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.     

Slow progression of juvenile metachromatic leukodystrophy 6 years after bone marrow transplantation.

Metachromatic leukodystrophy refers to a group of genetic neurologic diseases caused by deficiencies of the enzyme arylsulfatase A and the resulting accumulation of sulfatides in white matter. Bone marrow transplantation has been advocated as a treatment in an attempt to correct the enzyme deficiency. Such a transplant was performed in 1991 in a 16-year-old girl with a form of late juvenile metachromatic leukodystrophy caused by a homozygous P426L mutation in the arylsulfatase A gene. Engraftment was prompt and resulted in constant enzymatic normalization of circulating lymphocytes. The elevated urinary excretion of sulfatides remained unaffected. Clinical findings up until transplantation consisted of gait disturbances, impairment of cognitive functioning, and deterioration in school performance over several years. During a 6-year follow-up period, the patient's condition was subject to major fluctuations but, on the whole, findings showed slow neurologic and neurophysiologic deterioration. The clinical course observed after bone marrow transplantation probably more or less reflects the natural course expected in this form of late-onset metachromatic leukodystrophy.     

A case of juvenile metachromatic leukodystrophy--the third case in Japan

We report here a case of juvenile metachromatic leukodystrophy. The patient is an 8-year-old boy with motor and mental deterioration, which began at about age 3. He has also suffered from astatic seizures since age 8. Arylsulfatase A activity in the patient was markedly decreased in peripheral leukocytes, cultured fibroblasts and urine. Sulfatide was detected in urine from the patient by thin-layer chromatography. Peripheral motor and sensory nerve conduction velocities were markedly reduced. Computerized tomography of the brain showed low density areas in the periventricular white matter which were not enhanced by intravenous contrast material. His parents' arylsulfatase A activities were about half those of normal controls. This is the third case of juvenile metachromatic leukodystrophy in Japan.     

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.     

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.     

Umbilical cord blood transplantation for juvenile metachromatic leukodystrophy

Three siblings with metachromatic leukodystrophy underwent umbilical cord blood transplantation at different stages of disease. Neuroimaging, nerve conduction studies, neurological examinations, and neuropsychological examinations were used to measure outcome over 2 years. After transplant, the oldest sibling experienced disease progression. His two siblings had near or total resolution of signal abnormalities on neuroimaging. Their neuropsychological testing remained stable, and nerve conduction studies have shown improvement. These results indicate pretransplantation neurological examinations may be the most significant predictor of outcome after transplant. To our knowledge, this report is the first to document neurological outcome of metachromatic leukodystrophy treated by umbilical cord blood transplantation. Ann Neurol 2008;64:583–587     

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.     

Amniotic tissue transplantation: clinical and biochemical evaluations for some lysosomal storage diseases.

Amniotic epithelial cells has been used for transplantation in patients with lysosomal storage diseases as an enzyme replacement therapy. But its clinical effect is still the question under debate. We performed amniotic tissue transplantation on patients with different lysosomal storage diseases: one with Tay-Sachs disease, one with juvenile Gaucher disease and one with juvenile metachromatic leukodystrophy. The patient having juvenile Gaucher disease received this grafting twice. Objective clinical improvement was observed in the first trial where this patient showed an increase of soluble beta-glucosidase one week after implantation. No clinical or biochemical changes were seen in the other patients. Although there are some advantages to amniotic tissue transplantation, original methods should be modified to cell transplantation in order to avoid graft-versus-host reaction which could happen in repeated implantation.     

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.     

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.     

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.     

Diffusion-weighted imaging findings in juvenile metachromatic leukodystrophy

Magnetic resonance (MR) imaging has an important role in the diagnosis of metachromatic leukodystrophy (MLD). We report diffusion-weighted MR imaging (DWI) findings of four cases of juvenile type MLD. DWI showed restricted diffusion lines with greater areas of increased diffusion in three patients and widespread increased diffusion in one patient. This variability in DWI findings can be related to the histological stage of the disease at the time of imaging, ranging from intracellular metachromatic material accumulation to breakdown of myelin membranes.     

Globoid cell leukodystrophy (Krabbe's disease): update

The classic globoid cell leukodystrophy (Krabbe's disease) is caused by genetic defects in a lysosomal enzyme, galactosylceramidase. It is one of the two classic genetic leukodystrophies, together with metachromatic leukodystrophy. The mode of inheritance is autosomal recessive. Typically, the disease occurs among infants and takes a rapidly fatal course, but rarer late-onset forms also exist. Clinical manifestations are exclusively neurologic with prominent white-matter signs. The pathology is unique, consisting of a rapid and nearly complete disappearance of myelin and myelin-forming cells--the oligodendrocytes in the central nervous system and the Schwann cells in the peripheral nervous system, reactive astroytic gliosis, and infiltration of the unique and often multinucleated macrophages ("globoid cells") that contain strongly periodic acid-Schiff (PAS)-positive materials. A normally insignificant but highly cytotoxic metabolite, galactosylsphingosine (psychosine), is also a substrate of galactosylceramidase and is considered to play a critical role in the pathogenesis. The galactosylceramidase gene has been cloned, and a large number of disease-causing mutations have been identified. Equivalent genetic galactosylceramidase deficiency occurs in several mammalian species, such as mouse, dog, and monkey. Recently, deficiency of one of the sphingolipid activator proteins, saposin A, was demonstrated to cause a late-onset, slowly progressive globoid cell leukodystrophy at least in the mouse, with all of the phenotypic consequences of impaired degradation of galactosylceramidase substrates. Human globoid cell leukodystrophy owing to saposin A deficiency might be anticipated and should be suspected in human patients with a late-onset leukodystrophy with normal galactosylceramidase activity when other possibilities are also excluded. The only serious attempt at treating human patients is bone marrow transplantation, which can provide significant alleviation of symptoms, particularly in those patients with later-onset, more slowly progressive globoid cell leukodystrophy.     

Epileptic seizures and electroencephalographic evolution in genetic leukodystrophies.

The purpose of this study is to explore and compare epileptic seizures and EEG evolution in the various types of genetic leukodystrophy (GL). The authors reviewed the medical records and analyzed 69 serial EEGs in 27 patients with GLs: 13 with late infantile metachromatic leukodystrophy, one with juvenile metachromatic leukodystrophy, one with globoid cell leukodystrophy, six with X-linked childhood adrenoleukodystrophy, one with neonatal adrenoleukodystrophy, four with classic Pelizaeus-Merzbacher disease (PMD), and 1 with connatal Pelizaeus-Merzbacher disease. The diagnoses were made by biochemical and molecular studies. Two or more EEG studies with both awake and sleep traces were recorded during the varying clinical stages for each patient. At the beginning of the GLs, the EEGs were normal or showed mild slowing of background activity. Clinical seizures, mainly of focal origin, with progressive slowing and paroxysmal discharges on EEGs, usually appeared during the later stages of metachromatic leukodystrophy, X-linked childhood adrenoleukodystrophy, and classic Pelizaeus-Merzbacher disease. However, intractable seizures, mainly generalized in nature, and more severe slowing and abundant paroxysmal discharges on EEGs, with commensurate neurologic deterioration, were observed during the earlier course of globoid cell leukodystrophy, neonatal adrenoleukodystrophy, and connatal Pelizaeus-Merzbacher disease. These results indicate that GLs involve not only white matter, but gray matter as well. In all types of GL, there is good correlation between the severity of EEG changes, the severity of the diseases, and the clinical state of the patient.     

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.     

Clinical course of adult metachromatic leukodystrophy presenting as schizophrenia. A report of two living cases in siblings.

Adult metachromatic leukodystrophy is a demyelinating disease due to an inherited lack of arylsulfatase A activity. The purpose of this paper is to present the characteristics of this disorder as they occurred chronologically in two siblings, prior to and subsequent to the appearance of gross neurological deficits. A deficit in spatial relationships, as contrasted with verbal abilities, was observed initially in both cases at age 13. Initial psychiatric symptoms were noted at age 16 and 18, with both patients being diagnosed subsequently as schizophrenic. Gross neurological deficits were observed 2 and 13 years, respectively, after the appearance of psychiatric symptoms. A deficit in spatial relationships may be a very sensitive early indicator of adult metachromatic leukodystrophy.     

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.     

White matter dysfunction and its neuropsychological correlates: A longitudinal study of a case of metachromatic leukodystrophy treated with bone marrow transplant

Abstract

A 10-year-old white female who had received a bone marrow transplant (BMT) at 57 months of age as treatment for late infantile onset metachromatic leukodystrophy (MLD), a neurodegenerative autosomal recessive storage disease, showed stabilization of the cognitive degenerative process and demonstrated a partial pattern of cognitive deficits and behavioral abnormalities that has been called NLD (nonverbal learning disabilities) associated with white matter disease. A pattern of good rote memory, reading skills, and concrete language contrasted with poor visual spatial skills, mathematics, and abstract problem solving. She did not show the usual speech prosody and social deficits associated with NLD.     

An Italian Cohort Study Identifies Four New Pathologic Mutations in the ARSA Gene

Metachromatic leukodystrophy is an autosomal recessive neurodegenerative disorder of the myelin metabolism due to the impaired function of the lysosomal enzyme arylsulfatase A. Three major clinical variants of metachromatic leukodystrophy (MLD) have been described: late infantile, juvenile, and late onset. The infantile form, whose clinical onset is usually before the age of 2 years, is the most frequent. The juvenile form manifests itself between 3 and 16 years and the late-onset form manifests at any time after puberty. As of today, more than 150 mutations causing MLD have been identified in the ARSA gene that encodes arylsulfatase A. In this paper, we report our experience with the diagnosis of MLD in seven Italian patients from unrelated families. We found 11 different mutations, four of which have not been previously described: c.1215_1223del9 (p.406_408del), c.601 T>C (p.Tyr201His), c.655 T>A (p.Phe219Ile), and c.87C>A (p.Asp29Glu). Our data show once more that there are still several mutations to be discovered in the ARSA gene and there are rarely repeating ones found in the population. The predictive value of the enzyme activity tests in regard to clinical manifestations is extremely limited.     

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.