CT and MRI in late-onset metachromatic leukodystrophy

A 23-year-old patient suffering from mental deterioration was referred for CT study following her first epileptic fit. The study disclosed generalized atrophy and diffuse symmetric white matter hypodensities. Similar findings were found in her 13-year-old retarded sister. The diagnosis of metachromatic leukodystrophy (MLD) was confirmed by the finding of low arylsulfatase A (ASA) levels in cultured fibroblasts in both sisters. MRI study revealed widespread high intensity signals of T2 nature in the periventricular regions indicating changes in white matter composition.     

Microglia damage precedes major myelin breakdown in X-linked adrenoleukodystrophy and metachromatic leukodystrophy

X-linked adrenoleukodystrophy (X-ALD) and metachromatic leukodystrophy (MLD) are two relatively common examples of hereditary demyelinating diseases caused by a dysfunction of peroxisomal or lysosomal lipid degradation. In both conditions, accumulation of nondegraded lipids leads to the destruction of cerebral white matter. Because of their high lipid content, oligodendrocytes are considered key to the pathophysiology of these leukodystrophies. However, the response to allogeneic stem cell transplantation points to the relevance of cells related to the hematopoietic lineage. In the present study, we aimed to better characterize the pathogenetic role of microglia in the above-mentioned diseases. Applying recently established microglia markers to human autopsy cases of X-ALD and MLD we were able to delineate distinct lesion stages in evolving demyelinating lesions. The immune-phenotype of microglia was altered already early in lesion evolution, and microglia loss preceded full-blown myelin degeneration both in X-ALD and MLD. DNA fragmentation indicating phagocyte death was observed in areas showing microglia loss. The morphology and dynamics of phagocyte decay differed between the diseases and between lesion stages, hinting at distinct pathways of programmed cell death. In summary, the present study shows an early and severe damage to microglia in the pathogenesis of X-ALD and MLD. This hints at a central pathophysiologic role of these cells in the diseases and provides evidence for an ongoing transfer of toxic substrates primarily enriched in myelinating cells to microglia.     

Sensory nerve conduction slowing is a specific marker for CIDP

Most current diagnostic criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) do not make use of sensory nerve conduction studies (NCSs). To investigate if surface sensory NCSs are clinically relevant in differentiating CIDP from axonal polyneuropathy, we conducted a retrospective cohort study of patients referred for electrodiagnostic testing to evaluate for CIDP. We found that sensory conduction velocity (CV) slowing is a highly specific, albeit insensitive, marker for differentiating CIDP from axonal polyneuropathy. Muscle Nerve 38: 1599–1603, 2008     

Seizures as a presenting feature of late onset metachromatic leukodystrophy

OBJECTIVES: We describe 2 patients with epilepsy as an early manifestation of late onset metachromatic leukodystrophy (MLD). METHODS AND RESULTS: The first patient presented with epileptic seizures at the age of 34 years while neurological and cognitive abnormalities appeared later. MRI findings were compatible with leukodystrophy and low levels of arylsulphatase-A activity confirmed MLD. The second patient developed epileptic seizures and behavioral disturbances at the age of 19 years. She remained stable and seizure free for 8 years. Afterwards she developed uncontrolled epileptic seizures and status epilepticus as well as neurological and cognitive impairment. Leukodystrophy was diagnosed by MRI findings and low levels of arylsulphatase-A activity were compatible with MLD. CONCLUSION: Our 2 cases postulate that epileptic seizures may be an early and prominent manifestation of late onset MLD.     

What is the best diagnostic index of conduction block and temporal dispersion?

In order to find the best diagnostic index of conduction block and abnormal temporal dispersion, the amplitude, duration, and area of the compound muscle action potentials (CMAP) were studied in 40 normal controls and 28 patients with acquired demyelinating neuropathies. In the normal subjects, there was a substantial difference among the various nerves in the degree of CMAP amplitude reduction and CMAP duration prolongation with proximal stimulation, and thus different criteria should be used for conduction block or abnormal temporal dispersion for a given nerve. In 28 patients with demyelinating neuropathy, 58 of 207 (28%) tested nerve segments showed nerve conduction velocity (NCV) evidence of demyelination. To identify “demyelination” in these segments, conduction block was best detected by the total area method in 71% of cases, and abnormal temporal dispersion was bast by the negative-peak duration method. This study showed that the best diagnostic index for conduction block is the total area method and for abnormal temporal dispersion, the negative-peak duration method. © 1994 John & Sons, Inc.     

Clinicopathological differences between juvenile and late infantile metachromatic leukodystrophy

The autopsy report of the juvenile type of metachromatic leukodystrophy is rare. The clinical and pathological difference between the juvenile and the late infantile type of metachromatic leukodystrophy was described. Loss of myelin sheaths was much less in the brain stem and spinal cord in the juvenile type than in the late infantile type, although that of the roots or cranial and spinal nerves was marked similarly in both types. The relationship of these pathological findings to clinical signs and laboratory data was discussed.     

Histopathological and ultrastructural study of a case of infantile metachromatic leukodystrophy

The histopathological and ultrastructural findings on a nerve biopsy specimen and on a CNS necropsy specimen in a case of IML with a typical clinical course are reported. Nerve biopsy once again proved to be a sure diagnostic guide even at an early stage of the disease. Some differences in the fine structure of the cytosomes between the nerve biopsy and CNS necropsy material studied four years later may be due to the different rates of catabolism of the constituent lipids as well as to post mortem artefacts.This work was supported by CNR Research Grant 81 00336 04     

The AB-variant of metachromatic leukodystrophy (Postulated activator protein deficiency)

Summary The histopathological findings in a sural nerve biopsy of a new distinct variant of metachromatic leukodystrophy (MLD) are compared to those of classical MLD. The clinical and histological features are typical of a sulfatide lipidosis, yet in vitro activities of arylsulfatases A and B and cerebroside sulfatase are normal. Intact skin fibroblasts, when cultured in a medium supplemented with labelled sulfatide, show impaired in vivo sulfatide hydrolysis. A deficiency of the requisite activator protein is postulated.     

中国异染性脑白质营养不良携带者筛查临床实践指南《中国异染性脑白质营养不良携带者筛查的临床实践指南》制订组

异染性脑白质营养不良（MLD）是一种常染色体隐性遗传疾病,表现为进行性加重的运动、感觉、认知等障碍,致残致死率高,目前尚无有效治疗。因此,开展孕前及孕早期夫妇携带者筛查,降低患儿出生率是防控关键。该临床实践指南目的在于发现携带MLD突变基因的高风险人群,及早为其提供减少生育风险的遗传咨询,促进MLD的规范化防控。国际神经病学神经外科学杂志, 2024, 51(2): 13-17]     

Focal conduction block in n-hexane polyneuropathy

A 19-year-old man with an asymptomatic history of recreational gasoline vapor inhalation presented with subacute progressive quadriparesis. For 2 weeks, he had intensely inhaled Coleman® fuel oil vapor, which contains n-hexane. Nerve conduction studies including near-nerve needle stimulation showed focal conduction block in the bilateral median and ulnar nerves. Sural nerve biopsy was consistent with giant axonal neuropathy. Conduction block as seen in this case has not heretofore been described in n-hexane polyneuropathy. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:964–969, 1998.     

Multifocal motor neuropathy without overt conduction block

One of the defining electrophysiological characteristics of multifocal motor neuropathy (MMN) is focal motor nerve conduction block. We have noted occasional patients with typical clinical features of MMN in whom there is no demonstrable conduction block. Upon review of 5 such cases, we conclude that otherwise typical MMN may present without overt conduction block. This subset of patients does not otherwise differ from patients with MMN in whom this hallmark electrodiagnostic feature is present. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21: 243–245, 1998.     

Electron microscopic investigation of inclusion material in a case of adult metachromatic leukodystrophy; Observations on kidney biopsy,peripheral nerve and cerebral white matter

Summary The fine structural characteristics of storage products in peripheral nerve, kidney and cerebral white matter, from a case of adult metachromatic leukodystrophy are described. There were pronounced differences from the fine structural aspects in late infantile cases. A large proportion of the inclusions did not exhibit a unit membrane. An hypothesis is proposed to clarify the delayed manifestation of this type of metachromatic leukodystrophy until adulthood.     

Central nervous system involvement in multifocal demyelinating neuropathy with persistent conduction block

We report the case of a 27 year-old man treated for bilateral optic neuritis 5 and 3 years before who within a few months developed sensori- motor disorders of the arms and legs Characterized by asymmetric distribution and distal prominence. In addition to sensorimotor defects, which were particularly marked in the left arm and right leg, clinical examination showed nearly generalized areflexia. Electrophysiological studies revealed a rnultifocal neuropathy with persistent distal and proximal conduction blocks associated with a considerable slowing of motor nerve conduction, as well as central nervous system involvement indicated by motor-, somatosensory-, and visual-evoked potentials. CSF analysis showed a mildly elevated protein level; anti-GM, activity was negative. Sural nerve biopsy revealed onion–bulb-like formations, and cerebral MRI showed a small, isolated, and aspecific high signal for white matter. First described by Lewis and Sumner in 1982, rnultifocal neuropathy with persistent conduction blocks may be associated with central demyelination. Our case is compared with 3 similar ones in the literature, and the favorable effects of steroid therapy are emphasized. © 1994 John Wiley & Sons, Inc.     

Physiology of conduction block in multifocal motor neuropathy and other demyelinating neuropathies

Conduction block is an important functional consequence of demyelination whereby nervous transmission is abolished. Its mechanism has been discussed with respect to the loss of insulation due to disruption of myelin. Recent development of threshold tracking techniques, which enabled noninvasive assessment of axonal membrane potentials and ion channels, has provided evidence that axonal excitability changes significantly and contributes to conduction failure. This view, based upon axo-glial interaction, clarifies the mechanism of muscle fatigue and fasciculation associated with peripheral demyelination and possibly explains selective motor involvement in multifocal motor neuropathy.     

Multifocal motor neuropathy with conduction block misdiagnosed as multiple entrapment neuropathies

We describe a 58-year-old male with a few years history of multifocal weakness in the upper limbs with minimal to absent sensory complaints. He was diagnosed as having multiple compressive neuropathies, which required repeated decompressive surgeries. Electrodiagnostic studies prior to diagnosis were limited to a few nerves, evaluating only distal segments. Because of delay in making the diagnosis, his condition progressed, and possibly because of the unnecessary surgeries, he developed atrophy in some muscles, which resulted in significant motor disability. He was later diagnosed as having multifocal motor neuropathy with conduction block and has partially responded to intravenous immunoglobulin therapy. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:813–815, 1998.     

4-aminopyridine leads to restoration of conduction in demyelinated rat sciatic nerve

Whole nerve and single axon recordings were obtained in vitro from rat sciatic nerve demyelinated with lysophosphatidyl choline. Compound action potentials recorded across the lesion site were attenuated in amplitude, and showed conduction slowing and temporal dispersion. Application of the potassium channel blocker 4-aminopyridine (4-AP), markedly enhanced the response recorded through the lesion demonstrating both an increase in amplitude and duration of the response. From single axon recordings, we observed two patterns of change in spike waveform following application of 4-AP: broadening of single axon spikes, and bursting of single axon spikes. Some axons that displayed conduction block along demyelinated segments before 4-AP was applied, showed restoration of conduction.     

Adult-type metachromatic leukodystrophy with a compound heterozygote mutation showing character change and dementia

A 26-year-old Japanese woman slowly developed a change of character such as hypospontaneity and blunted affect, followed by obvious mental deterioration. She was diagnosed as having a disorganized type of schizophrenia at the first examination. Brain magnetic resonance imaging demonstrated diffuse high intensity in the cerebral white matter, particularly in the frontal lobes. The single photon emission computed tomography images using 123I-IMP disclosed diffuse cerebral hypofusion, especially in the frontal lobes. Electroencephalogram showed a moderate amount of 5-6Hz theta waves on the background of alpha activity. Nerve conduction velocities in the extremities were delayed. The level of leucocyte arylsulphatase was low. In the arylsulphatase A gene analysis, a compound heterozygote having the 99Gly-->Asp and 409Thr-->Ile mutations was confirmed. The patient was diagnosed as having metachromatic leukodystrophy. She gradually showed obvious dementing symptoms such as memory disturbance and disorientation. The characteristics of the psychiatric symptoms in the leukodystrophy are discussed.     

AAEM case report #30: Multifocal motor neuropathy

A 73-year-old man with a 16-year history of fasciculations and 15 years of weakness in his right arm was diagnosed with focal motor neuron disease. After 10 years of purely motor symptoms, he developed mild parasthesias although his sensory examination remained normal. Reflexes were reduced or absent in the weak muscles but were normal elsewhere. Nerve conduction was studied in nerves innervating weak muscles and showed severe motor conduction block. Sensory nerve conduction studies were minimally abnormal, showing reduced amplitudes with normal velocities. Based on the clinical picture and the presence of severe motor conduction block, the patient was diagnosed with multifocal motor neuropathy. Treatment with high-dose intravenous immunoglobulin was given with significant improvement in strength and partial resolution of the conduction block. As this case demonstrates, this treatable disorder may occasionally be mistaken for motor neuron disease although the resemblance is only superficial, and it should never be mistaken for amyotrophic lateral sclerosis. Multifocal motor neuropathy is an inflammatory, demyelinating neuropathy which, like chronic inflammatory demyelinating polyneuropathy (CIDP), is probably immune-mediated. It differs from typical CIDP by virtue of a marked predilection for motor axons, a strikingly restricted distribution, and a protracted course. Treatment with high-dose intravenous immunoglobulin is frequently helpful, but other forms of immune manipulation are less effective. © 1996 Gareth J. Parry, MD, FRACP. Published by John Wiley & Sons, Inc.