Low Arylsulfatase Research Articles

Extremely low arylsulfatase A enzyme activity does not necessarily cause symptoms: A long-term follow-up and review of the literature.

Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by deficiency of arylsulfatase A (ARSA). Heterozygous carriers of disease‐causing variants and individuals harbouring pseudodeficiency alleles in the ARSA gene exhibit reduced ARSA activity. In the context of these genotypes, low ARSA activity has been suggested to lead to an atypical form of MLD or other neurological abnormalities, but data are limited. The aim of our study was to analyse the impact of low ARSA activity in two subjects who are heterozygous for the ARSA pseudodeficiency allele and a disease‐causing variant. Biochemical testing included ARSA activity measurements and urinary sulfatide analysis. Biochemical data of a large cohort of MLD patients, heterozygotes, pseudodeficient individuals and healthy controls were analysed. MRI was performed at 3T using T1‐ and T2‐weighted sequences and MR spectroscopy. We present two long‐term follow‐ups who are heterozygous for the ARSA pseudodeficiency allele and a disease‐causing variant in the ARSA gene in cis. The two related index cases exhibit markedly reduced ARSA activity compared to controls and heterozygous carriers. The neurological evaluation and MRI do not reveal any abnormalities. Our data underline that extremely low enzyme activity due to a pseudodeficiency allele and a disease‐causing variant in the ARSA gene even in cis does not lead to clinical symptoms or pre‐symptomatic MRI changes suspicious for MLD. The review of literature corroborates that any association of low ARSA activity with disease features remains questionable. It seems important to combine the measurement of ARSA activity with elevated sulfatide as well as genetic testing, as done in current newborn screening approaches. Heterozygosity for metachromatic leukodystrophy and an arylsulfatase A pseudodeficiency allele does not cause neurological or neuropsychiatric features.

Lighthouse in the open sea of spastic ataxia

First, I would like to congratulate Sangmin Park and collaborators on their excellent article entitled “Lighthouse in the open sea of spastic ataxia.” The authors report the case of a 32-year-old patient with spastic ataxia and low arylsulfatase A (ARSA) activity range who was initially diagnosed as having metachromatic leukodystrophy (MLD). Their diagnosis was subsequently reevaluated based on genetic testing and particularly brain MRI imaging findings and they reached a definite diagnosis of spastic paraplegia type 11 (SPG11).

A Novel Pathological ARSB Mutation (c.870G>A; p.Trp290stop) in Mucopolysaccharidosis Type VI Patients

Mucopolysaccharidosis (MPS) type VI, also known as Maroteaux-Lamy syndrome, is a lysosomal storage disorder, characterized by the deficiency of the arylsulfatase B enzyme. The clinical phenotype and severity of the illness varies according to the residual enzyme activity. Typical features are a short stature, shortened trunk, protuberant abdomen, flexed-knee stance, arched back, corneal clouding, joint stiffness and contractures as well as a waddling gait. Patients typically have Hurler-like dysmorphic facial features: microcephaly, prominent forehead and eyes, a broad nose, low nasal bridge, thick lips, and hyperplastic gums with widely spaced teeth. Complications of the illness include obstructive airway, cardiac valvular problems, splenomegaly, hernias, and pneumonia. Unlike other MPS diseases, MPS VI is characterized by normal intellectual development. Since the disease is due to deficient glycosaminoglycan (mucopolysaccharide) metabolism, elevated urinary glycosaminoglycan levels are a main indicator of MPS. Diagnosis is confirmed by enzyme assays, specifically low arylsulfatase B activity in conjunction with the normal activity of other lysosomal enzymes. Enzyme replacement therapy and hematopoietic stem cell therapy are showing positive results in the management of the condition. The more severely affected patients, with a rapidly advancing form of the disease, have a short life span and succumb, most commonly to heart failure, by early adulthood. The frequency of ARSB variants in patients with MPS VI are as follows: 59.5% missense, 13.5% small deletions, 12% nonsense, 5% splice site or intronic variants, 3% small duplications, 3% large deletions, and 1% stop-loss. We report an Albanian family with siblings diagnosed with MPS Vl after clinical examination, biochemical tests, and molecular analysis. Hereby, a novel c.870G>A nonsense homozygous mutation was found responsible for the loss of the enzyme activity.

A patient presenting a 22q13 deletion associated with an apparently balanced translocation t(16;22): an illustrative case in the investigation of patients with low ARSA activity

A 10-year-old speechless, mentally deficient male, with low arylsulfatase A (ARSA) activity, and presumably, methachromatic leukodystrophy, underwent genetic evaluation. As the clinical picture was not compatible with this diagnosisan ARSA gene and chromosome analysis were performed, showing the presence of a pseudodeficiency ARSA allele and a de novo apparently balanced t(16;22)(p11.2;q13) translocation. A deletion on the long arm of chromosome 22 encompassing the ARSA gene, as shown by FISH and array-CGH, indicated a 22q13 deletion syndrome. This case illustrates the importance of detailed cytogenetic investigation in patients presenting low arylsulfatase A activity and atypical/unspecific clinical features.

Chromosomal deletion unmasking a recessive disease: 22q13 deletion syndrome and metachromatic leukodystrophy

A deletion on one chromosome and a mutant allele on the other may cause an autosomal recessive disease. We report on two patients with mental retardation, dysmorphic features and low catalytic activity of arylsulfatase A. One patient had a pathogenic mutation in the arylsulfatase A gene (ARSA) and succumbed to metachromatic leukodystrophy (MLD). The other patient had a pseudoallele, which does not lead to MLD. The presenting clinical features and low arylsulfatase A activity were explained, in each patients, by a deletion of 22q13 and, thereby, of one allele of ARSA.

Green manure effects on soil quality in relation to suppression of Verticillium wilt of potatoes

Verticillium dahliae is a major, persistent pathogen in soil but conventional control is becoming more difficult because of increasing costs and environmental impacts of pesticides. Organic amendments can naturally suppress plant diseases, but to be reliable, mechanisms and suppressive soil indicators need to be understood. Consequently, a 3 × 3 factorial experiment was conducted in two separate fields over 2 years with three green manure types (Austrian winter pea, Pisum sativum L.; broccoli Brassica oleracea L.; or Sudan grass, Sorghum vulgare), incorporated at three rates (6, 12, or 24 Mg ha−1 dry biomass). The relationship between soil chemical and microbiological properties and suppression of Verticillium wilt of potato was investigated using correlation and stepwise multiple-linear-regression (MLR) analysis. V. dahliae inoculum density (ID) were positively correlated with relative area under the senescence progress curve (RAUSPC) in both 2002 and 2003. In 2002, in addition to ID, low soil pH, low Ca, high K, high Mg, high total soil C, and low arylsulfatase activity were associated with low RAUSPC. Soil pH, Ca, K, and Mg were not impacted by green manure treatments, but rather indicated a pre-existing soil gradient at the 2002 site. In 2003, in addition to ID, high values of NO3−−N, total C, fluorescein diacetate hydrolysis (FDA), microbial respiration, and microbial biomass C were associated with low RAUSPC. These six factors were affected by green manure treatments. The best MLR model included terms for ID, FDA, and soil pH, and accounted for 70% of the variability in RAUSPC.

Arylsufatase activity in the rhizosphere and roots of different crop species

It is assumed that arylsulfatase contributes to the mineralization of organic S to SO 4 2− for plant uptake. However, the impacts of agronomic measures (long-term organic manure) or crop species on enzyme activity are not well understood. Therefore, in the present investigations arylsulfatase activity was quantified within the rhizosphere of Sinapis album, Lolium perenne, Triticum aestivum and Brassica napus, grown on three different soils from a long-term field experiment. Highest activities were found within 0.25 mm from the root surface. Highest over all activities were found with B. napus and T. aestivum, lowest with S. album and L. perenne at a distance of 1.75 mm. As compared to soil supplemented with mineral fertilizer, compost and farmyard manure, respectively, arylsulfatase activity was higher in the soil with long-term compost application. In the protein extracts of sterile-grown roots a low arylsulfatase activity could be detected. The enzyme is induced under sulfate deficiency conditions. Preliminary biochemical data obtained from studies with T. aestivum arylsulfatase indicate conformity with biochemical properties of arylsulfatases originated from micro-organisms, vertebrates and invertebrata. From our results we assume that arylfulfatase activity determined in roots of sterile-grown plants is derived from endophytic bacteria and not by higher plants.

Long-term follow-up of children with chronic relapsing polyneuropathy

Long-term follow-up of three children with early-onset chronic inflammatory demyelinating polyneuropathy is presented. A 3-year-old male (Patient 1) manifested initially progressive muscle weakness during 6 months with spontaneous regression, followed by two severe relapses at 5 and 6 years of age. Decreased arylsulfatase A activity was present in Patient 1 (17.6) and his family members (24.1-40 nmol/mg/hour). Arterial hypertension up to 20/12 kPa was present in two patients in the initial phase associated with muscle stiffness, occasional meningism, and left ventricular hypertrophy in one of them (Patient 3). Subsequently, they both developed two mild relapses at 3.5 and 6 years of age. Clinical outcome was excellent in all three cases, although clinical course, therapy response, and electrophysiologic outcome was quite different in the only patient with low arylsulfatase A activity. The significance of this difference is discussed.

Leukocyte arylsulfatase A activity in patients with alcohol‐related cirrhosis

Arylsulfatase (ASA) enzyme deficiency is associated with metachromatic leukodystrophy (MLD), which is a hereditary myelin metabolic disease. It has been proposed that in alcoholic subjects with abnormal ASA, the accumulation of sulfatides may lead to demyelinization and generalized cerebral atrophy. ASA may be diminished in subjects with alcoholic cirrhosis having encephalopathic manifestations. This idea has not been previously proposed. Leukocyte arylsulfatase A (ASA) activity was measured in 30 healthy male volunteers and 28 patients with alcohol-related cirrhosis. The patients were divided into two groups: patients with alcohol-related cirrhosis with hepatic encephalopathy history and patients with alcoholic cirrhosis without history of hepatic encephalopathy. Alcoholic cirrhotic patients with history of encephalopathy showed 58.21% (40.95 nmol/mg protein/h) less enzymatic activity than a control group (98.00 nmol/mg protein/h), whereas the group without history of encephalopathy showed an ASA value which was 38.2% (60.55 nmol/mg protein/h) less than the control group. The results suggest that the low ASA activity is a factor associated to the appearance of encephalopathy in patients with alcohol-related cirrhosis. Am. J. Hum. Biol. 13:297–300, 2001. © 2001 Wiley-Liss, Inc.

Leukocyte arylsulfatase A activity in patients with alcohol-related cirrhosis.

Arylsulfatase (ASA) enzyme deficiency is associated with metachromatic leukodystrophy (MLD), which is a hereditary myelin metabolic disease. It has been proposed that in alcoholic subjects with abnormal ASA, the accumulation of sulfatides may lead to demyelinization and generalized cerebral atrophy. ASA may be diminished in subjects with alcoholic cirrhosis having encephalopathic manifestations. This idea has not been previously proposed. Leukocyte arylsulfatase A (ASA) activity was measured in 30 healthy male volunteers and 28 patients with alcohol-related cirrhosis. The patients were divided into two groups: patients with alcohol-related cirrhosis with hepatic encephalopathy history and patients with alcoholic cirrhosis without history of hepatic encephalopathy. Alcoholic cirrhotic patients with history of encephalopathy showed 58.21% (40.95 nmol/mg protein/h) less enzymatic activity than a control group (98.00 nmol/mg protein/h), whereas the group without history of encephalopathy showed an ASA value which was 38.2% (60.55 nmol/mg protein/h) less than the control group. The results suggest that the low ASA activity is a factor associated to the appearance of encephalopathy in patients with alcohol-related cirrhosis.

Arylsulfatase A Levels in Patients with Chronic Alcoholism

Background The goal of this study was to find the association between low arylsulfatase A (ASA) activity and psychiatric disorders in chronic alcoholic patients. Methods The study was carried out in 30 chronic alcoholic patients (27 male, 3 female); age range was 25–65 years. There were 20 normal controls (18 males, 2 females), and age range was 24–67 years. ASA and routine aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activity laboratory tests were measured in blood serum from all patients and control subjects. Results Alcoholic patients with psychiatric disorders have ASA average values of 68.25 nmol/mL/4 h. This is less than averages found in the alcoholics without psychiatric disorders group (82.48 nmol/mL/4 h) and the control group (90.8 nmol/mL/4 h). There were no statistically significant differences among the three groups studied. Alcoholic subjects with elevated activity of AST and ALT ( n = 10) have ASA activity average values of 134.82 nmol/mL/4 h), which is 48.8% higher than the control group (90.6 nmol/mL/4 h). These means show statistically significant differences ( p <0.05). Conclusions Results indicate an association between low serum ASA activity and alcoholism. The appearance of psychiatric manifestations could be related to the low activity of this enzyme in chronic alcoholic patients. Alcoholic patients with elevated enzyme activity of AST and ALT in sera also have elevated sera arylsulfatase A (ASA) activity. We consider that these findings may be useful for evaluating the psychiatric state as a prognosis in chronic alcoholic patients, and should be a routine laboratory test in alcoholic patients.

DNA-based diagnosis of arylsulfatase A deficiencies as a supplement to enzyme assay: A case in point

Objective: To identify the molecular basis of arylsulfatase A deficiency in a family at risk for metachromatic leukodystrophy (MLD) and determine the genetic risk in the offspring. Methods: Mutations in the arylsulfatase A gene were identified by PCR amplification and restriction enzyme digestion. Individuals had previously been tested for arylsulfatase A activit Results: Assays of arylsulfatase A activity had resulted in ambiguous results for MLD carrier identification. DNA analysis clearly identified two MLD mutations in the family, and an unsuspected arylsulfatase A pseudodeficiency. The DNA information immediately clarified the MLD risk for the family and confirmed that a newborn with low arylsulfatase A activity was unaffected. Conclusions: The overlap between activities for various combinations of MLD and pseudodeficiency alleles and the variability inherent in the assay of arylsulfatase A complicate the interpretation of activity levels in families at risk for MLD. Use of simple molecular biological tests for pseudodeficiency and the common MLD mutations in combination with the enzyme data can facilitate carrier identification and prenatal diagnosis.

Serum arylsulfatase A assay in metachromatic leukodystrophy: An experience in a neuropsychiatric set-up

Metachromatic leukodystrophy is a lysosomal disease caused mainly by a deficiency of the enzyme arylsulfatase A. The assay of arylsulfatase A in the serum provides a fast and easy method for the confirmatory diagnosis of this disorder. Serum arylsulfatase A was estimated in 52 normal healthy control subjects and 269 patients with symptoms of cerebral white matter disease in order to diagnose and confirm metachromatic leukodystrophy. A total of eight cases of metachromatic leukodystrophy with a low serum arylsulfatase A was detected, of which three cases were of the late-infantile type, four cases the juvenile type and only one case the adult type.

Clinical Symptoms of Adult Metachromatic Leukodystrophy and Arylsulfatase A Pseudodeficiency

To determine the clinical symptoms in adult metachromatic leukodystrophy and in adult pseudodeficiency for arylsulfatase A. Case series. University hospital. Twenty-five adult patients with very low arylsulfatase A activity. In 13 patients, a diagnosis of adult metachromatic leukodystrophy was made. The main symptoms were dementia, behavioral abnormalities, ataxia, and polyneuropathy. In 12 patients, a diagnosis of arylsulfatase A pseudodeficiency was made. No characteristic clinical syndrome could be detected in these patients. Adult metachromatic leukodystrophy is a progressive metabolic disease with symptoms of demyelination of the central and peripheral nervous systems. Diagnosis must be confirmed by determination of arylsulfatase A activity and accumulation of sulfatides. Pseudodeficiency for arylsulfatase A can be confirmed or excluded by means of DNA analysis.

Pseudodeficiencies of Arylsulfatase A and Galactocerebrosidase Activities

Pseudodeficiency is defined as the in vitro measurement of low activity (usually under 15% of the normal mean for controls) of an enzyme in a healthy person. They may be hard to distinguish from presymptomatic people who will present with adult-onset clinical disease. The finding of healthy people with low arylsulfatase A and galactocerebrosidase activities is well documented. This confuses the laboratory doing testing and the clinician providing the sample. Therefore confirmation of a diagnosis of metachromatic leukodystrophy and Krabbe disease, as well as accurate identification of carriers, requires additional testing including 14C-sulfatide loading in cultured skin fibroblasts, examination of urine for excretion of undegraded lipids, examination of enzyme levels in additional family members including grandparents, and molecular analysis of DNA samples for known mutations.

Prevention of Deterioration in Metachromatic Leukodystrophy by Bone Marrow Transplantation

The first girl in a family was affected with late infantile metachromatic leukodystrophy (MLD) and had the expected characteristic central nervous system progressive deterioration, which resulted in decerebration and death. The second girl (propositus) demonstrated similar symptoms and signs at the same age. Both girls had characteristically low arylsulfatase A levels. The propositus underwent allogeneic bone marrow transplantation (BMT) from a normal histocompatible sibling. Two and a half years later, the propositus has not developed the intellectual and neurologic impairment demonstrated by the first sibling, although nerve conduction has continued to worsen. These results suggest that the induction of normal enzyme levels by BMT may be retarding or inhibiting CNS deterioration. These results, confirming earlier results of others, are sufficiently promising to warrant a larger scale critical trial of BMT early in the course of MLD.

The influence of low arylsulfatase A activity on neuropsychiatric morbidity: a large-scale screening in patients.

A total of 1728 patients consecutively admitted to a neuropsychiatric hospital and 379 chronically ill inpatients were examined for activity of arylsulphatase A (ASA) in leucocytes. A further 519 healthy individuals served as controls. We did not find evidence for the involvement of low ASA activity in chronic patients. The consecutive admissions showed a slight preponderance in the lower ASA activity classes. This activity range covers persons heterozygous for ASA deficiency alleles. The data are compatible with the hypothesis that carriers of low ASA activity alleles are at a slightly higher risk for neuropsychiatric disorders.

Impaired cerebroside sulfate hydrolysis in fibroblasts of sibs with "pseudo" arylsulfatase A deficiency without metachromatic leukodystrophy.

Low arylsulfatase A levels are reported in two siblings, one with a neurologic disability not typical for metachromatic leukodystrophy, the other a healthy 18-year-old female with a normal developmental history. In both individuals, arylsulfatase A levels in white blood cells were 7-8% of control values. Cultured fibroblasts gave low values (8-10% of normal) for both cerebroside sulfatase and arylsulfatase A activities. Other family members had enzyme levels consistent with heterozygote or normal status. Cerebroside sulfate loading tests of cultured fibroblasts in 199-CO2 media were normal for all family members who were tested. In MEM-HEPES media, however, cells from the two arylsulfatase A deficient siblings showed attenuated sulfolipid catabolism. Additional clinical and laboratory studies on these individuals failed to demonstrate any features suggestive of metachromatic leukodystrophy, i.e., normal nerve conduction velocities, normal sural nerve biopsy results, and normal urinary sulfatide excretion. It is concluded that the neurologic abnormalities in the one sibling are not the result of the low enzyme activity and that both individuals represent examples of pseudo arylsulfatase A deficiency (arylsulfatase A deficiency without metachromatic leukodystrophy). These results thus call into question the ability of the high-sensitivity cerebroside sulfate loading test as carried out in MEM-HEPES media to differentiate pathologically significant defects i.e., metachromatic leukodystrophy from benign "pseudo-deficiencies."

Cerebroside sulfatase activity in cultivated human skin fibroblasts and amniotic fluid cells

In an effort to improve the precision in prenatal monitoring for metachromatic leukodystrophy, levels of cerebroside sulfatase were determined in fibroblasts and amniotic fluid cells. Cells from MLD patients demonstrated no significant sulfatide hydrolysis, whereas cultures from heterozygous subjects hydrolyzed diminished but definite amounts of sulfatide. Cells from a fetus with low arylsulfatase A activity were able to cleave considerable amounts of sulfatide; enzyme assays performed postnatally suggest that the infant is heterozygous for MLD. This report documents the value of cerebroside sulfatase assays in the in utero monitoring for MLD.