A preclinical case of late adult metachromatic leukodystrophy?: Manifestation only with lipid abnormalities in urine,enzyme deficiency,and decrease of nerve conduction velocity

In a clinically unremarkable 39 year old sister of a patient afflicted with late adult metachromatic leukodystrophy, metachromatic deposits in the epithelial cells of the urine sediment, a high sulphatide excretion in the urine, and a deficiency of arylsulphatase A in urine and leucocytes were found. The motor nerve conduction velocity of the peripheral nerves in upper and lower extremities was distinctly decreased. Cerebral disturbances were not evident. It is surmised that this patient is a case of late adult metachromatic leukodystrophy in an early stage of the disease without obvious clinical signs. The peripheral neuropathy found by neurophysiological examination is interpreted as an early symptom of the disease.     

Stabilization of juvenile metachromatic leukodystrophy after bone marrow transplantation: a 13-year follow-up

A 29-year-old female patient with juvenile metachromatic leukodystrophy diagnosed at age 14 years received a bone marrow transplant at age 16 years. A report was published 6 years after bone marrow transplantation concluding that the disease had slowly progressed in the 2 years following bone marrow transplantation. We now report on a further 7-year follow-up, typified by a steady state of spastic paraplegia and mild dementia. Neurophysiological, neuroradiological, and psychological status also remained stable. In the patient's leukocytes, the activity of arylsulfatase A, the enzyme deficient in untreated metachromatic leukodystrophy, was within the normal range whereas urinary sulfatides remained elevated. Data on the natural course of juvenile metachromatic leukodystrophy are rare, so in the present case it is difficult to establish whether the rather favorable course can be attributed with certainty to bone marrow transplantation. The long-term stabilization in this patient, however, suggested that bone marrow transplantation may halt the progression of juvenile metachromatic leukodystrophy.     

Longitudinal neurophysiologic studies in a patient with metachromatic leukodystrophy following bone marrow transplantation.

We describe a girl with late infantile metachromatic leukodystrophy. The patient has been followed up with serial neurologic and neurophysiologic examinations for 8 years following bone marrow transplantation, which she underwent when she was 4 3/4 years old. Her older sister died from metachromatic leukodystrophy at the age of 8 years, whereas our patient has retained significant cognitive and motor skills. Serial neurophysiologic studies initially demonstrated continued deterioration after the bone marrow transplantation, but since then, most results have remained stable or improved. Although, to our knowledge, there have been no previous serial studies of metachromatic leukodystrophy, individual case studies suggest that these findings in our patient are very unusual. With the advent of possible treatment for this condition, there is a need for further serial neurophysiologic studies to characterize the natural progression and the possible detection of progression or reversal with treatment.     

Psychiatric disturbances in metachromatic leukodystrophy. Insights into the neurobiology of psychosis.

Metachromatic leukodystrophy is a rare inherited disorder of the nervous system. Symptoms initially can present during childhood, adolescence, or adulthood. Psychiatric symptoms, including complex auditory hallucinations and bizarre delusions, are a prominent feature of metachromatic leukodystrophy presenting when the patient is between 12 and 30 years. One hundred twenty-nine published case reports were reviewed, focusing on the presence of psychosis. Psychosis was present in 53% of the published case reports of adolescent and early adult-onset metachromatic leukodystrophy, a much higher prevalence than that seen with other primary neurological disorders. The pathological lesion of metachromatic leukodystrophy is demyelination of the central and peripheral nervous systems, particularly the subfrontal white matter, suggesting that psychosis may result from the disruption of corticocortical and corticosubcortical connections, especially involving the frontal lobes. While similar lesions appear in the infantile, juvenile, and late adult forms of metachromatic leukodystrophy, psychotic symptoms were reported only in those cases presenting in adolescence and young adulthood, suggesting that age is another important neurobiological factor in the development of psychosis.     

Metachromatic leukodystrophy: report of 2 cases with histochemistry of nerves and muscles

Two cases of metachromatic leukodystrophy, of the late infantile form are reported. The patients were a girl and a boy of 2 years 10 months old, with initial normal development, but by the age of 18 months began with gait disturbances, difficulty to speak and developed progressive mental deterioration, with signs of long tract involvement, absence of deep tendon reflexes, spasticity, blindness, muscle atrophy and finished in a vegetative state. The diagnosis was made electromyography (signs of denervation), motor nerve conduction velocity (very decreased), assay of arylsulfatase A in the urine (absence of activity), sural nerve biopsy (demyelination and presence of metachromatic granules by the cresyl-violet and toluidine blue) and muscle biopsy (atrophy of type I fibers and presence of metachromatic material in the intramuscular nerve fibers). A quick revision about diagnostic methods, transmission, pathogenesis and variant forms is made.     

Multifocal slowing of nerve conduction in metachromatic leukodystrophy

Polyneuropathy is invariably associated with the late-infantile form of metachromatic leukodystrophy (MLD), and occurs frequently in the early juvenile, juvenile, and adult variants. Uniform slowing of nerve conduction velocity is the neurophysiologic hallmark of metachromatic leukodystrophy and other inherited demyelinating polyneuropathies. To evaluate the consistency of this principle, we reviewed nerve conduction studies in 9 children with late-infantile or early-juvenile metachromatic leukodystrophy. Each child had significant slowing of motor nerve conduction velocity (NCV). The compound muscle action potentials showed abnormal temporal dispersion in 3 of the 9 children, which is usually regarded as the hallmark of acquired demyelinating polyneuropathies. There are reports of multifocal slowing in other hereditary processes including X-linked Charcot-Marie-Tooth disease, hereditary neuropathy with liability to pressure palsies, and adrenomyeloneuropathy. Although multifocal NCV slowing in a child with polyneuropathy is seen most commonly in acquired conditions, a hereditary process, including MLD, cannot always be excluded in this setting.     

Neurophysiology and MRI in late-infantile metachromatic leukodystrophy

We present serial clinical, radiologic, and neurophysiologic findings of a patient with late-infantile metachromatic leukodystrophy who was first admitted at 30 months of age because of gait disturbance. The neurologic findings were consistent with mild spastic diplegia (occasionally with toe walking). Magnetic resonance imaging disclosed diffuse high intensity in the cerebral white matter on T₂-weighted images. Nerve conduction velocity studies and evoked-potential studies were markedly abnormal. Assay of arylsulfatase A activity in leukocyte culture disclosed a marked deficiency of the enzyme, confirming the diagnosis of late-infantile metachromatic leukodystrophy. Serial neurophysiologic studies demonstrated a marked decrease of nerve conduction velocities, both motor and sensory, as well as prolongation or disappearance of brainstem auditory-, visual-, and somatosensory–evoked potential latencies. Magnetic resonance imaging studies revealed initially diffuse increased signal intensity of periventricular and subcortical white matter on T₂-weighted images, progressing to cortical atrophy with involvement of the arcuate fibers and the cerebellar white matter, correlating with the clinical deterioration (severe spastic tetraplegia with optic atrophy and epilepsy).     

Late-onset metachromatic leukodystrophy: Diagnostic problems elucidated by a case report

Summary A 20-year-old female had psychiatric symptoms of organic brain disease for five years but without clinical or neurophysiological signs of polyneuropathy. Late-onset metachromatic leukodystrophy was confirmed by finding severely reduced arylsulfatase A activity in her urine and leukocytes, marked excretion of sulfatides in the urine and the presence of lysosomal residual bodies in a sural nerve biopsy. This case report emphasizes the need to screen patients with early onset dementia of unknown origin or atypical hebephrenia, who are often confined to mental institutions early in the course of their disease.The morphological studies were supported by grants to H. H. G. from the Deutsche Forschungsgemeinschaft and the Stiftung Volkswagenwerk     

The natural course of gross motor deterioration in metachromatic leukodystrophy

Aim Motor deterioration is a key feature in metachromatic leukodystrophy (MLD). The lack of data about its natural course impedes evaluation of therapeutic interventions. This study aimed to provide data about motor decline in MLD. Method Fifty‐nine patients (27 males, 32 females) with MLD (21 with late‐infantile MLD and 38 with juvenile MLD) were recruited within a nationwide survey (the German LEUKONET). Median (range) age at onset was 17 months (9–27) for the group with late‐infantile MLD and 6 years 2 months (2y 11mo–14y) for the group with juvenile MLD. Gross motor function was assessed using the Gross Motor Function Classification for MLD. Results In late‐infantile MLD, all patients showed loss of all gross motor function until 3 years 4 months of age. Patients with juvenile MLD showed a more variable and significantly longer motor decline (p<0.001). For a patient with the juvenile form showing first gait disturbances, the probability of remaining stable for more than 1 year was 84%, and 51% for more than 2 years. Having lost independent walking, subsequent motor decline was as steep as in the late‐infantile form (median 5mo, interquartile range 3–22). Interpretation The course of motor disease was more variable in juvenile MLD with respect to onset and dynamics. However, the motor decline after the loss of independent walking was similarly steep in both forms. These data can serve as a reference for clinical studies that are topics of current research and allow definition of inclusion/exclusion criteria.     

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.     

Variable onset of metachromatic leukodystrophy in a Vietnamese family

We report two siblings with metachromatic leukodystrophy, one who presented at 7 years of age (juvenile onset) and his sister who presented at 22 years of age (adult onset). They are compound heterozygotes for two novel mutations in the arylsufatase A gene (ARSA). The responsible mutations in this Vietnamese family consist of a missense mutation with 5% enzyme activity (R143G) and a nonsense mutation (W318ter), from which no enzyme activity would be expected. These mutations in the ARSA gene have not been previously reported and may be useful when diagnosing metachromatic leukodystrophy in other affected Vietnamese individuals. The variability in presentation suggests that the genotype alone is not sufficient to determine the onset and course of the disease and modifying genetic and perhaps nongenetic factors likely contribute.     

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.     

Juvenile metachromatic leukodystrophy. Clinical, biochemical, and neuropathologic studies in nine new cases

We describe nine patients with metachromatic leukodystrophy. Seven patients had the juvenile form; in two others, the age at onset was 1 year, but the clinical course was different from the late infantile form. The age at onset ranged from 1 to 18 years; the duration ranged from three to 17 years. Mental retardation associated with motor impairment and pathological EEG and electromyographic findings were the main clinical findings. In patients with early onset, mental retardation was almost the only symptom for the first ten years. Segmental demyelination, remyelination, onion bulb formation, and occasional perivascular macrophages containing metachromatic lipid were the main findings in sural nerves studied after biopsy. The mean arylsulfatase-A (ASA) activity was 1.3 nmoles of nitrocatechol sulfate per milligram of protein per 30 minutes in peripheral leukocytes of the patients, 62.0 in the heterozygotes, and 139.0 in the controls. The ASA band could not be detected in enzyme electrophoresis.     

Metachromatic leukodystrophy manifesting as a schizophrenic disorder: computed tomographic correlation

A 32-year-old woman with a 12-year history of schizophrenia demonstrated symmetrical bifrontal and biparietal periventricular hypodensities on computed tomographic scan. Sural nerve biopsy and urine and leukocyte enzyme assay confirmed the diagnosis of metachromatic leukodystrophy. The computed tomographic correlate in an adult with metachromatic leukodystrophy in whom the psychiatric manifestations were the predominant clinical feature is described.     

Late-onset metachromatic leukodystrophy clinically presenting as isolated peripheral neuropathy: compound heterozygosity for the IVS2+1G-->A mutation and a newly identified missense mutation (Thr408Ile) in a Spanish family.

We report the case of a 50-year-old woman and her 32-year-old daughter, both of whom are affected with adult-onset metachromatic leukodystrophy (MLD) clinically presenting as peripheral neuropathy. Arylsulfatase A (ARSA) activities were markedly reduced, and electrophysiology showed a severe demyelinating neuropathy with features of chronic acquired demyelinating polyneuropathy. Molecular genetic studies of the family revealed that the proband and her affected daughter are compound heterozygotes for the common IVS2+ 1G-->A mutation and a newly identified missense mutation, Thr408Ile. This case indicates that adult metachromatic leukodystrophy should be considered in adult patients with demyelinating peripheral neuropathy of unknown etiology.     

A case of juvenile Sandhoff disease

A Japanese male with juvenile Sandhoff disease is described. The patient was a product of full-term normal pregnancy from non-consanguineous parents. Since age 10, he developed progressive dysarthria and proximal muscle atrophy and weakness. Mental deterioration and cerebellar ataxia are also noted since the age of 20. On neurological examination at age 35, he showed decreased mentality (IQ 62), marked atrophy and weakness of proximal muscles, cerebellar ataxia and increased deep tendon reflexes. Brain CT scans revealed moderate to marked atrophy of cerebellum. Giant MUP, fasciculation potentials and positive sharp waves were observed on EMG examination. Biopsied sural nerve showed markedly decreased myelinated fibers. Hexosaminidase A and B activities in leukocytes and cultured fibroblasts were about 10% of normal values, while other lysosomal enzyme activities were within normal range. Rectal biopsy demonstrated lamellar inclusion bodies in submucosal ganglion cells. This is the first Japanese patient with juvenile Sandhoff disease presenting symptoms similar to motor neuron disease and cerebellar degeneration.     

Leukodystrophy Presenting as Acute-Onset Polyradiculoneuropathy

BackgroundSulfatides, the most abundant glycosphingolipids, are a major component of myelin. They are degraded by the combined action of sphingolipid activator protein and arylsulfatase A. Deficiency of either of these entities causes metachromatic leukodystrophy (MLD). On the basis of age of onset, this entity is divided into late infantile, juvenile, and adult subtypes. Late infantile form, the commonest subtype, can exhibit peripheral neuropathy as the initial manifestation. The other two forms usually manifest peripheral neuropathy later in the disease course.PatientA 1.5-year-old girl with preexisting isolated motor delay presented with acute-onset ascending flaccid quadriparesis, ptosis, and respiratory failure. Ptosis and respiratory failure responded completely to intravenous immunoglobulin, whereas quadriparesis showed minimal improvement. Nerve biopsy revealed metachromatic granules with demyelination, and serum arylsulfatase A levels were undetectable.ConclusionThe severity and nature of the disease coupled with the response to immunotherapy makes this case unusual. This child may represent either an atypical presentation of MLD with coincidental response to immunotherapy or an episode of immune mediated neuropathy in an individual with already diseased nerves due to MLD.     

Juvenile-onset metachromatic leukodystrophy: biochemical and electrophysiologic studies.

A 15-year-old girl with juvenile-onset metachromatic leukodystrophy (MLD) had markedly decreased leukocyte arylsulfatase A activity and low levels of leukocyte beta galactosidase and serum acid phosphatase. There was marked slowing of nerve condition velocity, and metachromasia was seen in biopsied sural nerve. Leukocyte arylsulfatase A activity was decreased in all members of the girl's family, and sural nerve action potentials were abnormal in two asymptomatic siblings. Electrophysiologic studies combined with biochemical studies may aid in the identification of presymptomatic metachromatic leukodystrophy homozygotes or asymptomatic heterozygotes.     

Partial seizures in two cases of metachromatic leukodystrophy: electrophysiologic and neuroradiologic findings.

This report concerns two cases of metachromatic leukodystrophy presenting partial seizures. One was a 2-year-old boy with a late infantile type and the other a 17-year-old girl with a juvenile type. The former had tonic-clonic seizures on the left with concomitant twitching of the left side of the face and adversive conjugate deviation of the eyes. After a while, his interictal sleep electroencephalogram (EEG) showed spikes in the right central area. The second case had hemiconvulsions on the right side, consisting mainly of tonic flexion of the upper limb followed by clonic flexions, and accompanied by adversive conjugate deviation of the head and eyes. Her ictal EEG showed rhythmic 6- to 7-Hz wave bursts in the left frontal area. To this date, no report has given a detailed discussion of the type of seizures and ictal EEG in metachromatic leukodystrophy. In addition, there have been few detailed reports of magnetic resonance imaging (MRI) in the juvenile type. It is interesting that typical partial seizures were observed in a hereditary metabolic disorder characterized by diffuse demyelination of the white matter, and the pathophysiology is discussed here mainly in relation to MRI findings of the case with the juvenile type.     

Atypical clinical course in juvenile metachromatic leukodystrophy involving novel arylsulfatase A gene mutations

A male and female with juvenile metachromatic leukodystrophy (MLD) with unusual manifestations are presented, each involving a novel arylsulfatase A gene mutation. One patient demonstrated acute intermittent encephalopathic episodes for 1 year after having received the diagnosis of MLD at the age of 6 years. The other patient presented at the age of 5 years with acute hemiparesis, which was diagnosed as acute disseminated encephalomyelitis and resolved in 3 weeks. After 2 years of remission he started to show progressive neurological deterioration. The episodic manifestations in both patients were associated with acute, resolving cerebral lesions on magnetic resonance imaging accompanying or preceding the classical demyelinating lesions of MLD. The diagnosis of MLD was based on arylsulfatase A enzyme activity levels and genetic analysis, and after the exclusion of neurological conditions such as encephalitis, vasculopathy, or mitochondrial disorders. The pathogenesis of this previously undescribed finding in MLD is unknown but might be related to a susceptibility of myelin to acute damage.