Metachromatic Leucodystrophy Research Articles

Lysosomal Storage Disorders: Clinical, Biochemical and molecular profile from Rare disease centre, India.

Introduction:Lysosomal storage disorders (LSDs) are a heterogeneous group of large molecule inborn errors of metabolism, rather commonly seen by clinician.Objectives:This study aims to highlight the more common type of LSDs, their frequency, clinical spectrum and outcome from Rare disease centre in Rajasthan.Methods:The retrospective data were collected including clinical profile, investigations, screening test and enzyme analysis results. All outcomes were recorded from follow-up clinic.Results:This cohort comprised 65 children with different type of LSDs including 54 males and 11 females. The average age of presentation of the LSD patients was 3.5 years (range 6 months to 13 years). Gaucher disease was the most commonly found LSD (46.1%) followed by mucopolysaccharidosis (35.3%). Common presentations among GD patients were anemia, thrombocytopenia, and abdominal distension due to splenohepatomegaly/hepatomegaly. Among MPS Disorder, MPS type 2 (Hunter syndrome) was the most common (39.1%), followed by MPS type 1(Hurler syndrome) (30%) and MPS type IVA (Morquio syndrome) (17.3%). Non GD non MPS group comprised most commonly of GM1 gangliosidosis followed by pompe disease, Metachromatic Leucodystrophy, Mucolipidosis type II (I cell disease), and Sandhoff disease.Conclusions:LSDs comprises an important group of genetic metabolic disorders. Among these GD are the most common, followed by MPS.

Subacute Sclerosing Panencephalitis


 Subacute sclerosing panencephalitis (SSPE) is chronic progressive encephalitis of childhood and young adoloscent due to persistent measles virus infection. This case illustrates a 14 year old girl presented with short history of intellectual decline, abnormal behavior, myoclonus and altered consciousness with suggestive neuroimaging mimicking metachromatic leucodystrophy. Subsequently she was diagnosed to be a case of Subacute sclerosing panencephalitis (SSPE) on the basis of Electroencephalography (EEG) and Cerebrospinal fluid(CSF) measles antibody titer.
 J Bangladesh Coll Phys Surg 2019; 37(4): 205-208

Early prenatal diagnosis of lysosomal storage disorders by enzymatic and molecular analysis.

To report the 4-year experience of early prenatal diagnosis of lysosomal storage disorders (LSDs) at a center in mainland China. Forty-seven pregnancies affected with LSDs were assed using enzymes and/or molecular studies. Prenatal studies were performed on 43 uncultured chorionic villi (CV) samples, two amniotic fluid samples, and two umbilical cord blood samples. Of the 47 fetuses, 23 (48.9%) were determined to normal, 13 (27.7%) to be carriers, and 11 (23.4%) diagnosed as affected. In this cohort, mucopolysaccharidoses (MPS) type II was the most common LSD, followed by Pompe disease and then metachromatic leucodystrophy. In the 17 MPS II cases, the four affected fetuses showed MPS II enzyme activity expression levels of 1.4% to 6.7%, while the enzyme activity levels of the 13 normal fetuses ranged from 72% to 240.4%. In the seven Pompe cases, three fetuses were normal with Pompe enzyme activity expression levels of 20%, 38.8%, and 77.3%, while four carrier pregnancies showed enzyme activity levels of 17.5%, 17.5%, 33.4%, and 13.8%, respectively. Based on different enzyme properties in uncultured CV, different prenatal diagnostic strategies should be adopted for MPS II and Pompe disease. Combining enzyme assay and molecular studies in uncultured CV improves the reliability of prenatal diagnosis of LSDs.

Arylsulfatase A: An Important Metabolic Factor in Pathophysiology of Different Diseases

Abstract Arylsulfatase A (ARSA) is a lysosomal enzyme that plays an important role in catalysis of degradation of cerebrosidesulphate. The deficiency of this lysosomal enzyme causes an autosomal recessive disorder, called metachromatic leucodystrophy. However, a low ARSA activity can be observed in clinically healthy people, called ARSA pseudodeficiency. In our study we investigated the possible linkage between ARSA activity and sulfatide deficiency causing characteristic aspects of degenerative diseases, such as end stage kidney disease, type 2 Diabetes mellitus, Parkinson syndrome, prostate cancer and HIV (Human Immunodeficiency Virus) infection. We used a spectrophotometric method to determine the activity of ARSA. This method of enzyme dosage is based on a 4 hour long hydrolysis of the ARSA enzyme on 4-nitrocatechol sulfate (p-NCS) substrate. The unit of this measurement is nmol/ml/4h. Our findings show significant values in type 2 diabetes, Parkinson syndrome and chronic kidney disease. The importance of sulfatide in these diseases is well-known, thus presumably the variation of the ARSA’s activity might play an important role in the pathophysiology of these diseases, involving a vicious cycle between sulfatide degradation andthese diseases.

Cyclic mood disorder heralding adult-onset autosomal dominant leucodystrophy: A clinical masquerader

Leucodystrophies are a heterogeneous group of progressive white matter diseases which may be inherited in dominant, recessive or X-linked fashion depending on the type. Adrenoleucodystrophy (ALD) and metachromatic leucodystrophy (MLD) are rather commoner forms of leucodystrophies whereas krabbes disease, alexander disease, cannavans disease etc. are of less common type. Adult-onset autosomal dominant leucodystrophy (ADLD) is a lately described rarer form of leucodystrophy with perhaps no case report from India. Various leucodystrophies may have different clinical presentations, ranging from subtle cognitive and psychiatric manifestations to gross motor disabilities, visual impairment and seizure. Psychiatric manifestations in the form of psychoses and frank schizophrenia are commonly described in MLD. Depression though uncommonly reported in MLD, cyclic mood disorders have been rarely described in any form of leucodystrophies. We are reporting an eye opener, a case of ADLD which masqueraded as a rapid cyclic mood disorder for initial four years, later to be followed by progressive neurological signs and symptoms. To the best of our knowledge, this is perhaps the first case report of ADLD presenting as rapid cyclic mood disorder in the world literature.

Development and reliability of a classification system for gross motor function in children with metachromatic leucodystrophy

Motor deterioration is a key feature of late infantile and juvenile metachromatic leucodystrophy (MLD). Assessment of the disease course implies the need for a standardized description of motor decline. The aim of this study was to establish a classification system for gross motor function in MLD and to assess its interrater reliability. The Gross Motor Function Classification in MLD (GMFC-MLD) was modelled analogous to the Gross Motor Function Classification System in cerebral palsy. Motor data from 59 individuals (27 male; 32 female) with MLD (21 late infantile; 38 juvenile) born between 1970 and 2007 were gathered from a nationwide survey and classified by six independent raters. Median age at onset was 17 months (range 9-27 mo) for the late infantile group and 74 months (35-168 mo) for the juvenile group. The GMFC-MLD consists of seven levels and is applicable from the age of 18 months. It represents all clinically relevant stages from normal (level 0) to loss of all gross motor function (level 6). The kappa coefficient was 0.90 for overall rater agreement. There were no significant differences between level-specific kappa coefficients. The GMFC-MLD is a highly reliable, feasible tool for standardized assessment of gross motor function in MLD which can be used for the description of the natural course of the disease and for evaluation of therapeutic options such as stem cell transplantation and enzyme replacement, both of which are topics of current research.

Plasma chitotriosidase activity in children with lysosomal storage disorders

Chitotriosidase (ChT) is an enzyme that is selectively activated in tissue macrophage. This property of ChT makes it a potential marker for many disease process and prognostication. Present study has been carried out to know the significance of ChT as a screening marker in lysosomal storage disorders (LSDs) where tissue macrophage activation is commonly observed due to accumulation of substrate in various organs of the body. Study comprises of 20 healthy children in the age range of 10 days to 5 yrs and 56 children in the age range of 2.5 months to 13 yrs with regression of milestones, skeletal dysplasia, neuroregression and hepatosplenomegaly were selected for plasma ChT who had confirmed LSDs as carried out by specific lysosomal enzyme study from the leukocytes or fibroblasts. Plasma ChT was 55.21 +/- 20.81 nmol/ml/hr in twenty healthy age matched controls. Plasma ChT level was 42.88 to 79.78 nmol/ml/hr in thirteen of 56 (23.21%) children with LSDs like Morquio-B, Pompe, Metachromatic leucodystrophy (MLD), Sandhoff and Niemann-Pick disease type C (NPD-C). While in 43 (76.78%) children it was in the range of 213.74 to 23,511.40 nmol/ml/hr. who had LSDs like Morquio-B, Sly syndrome, MLD, GM2 Gangliosidosis, NPD-A/B and Gaucher disease (GD). Marked elevated ChT (4,000 to 23,511 nmol/ml/hr) was observed in all cases of GD (n=7) and NDP-A/B. It can be concluded from the present study that moderately raised activity of ChT can be utilized as a positive predictive test for certain LSD's. Those with marked elevated ChT have confirmed GD or NPD-A/B making it a strong screening marker for this group of diseases.

Clinical course of metachromatic leucodystrophy (MLD) in children – an analysis using standardized functional motor scores

Clinical course of metachromatic leucodystrophy (MLD) in children – an analysis using standardized functional motor scores

Early symptoms and time period from the occurrence of first symptoms to the diagnosis of metachromatic leucodystrophy (MLD)

Early symptoms and time period from the occurrence of first symptoms to the diagnosis of metachromatic leucodystrophy (MLD)

Polyneuropathies in teenagers: A clinicopathological study of 45 cases

The aim of the present study was to investigate the causes of polyneuropathy in teenagers and to describe some characteristic clinical, laboratory, electrophysiological and pathological features. Forty-five patients with peripheral nervous disorders aged 13–19 were studied. Hereditary polyneuropathy of different types was diagnosed in 28 patients (62%); nine showed chronic inflammatory demyelinating polyneuropathy (CIDP) and two showed vasculitic neuropathy. In two more cases polyneuropathy was attributed to toxic agents, while among the rest, one was diagnosed as metachromatic leucodystrophy (juvenile type), one as adrenoleucodystrophy, one as porphyric neuropathy and one as Fabry disease. The high incidence of hereditary neuropathies in teenagers differs from that in adults, but is similar to that encountered in children. In our study, CIDP appears to be a frequent cause of neuropathy in teenagers, while the other causes are broadly similar to those found in studies concerning children rather than adults.

Peripheral neuropathy in metachromatic leucodystrophy. A study of 40 cases from south India

Background: There is a paucity of literature from India on metachromatic leucodystrophy (MLD), a rare metabolic disorder of childhood resulting from aryl sulfatase A (ASA) deficiency. Patients/Methods: Case records of...

Low Arylsulphatase A Activity in the Development of Psychiatric Disorders

Previous studies have suggested that arylsulphatase A (ASA) deficiency may be present in psychiatric patients. A number of patients with low ASA activity and various neuropsychiatric symptoms have been observed. Metachromatic leucodystrophy (MLD) is a disease caused by deficiency of the enzyme ASA. Clinically, adult MLD may present as a schizophrenia-like psychosis, deterioration of cognitive functions, personality changes, depression and dementia. However, there are individuals with low ASA activity without clinical symptoms of MLD. This state is described as ASA pseudodeficiency. It remains controversial whether low ASA activity predisposes to or influences the development of psychiatric symptoms. Relatively little attention has been paid to the role of neurodegenerative processes in the pathophysiology of psychiatric disorders. The hypothesis underlying this work is that there is a subclass of mentally ill patients whose psychiatric problems are at least partly caused by an abnormal ASA. The purpose of this particular study was to determine whether an abnormal ASA could be detected in schizoprenic, major depressed and demented patients and control subjects. There were 66 schizophrenic, 59 major depressed and 61 demented patients. The control group consisted of 102 healthy volunteers. Leucocyte ASA activity was determined from blood samples, using p-nitrocatechol sulphate as substrate. Our results show that low ASA activity is more frequently found in psychiatric patients than in control subjects. Our findings indicate that clinical types of major depression and schizophrenia could be connected with low ASA activity. The presence of a decreased ASA activity points to the conclusion that an enzyme deficit entails vulnerability to psychiatric disorders.

Broad screening test for sphingolipid-storage diseases

Lipid-storage diseases are collectively important because they cause substantial morbidity and mortality, and because they may present as dementia, major psychiatric illness, developmental delay, or cerebral palsy. At present, no single assay can be used as an initial general screen for lipid-storage diseases. We used a fluorescent analogue of lactosylceramide, called N-[5-(5,7-dimethylborondipyrromethenedifluoride)-1-pentanoyl]D- lactosylsphingosine (BODIPY-LacCer), the emission of which changes from green to red wavelengths with increasing concentrations in membranes, to examine the intracellular distribution of the lipid within living cells. During a brief pulse-chase experiment, the fluorescent lipid accumulated in the lysosomes of fibroblasts from patients with Fabry's disease, GM1 gangliosidosis, GM2 gangliosidosis (Tay-Sachs and Sandhoff forms), metachromatic leucodystrophy, mucolipidosis type IV, Niemann-Pick disease (types A, B, and C), and sphingolipid-activator-protein-precursor (prosaposin) deficiency. In control cells, the lipid was mainly confined to the Golgi complex. In a masked study, replicate samples of 25 of 26 unique cell lines representing ten different lipid-storage diseases, and 18 of 20 unique cell lines representing controls were correctly identified; the sensitivity was 96.2% (95% CI 80.4-99.9) and the specificity 90.0% (68.3-98.8). This method may be useful as an initial general screen for lipid-storage diseases, and, with modification, could be used for large-scale automated screening of drugs to abrogate lysosomal storage in various lipidoses. The unexpected accumulation of BODIPY-LacCer in several biochemically distinct diseases raises important questions about common mechanisms of cellular dysfunction in these disorders.

A superfamily of metalloenzymes unifies phosphopentomutase and cofactor-independent phosphoglycerate mutase with alkaline phosphatases and sulfatases.

Sequence analysis of the probable archaeal phosphoglycerate mutase resulted in the identification of a superfamily of metalloenzymes with similar metal-binding sites and predicted conserved structural fold. This superfamily unites alkaline phosphatase, N-acetylgalactosamine-4-sulfatase, and cerebroside sulfatase, enzymes with known three-dimensional structures, with phosphopentomutase, 2,3-bisphosphoglycerate-independent phosphoglycerate mutase, phosphoglycerol transferase, phosphonate monoesterase, streptomycin-6-phosphate phosphatase, alkaline phosphodiesterase/nucleotide pyrophosphatase PC-1, and several closely related sulfatases. In addition to the metal-binding motifs, all these enzymes contain a set of conserved amino acid residues that are likely to be required for the enzymatic activity. Mutational changes in the vicinity of these residues in several sulfatases cause mucopolysaccharidosis (Hunter, Maroteaux-Lamy, Morquio, and Sanfilippo syndromes) and metachromatic leucodystrophy.

Prenatal diagnosis of lysosomal storage diseases.

The prenatal diagnosis of lysosomal storage disorders can be achieved, once the diagnosis is confirmed in the index case, by a variety of techniques including analysis of amniotic fluid, asay of enzymic activity in cultured amniotic fluid cells, cultured chorionic villus cells and by direct assay of activity in chorionic villus samples. These studies can be accompanied by ultrastructural observations which give an independent means of diagnosis. In some instances molecular genetic studies for mutation detection or linkage analysis are appropriate for prenatal diagnosis. Pseudodeficiencies of some of the lysosomal enzymes, which cause no clinical problems, can complicate the initial diagnosis particularly in metachromatic leucodystrophy where the pseudodeficiency is more common than the disease itself. Mutation analysis as well as enzyme assay is necessary not only in the index case but also in the parents before the same techniques are applied to a sample for prenatal diagnosis. A large number of lysosomal storage disorders may present as fetal hydrops and the diagnosis can be established at this late stage by fetal blood sampling and examination by microscopy as well as by biochemical assay of the appropriate enzyme or metabolite in amniotic fluid. All prenatal diagnoses in which an affected fetus is indicated should have confirmation of the diagnosis as soon as possible to reassure anxious parents, and to act as audit of the laboratory's competence to undertake prenatal diagnosis. A combined approach to prenatal diagnosis involving biochemical, molecular genetic and morphological studies is recommended.

Metachromatic leucodystrophy in three families from Nova Scotia, Canada: a recurring mutation in the arylsulphatase A gene.

Metachromatic leucodystrophy (MLD) is a lysosomal storage disease resulting from a deficiency of arylsulphatase A. We have identified a child with infantile onset MLD who is homozygous for an A212V...

Molecular analysis of the arylsulphatase A gene in late infantile metachromatic leucodystrophy patients and healthy subjects from Italy.

A molecular analysis of the arylsulphatase A gene was performed on 26 unrelated, Italian, late infantile metachromatic leucodystrophy patients. The frequency of the common disease causing mutations 609A and 2381T was 28.8% and 1.9% respectively. Pseudodeficiency allele frequency in patients was found to be 13.5% and a frequency of 10.1% was found in 89 unaffected normal controls. The frequency of the 609A mutation in Italian late infantile patients is lower than in late infantile patients from northern Europe, suggesting a higher frequency of different sporadic mutations in the Italian population. A cooperative in cis effect in phenotype determination involving arylsulphatase A mutations and the eventual background of the pseudodeficiency allele is proposed.

Metachromatic leucodystrophy (MLD) in a patient with a constitutional ring chromosome 22

Metachromatic leucodystrophy (MLD) is an autosomal recessive lysosomal storage disease resulting from a severe deficiency of arylsulphatase A. The arylsulphatase A gene is located on chromosome 22 at q13.3. An MLD patient is described who carries a common splicing mutation (“I” allele) and a de novo ring 22 deleted for the arylsulphatase A gene. The fatehr was determined to be a heterozygous carrier of the “I” allele and the mother a heterozygous carrier of the arylsulphatase A pseudodeficiency allele. The ring 22 was shown by Southern blotting to be deleted in one copy of the arylsulphatase A gene. Minisatellite analysis showed the extent of the deletion and confirmed the biparental inheritance of chromosome 22 sequences. The carrier status of the parents and the patient9s 46,XX,r(22) karyotype complicated the initial diagnosis in this family. However, the causal relationship of the ring 22 and MLD have implications for the recurrence risk in this family.

A single origin for the most frequent mutation causing late infantile metachromatic leucodystrophy.

Metachromatic leucodystrophy is an autosomal recessive degenerative disease of the nervous system caused by the deficiency of the lysosomal enzyme arylsulphatase A (ARSA). We report here on the high incidence of late infantile MLD among Muslim Arabs originating from Jerusalem, most probably because of a founder effect. All the patients were found to be homozygous for 459 + 1 G-->A, a mutation which destroys the splice donor site of exon 2 of the ARSA gene. This mutation has been reported to be the most common mutation causing MLD. We studied the ARSA haplotype defined by three intragenic polymorphic sites in DNA samples from Muslim Arab patients from Jerusalem, a Christian Arab patient originating from the region, and eight other white patients, all homozygous for the 459 + 1 G-->A mutation. All the alleles carried the same haplotype which is in complete linkage disequilibrium with the mutation. This finding indicates a common origin for the 459 + 1 G-->A mutation which may have been introduced into Jerusalem at the time of the Crusades.

Lysosomal Storage Diseases in Adults

Most lysosomal storage disorders are known as pediatric diseases. In recent years late onset and adult forms of these disorders have been recognized. The adult form of a given lysosomal storage disorder differs from the childhood disease in several respects. Adult disorders are, with some exceptions, less common than the childhood diseases. The clinical picture is not only less severe, but often shows quite different clinical signs and symptoms than the early onset form. Metachromatic leucodystrophy, GM1 and GM2 gangliosidoses, Gaucher disease and aspartylglucosaminuria are presented as examples of lysosomal storage disorders manifesting as adult diseases. The differences of the early and late onset disorders are discussed in the light of recent results of molecular genetics, residual enzyme activity and pseudodeficiency.