Medical College. Dr. Rubin reports no financial relationships relevant to this field of study.

Synopsis: Krabbe disease can rarely present in adults as a combined central nervous system disorder with polyneuropathy.

Source: Malandrini A, et al. Peripheral neuropathy in late-onset Krabbe disease: Report of three cases. Neurol Sci DOI 10.1007/s10072-012-0956-6.

More than 80 reported mutations of the galactocerebrosidase (GALC) gene on chromosome 14q31 result in Krabbe disease (globoid cell leukodystrophy), causing liposomal hydrolysis of galactolipids formed during white matter myelination, with consequent central and peripheral nervous system demyelinating disease. Most patients present within the first 6 months of life, predominantly with central nervous system manifestations, including microcephaly, hypotonia, developmental delay, and optic atrophy. Peripheral neuropathy is seen in all patients, usually small fiber or demyelinating in nature, and neuropathy predominates in the rare, adult-onset cases, and presents with burning dysesthesiae, or distal weakness and numbness. With three atypical, adult-onset, Krabbe disease patients reported, the spectrum of its presentation is expanded.

Falling and progressively deteriorating unsteady gait of 7 years' duration was the presenting feature in a 44-year-old woman whose neurological examination demonstrated spastic ataxia, hyper-reflexia, bilaterally up-going toes, dysarthria, dysphagia, and left leg weakness. T2-weighted brain MRI demonstrated areas of white matter hyperintensity bilaterally, particularly in the frontoparietal regions. Mild axonal neuropathy was noted on electrophysiological study, and sural nerve biopsy revealed normal myelinated fiber density and teased fibers. Cytoplasmic membrane-bound vacuoles containing lamellar and tubular material were observed in 20% of Schwann cells and some macrophages, and leukocyte lysosomal GALC activity was 0.8 nmol/h/mg protein (normal 2.0–6.0).

Progressive unsteadiness, gait problems, and cognitive impairment of 4 years' duration were the presenting features in a 57-year-old man whose neurological examination demonstrated impaired cognition, dysarthria, dysphagia, right-sided weakness, hyper-reflexia, and Babinski sign. T2-weighted brain MRI demonstrated areas of white matter hyperintensity bilaterally, particularly in the periventricular region. Severe axonal sensorimotor neuropathy was noted on electrophysiological study, and sural nerve biopsy revealed complete loss of large diameter myelinated fibers. Cytoplasmic curved lamellar inclusions were seen in 18% of Schwann cells and some macrophages, and leukocyte lysosomal GALC activity was 1.0 nmol/h/mg protein.

Gait problems, leg pain, and weight loss of 2 years' duration were the presenting features in a 44-year-old woman whose neurological examination demonstrated spastic ataxia, hyper-reflexia, bilaterally up-going toes, and vibratory loss in the feet. T2-weighted brain MRI demonstrated areas of white matter hyperintensity bilaterally, particularly in the corticospinal tracts. Demyelinating sensorimotor neuropathy was noted on electrophysiological study, and sural nerve biopsy revealed slight loss of large diameter myelinated fiber density. Zebra-body-like inclusions were seen in 14% of Schwann cells and some macrophages, and leukocyte lysosomal GALC activity was 1.1 nmol/h/mg protein.

Late-onset Krabbe disease should be considered in any patient with a combination of peripheral neuropathy and progressive central nervous system disease.

Commentary

Globoid-cell leukodystrophy, the descriptive name for Krabbe disease, encapsulates its neuropathology, encompassing widespread demyelination and axonal degeneration, oligodendroglial loss, and astroglial proliferation in the brain and spinal cord. Globoid cells, found around capillaries especially where demyelination is active in the brain and spinal cord, are large, multinucleated cells of mononuclear macrophage origin, and contain abnormal, freely scattered, cytoplasmic inclusions. Psychosine (β-galactosylsphingosine) accumulates and is cytotoxic, generating cytokines and arachidonic acid, and acting by inhibiting a key signaling molecule, protein kinase C (PKC), and reducing PKC-dependent myelin basic protein phosphorylation in oligodendrocytes and Schwann cells. As a result, psychosines interrupt cell division, and promote intracellular clumping of F-actin polymers with resultant formation of vacuoles. Precisely how psychosines accumulate remains unclear.