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.     

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.     

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).     

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     

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.     

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.     

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.     

Improved cerebrovascular patency following therapy in patients with sickle cell disease: initial results in 4 patients who received HLA-identical hematopoietic stem cell allografts

To test whether magnetic resonance angiography can document the evolution of vasculopathy in patients with sickle cell disease, we reviewed records to identify all patients who underwent magnetic resonance angiography from 1993 to 1999. Of 512 angiographies performed, 105 were of sickle cell disease patients, and 24 sickle cell disease patients 7 years of age or older underwent baseline and follow-up examinations. Films were paired by patient, blinded as to examination date and treatment, and quantitatively compared. Four patients who received allogeneic bone marrow transplantation were compared to 7 patients who received other therapy and to 13 untreated patients. Quantitative analysis revealed a 10% increase in the measured diameter of 64 vessels (p = 0.001) following any treatment. Patients who had undergone allogeneic bone marrow transplantation exhibited a 12% increase in the lumen of 22 vessels (p = 0.041), whereas patients treated with chronic transfusion or hydroxyurea exhibited an 8% increase in 42 vessels (p = 0.016). In 2 patients with severe stenosis, the artery normalized after transplantation, and the blood flow rate was reduced in all patients who underwent transplantation. In untreated patients, there was a trend for the size of the arterial lumen to decrease, which is consistent with disease progression. Results suggest that treatment can reverse progression of vasculopathy. Bone marrow transplantation may enable stenoses to heal and can substantially reduce cranial blood velocity, suggesting that allogeneic bone marrow transplantation may prevent infarction or brain damage.     

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.     

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.     

A 40-year-old woman with progressive dementia and abnormal behavior]

We report a 40-year-old Japanese woman who died after 12 years history of progressive dementia and abnormal behaviors. She was well until 1985 at her age of 28 years old, when she had an onset of behavioral change in which she drank much, neglected house-keeping works, and her life style became sloppy. At age 30, she became unable to understand written sentences, and paced up- and down in and out of her house. She was admitted to other hospital where marked dementia with disorientation and memory loss were noted. Slight increase in CSF protein and decrease in the peripheral nerve conduction velocity were also noted at that time. In the next year, she started to have convulsions. These symptoms had progressively become worse and was admitted to Tokyo Metropolital Matsuzawa Hospital in June of 1991 when she was 34 years of age. Despite marked dementia, she was able to walk normally, no motor paralysis, cerebellar ataxia, nor dyskinesia were noted. Deep tendon reflexes were diminished. MRI revealed T-2 high signal intensity lesions involving the white matter of the cerebrum predominantly in the frontal region. In about one year, she started to show difficulty in gait, and she became bed-ridden in July of 1994. She was discharged to home for a while, but required admission again. She expired on February 5, 1998. Her younger brother had an essentially similar dementing disease and he expired at the age of 35 years. The parents were of first cousins. The patient was discussed in a neurological CPC, and the chief discussant arrived at the conclusion that the patient had adult form of metachromatic leukodystrophy, because of white matter change in the frontal lobe, decrease in nerve conduction velocity, convulsion, marked dementia, and consanguineous marriage with a similarly affected brother. Most of the audience agreed with this conclusion, but the differential diagnosis from globoid cell leukodystrophy was felt difficult from the clinical findings alone. Post-mortem examination revealed marked atrophy in the frontal lobe. Cerebellum appeared to be smaller than normal. In the coronal sections, marked atrophy of the white matter with brown discoloration was noted. The lateral ventricles were dilated. Klüver-Barrera staining revealed marked demyelination with relative preservation of the U-fibers. PAS-positive materials were deposited in some astrocytes as well as neurons. Metachromatic deposits were noted not only in the cerebrum but also cerebllum after staining with acid cresyl violet. Pathologic diagnosis was consistent with adult type of metachromatic leukodystrophy.     

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.     

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.     

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.     

Immune response in leukodystrophies

Although the genetics and biochemistry of leukodystrophies have been extensively explored, the immune response in these disorders has received relatively little attention. Both the disease course and its response to treatment may be highly dependent on the immune system. In this review, we compare three common leukodystrophies, each with a different immune response: (1) X-linked adrenoleukodystrophy, which demonstrates a severe, lymphocytic inflammatory response; (2) metachromatic leukodystrophy, which yields a histiocytic response; and (3) vanishing white-matter disease, in which no inflammation is typically seen. We highlight the biochemical, pathologic, and clinical differences, while focusing on the immune response in each disease. We also review the response of leukodystrophies to immunomodulatory therapies and interventions such as hematopoietic stem-cell transplantation. Future studies may delineate specific inflammatory markers as possible candidates for therapeutic intervention.     

Intestinal involvement in metachromatic leukodystrophy

Metachromatic leukodystrophy is a lysosomal storage disease caused by the deficiency of the enzyme arylsulfatase A. If arylsulfatase A is deficient, sulfatide accumulates. Functionally, this accumulation results in progressive neurological deterioration. The reports about the extra nervous system manifestations of metachromatic leukodystrophy are related to the gallbladder involvement such as polyposis. Unexplained vomiting began in a 5½-year-old girl with late infantile metachromatic leukodystrophy. Endoscopy showed multiple polypoid masses in the pylor of the stomach and duodenum. Severe gastrointestinal bleedings occurred during nasogastric feeding. Intestinal intussusception developed later. To the authors' knowledge, intestinal polypoid masses and obstruction with metachromatic leukodystrophy have not previously been reported. The persistent vomiting may be a symptom of intestinal obstruction due to intestinal polypoid masses with metachromatic leukodystrophy. There may be a trend for the development of polypoid masses in intestine as well as in the gallbladder in metachromatic leukodystrophy.     

Adult metachromatic leukodystrophy. Arylsulphatase-A values in four generations of one family and some reflections about the genetics.

The authors describe an investigation of Adult Metachromatic Leukodystrophy in a Dutch family, of which two persons were affected. The studies of leukocyte arylsulphatase-A activity were made in 47 members of 4 generations of the same family. The propositus, a 30-year old man, showed a conspicious organic brain syndrome, that progressed in two years to a complete dementia. His leukocyte, liver and kidney arylsulphatase-A activities (ASA) were very low; leukocyte-ASA activity increased after aceto-salicylate. His brother had died at 34 years, after a progressive debelitating neuropsychiatric illness of eight years; postmortem metachromatic leukodystrophy was diagnosed. In all living family members, urine and leukocyte arylsulphatase-A activities were determined. The findings are discussed in relation to the genetics and pathogenesis of this adult form of metachromatic leukodystrophy. Allelic heterozygoty is proposed as inheritance model in this family. Suggestions for further research are made.     

Frontotemporal dementia in metachromatic leukodystrophy

The case of a 39-year old woman with metachromatic leukodystrophy (MLD) is presented. In the clinical examination she revealed symptoms of a frontotemporal dementia without any signs of polyneuropathy. If frontotemporal dementia is diagnosed MLD should be excluded.     

Osmiophilic deposits in cytosomes in Hallervorden-Spatz syndrome.

A young child with Hallervorden-Spatz syndrome is presented. She was well until 8 years of age when she lost interest in activities and her school performance declined. At age 11 years, she began having episodes of blepharospasm, accompanied by bilateral ptosis and occasional episodes of oculogyric crisis. By age 12 years, her motor coordination had declined and she began to exhibit evidence of dementia, dystonia, dysarthria, and tremor. Motor incoordination, dystonia, and tremor progressed until the patient was wheel-chair-bound. Multiple tests were performed, including metabolic studies, magnetic resonance imaging, bone marrow biopsy, and electron microscopy of the buffy coat. Both bone marrow and buffy coat revealed inclusions in the cytosomes which were granular and osmiophilic. To our knowledge, this is the third case report of inclusion bodies found in patients with manifestations of Hallervorden-Spatz syndrome. These findings suggest that obtaining a buffy coat and bone marrow biopsy may aid in the diagnosis of Hallervorden-Spatz syndrome and ultimately provide information regarding etiology.     

Muscle-specific kinase antibody associated myasthenia gravis after bone marrow transplantation

Myasthenia gravis is a rare complication of bone marrow transplantation and graft versus host disease. We report a 30-year-old woman presented with oculobulbar and proximal limb weakness after allogeneic bone marrow transplantation for chronic myelogenous leukemia. Also, she developed graft versus host disease following bone marrow transplantation. Investigations led to the diagnosis of muscle specific kinase antibody related myasthenia gravis. There have been only two case reports of muscle specific kinase antibody positive myasthenia gravis after bone marrow transplantation in the literature, but none of the previously reported cases had graft versus host disease.