Neurology India Medknow Publications on behalf of the Neurological Society of India ISSN: 0028-3886 EISSN: 1998-4022 Vol. 55, Num. 4, 2007, pp. 399-402

Neurology India, Vol. 55, No. 4, October-December, 2007, pp. 399-402

Case Report

Dysmyelinating neuropathy in benign form of megalencephalic leukoencephalopathy with subcortical cysts: A novel observation from south India

J. Panicker, S. Sinha, A. B. Taly, A. Mahadevan*, C. Sagar*, S. G. Srikanth**, G. R. Arunodaya, S. K. Shankar*

Departments of Neurology, *Neuropathology and **Neuroradiology, National Institute of Mental Health and Neurosciences, Bangalore, India
Correspondence Address:Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore – 560 029 sanjib_sinha2004@yahoo.co.in

Date of Acceptance: 10-Apr-2007

Code Number: ni07117

Abstract

Keywords: Benign leukodystrophy; dysmyelinating neuropathy; leukoencephalopathy with subcortical cysts, megalencephalic

The spectrum of leukodystrophies has expanded with many newer syndromes being identified, based on magnetic resonance imaging (MRI) and genetic studies. One such distinct entity, megalencephalic leukoencephalopathy with subcortical cysts (MLC), is characterized by large head, variable cognitive impairment, spasticity and leukodystrophy with subcortical cysts on imaging and is considered a developmental disorder of the central nervous system white matter. ^[1]

We report a patient with phenotype characteristic of MLC having a relatively benign course and evidence of peripheral nervous system dysmyelination. This novel observation has not been described earlier.

Case Report

Our patient was a 37-year-old gentleman, born to non-consanguineous healthy parents. He was born at term with normal antenatal and peri-natal history and had a relatively large head. He had mildly delayed walking, which started at 18 months of his age. At three years of age, he was noted to have a large head, 55cm circumference, which remained static on serial evaluation. His subsequent physical milestones were normal but he had a below average scholastic performance. He was slower than other children when performing motor tasks. At 15 years of age, he noticed stiffness of the legs and repeated falls while walking but was leading an independent life. He completed schooling and later was employed as ′office assistant′. At the age of 37, he developed one episode of unconsciousness associated with tonic spasms. There was no history of trauma. A diagnosis of seizure was considered and phenytoin sodium was initiated at a peripheral center. He noticed unsteadiness while walking and tendency to sway while standing and needed support for walking. There was no history of visual impairment, sensory or bladder complaints or features of raised intracranial tension. He belonged to a south Indian Brahmin family, with no links to north Indian Agarwals, who are known to suffer from a similar illness. ^[2] Family history was negative for any neurological illness but his asymptomatic father with no neurological signs had a large head (circumference = 58.5cm).

Our patient′s head circumference was 61cm. He scored 29 out of 30 on the Mini-mental status examination (Folstein) but a detailed neuropsychological evaluation revealed slight impairment in abstract thinking and working memory suggesting minimal fronto-temporal impairment. Cranial nerves including optic fundi were normal. He had spasticity and pyramidal pattern of weakness, predominantly in the lower limbs. Muscle stretch reflexes in the upper limbs were brisk while knee jerks were normal and ankle jerks were absent bilaterally. Plantar response was flexor. He had released reflexes in the form of preserved glabellar tap and snout and palmomental reflexes. Joint and position sensation was impaired in the lower limbs. On the left side he had mild left-sided finger-nose and heel-shin incoordination. He had a spastic ataxic gait with tremulousness. There was no hepato-splenomegaly.

Routine hemogram including hemoglobin, leucocyte counts, ESR and peripheral smear were normal. Biochemical tests like blood glucose, renal and liver function tests; metabolic screening like urine for porphobilinogen, abnormal metabolites and aminoacids; serum electrolytes and routine urine analysis were normal. Serum vitamin B12 level was normal (265pg/ml). Both serum arylsulphatase A and B levels were within normal limits and urine was negative for metachromatic granules. Magnetic resonance imaging (MRI) of the brain showed extensive white matter signal changes, anteriorly and posteriorly, also involving the subcortical U fibers with relative sparing of the internal capsule and corpus callosum. There was evidence of cortical and subcortical atrophy and frontal and temporal subcortical cysts. Incidental left-sided thin subacute subdural hematoma without any mass effect was also noted [Figure 1]A to C. Deep ganglionic structures were not affected. Proton magnetic resonance spectroscopy failed to reveal N- Acetyl aspartate (NAA) peak in the affected white matter. Nerve conduction study using standard methodology, showed reduced conduction velocities and prolonged distal latencies in the sural nerves bilaterally with normal amplitude, suggesting demyelination [Table 1]. EMG of the tibialis anterior (TA) revealed occasional spontaneous activity (fibrillations), however, motor unit potentials were normal. The sural nerve biopsy on histological examination by semithin sections stained with toluidine blue and ultrastructural study revealed significant reduction of both large and small myelinated fiber density with uniform affection of all fascicles [Figure 2]A,B. Many of the preserved fibers possessed thin myelin sheaths with occasional ones showing redundant loops ([Figure 2]A, inset). No active myelin or axonal degeneration was detectable. There was increase in collagen pockets in the endoneurium. Blood vessels included in the biopsy were normal. No inflammatory infiltrates or vasculitis was found. Ultrastructurally, the density of both myelinated and unmyelinated fibers was reduced [Figure 2]B. Increased numbers of denervated Schwann cell subunit profiles were seen surrounding single non-myelinated axons enclosed within redundant loops of Schwann cell cytoplasmic processes [Figure 2]C. The caliber of these non-myelinated axons is larger than the usual 2micron diameter unmyelinated axons which under normal circumstances should have been encompassed by a myelin sheath. This may represent failure of Schwann cells to myelinate small-caliber axons. The axons of these non-myelinated fibers revealed increased neurofilament density and dense mitochondria [Figure 2]C. Accumulation of multiple vesicular bodies, mitochondria and neurofilament without enlarging the axon was also observed within the axoplasm of myelinated fibres [Figure 2]D. Reparative response in the form of axonal regeneration, Schwann cell proliferation to form onion bulbs or bands of bungner was conspicuously absent. No adventitious storage material or metachromatic deposits were detectable in the nerve. The pathological features seen suggest a slow, indolent demyelinating process with conspicuous absence of a reparative response by axonal or Schwann cell proliferation, suggestive of an inherited neuropathy. Visual evoked potentials (VEP) and brainstem evoked responses (BAER) were normal while right posterior tibial somatosensory evoked potential (SSEP) was absent. Cranial CT and lower limb nerve conduction study of his father were normal. Genetic studies could not be carried out due to non-availability.

A diagnosis of megalencephalic leukoencephalopathy with subcortical cysts and peripheral nerve dysmyelination was considered. Subdural hematoma did not require surgical evacuation. At follow-up after one year he reported deterioration in motor functions. He required support while walking and assistance for activities of daily living. Nerve conduction repeated after one year revealed mild worsening of demyelinating neuropathy. The patient was lost to follow-up.

Discussion

We report a patient whose phenotype was characteristic of megalencephalic leukoencephalopathy with subcortical cysts (MLC) with additional peripheral nerve demyelination. Our patient had symptoms from young age, as demonstrated by enlarged head circumference beyond the 97 ^th percentile for the Indian population ^[3] and delayed motor milestones. He had a slowly progressive illness with mild cognitive impairment, as evidenced by neuropsychological assessment and a mild increase in head circumference. There was extensive cerebral white matter involvement. Similar severe abnormality of the white matter on cranial MRI, contrasted with the remarkably slow course of functional decline, has been reported by van der Knaap et al . ^[1] A new observation in our patient was involvement of the peripheral nerve, absent ankle jerks, electrophysiological evidence of mild sensory neuropathy and a nerve biopsy that confirmed presence of a slow, indolent demyelinating process without any reparative response, suggesting an inherited cause.

Several inherited white matter diseases can be associated with peripheral neuropathy. Notable among them are metachromatic leucodystrophy, Krabbe′s leucodystrophy, Adreno-leucodystrophy etc. In the absence of N-acetyl aspartate peak in the proton magnetic resonance spectroscopy, Canavan′s disease was unlikely. ^[4] Though parenchymal cavitation as seen in our patient can occur in Alexander′s disease, it is often noted in the periventricular white matter and there is usually basal ganglia involvement. ^[5] Also, the relatively benign course and absence of significant cognitive impairment made Alexander′s disease less likely. The pattern of clinical, biochemical and radiological features was not suggestive of hexosaminidase deficiency. Metachromatic leukodystrophy was ruled out, based on the absence of metachromasia in the nerve biopsy. The MRI in Krabbe′s leucodystrophy shows characteristic thalamic signal changes, a feature not observed in MLC. In adreno-leucodystrophy, there is occipito-parietal involvement with enhancement of advancing edge, a feature not reported in MLC. However, genetic analysis and tests for biochemical defects for these disorders could not be carried out.

In MLC, nerve conduction study was normal in all the eight patients initially described by van der Knaap et al . ^[1] Subsequent series from India ^[2] and Turkey ^[6] did not report nerve conduction abnormalities or nerve biopsy changes. It cannot be excluded that the presence of the neuropathy could be co-incidental. But the slow indolent nature of the process, characterized by reduced density of myelinated fibers and thin myelin sheaths around the remaining fibers without any evidence of active degradation or repair, would rather suggest a dysmyelinating neuropathy as part of the MLC disease process. Absence of a reparative response by axonal or Schwann cell proliferation would suggest an inherited basis for the neuropathy. In view of the rarity of both the disorders in the community, we believe that our patient has a diffuse demyelinating process involving both the central and peripheral nervous systems. This report is possibly the first in the literature highlighting this aspect of MLC.

Megalencephalic leukoencephalopathy with subcortical cysts is caused by mutations in the gene MLC1, which encodes a protein, MLC1. About 50 mutations in this gene have been found. ^[7] Mutations occur throughout the entire coding region and include: 24 mis-sense mutations, 14 deletions and insertions, 11 splice-site mutations and one nonsense mutation. Six polymorphisms within the coding sequence of MLC1 have also been reported. In about 20% of the patients with a typical clinical and MRI picture, no mutations in the MLC1 gene are found. ^[7] The variant of megalencephalic leukodystrophy with a relatively benign course described in the Agarwal population from India was recently found to have the same genetic basis as MLC. ^[8],[9] Genetic analysis of our case would expand the clinical spectrum of MLC and associated myelin pathology.

References

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