A closer look at ARSA activity in a patient with metachromatic leukodystrophy.

Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease mainly caused by a deficiency of arylsulfatase A activity. The typical clinical course of patients with the late infantile form includes a regression in motor skills with progression to dysphagia, seizures, hypotonia and death. We present a case of a 4-year-old female with rapidly progressive developmental regression with loss of motor milestones, spasticity and dysphagia. MRI showed volume loss and markedly abnormal deep white matter. Enzymatic testing in one laboratory showed arylsulfatase A activity in their normal range. However, extraction of urine showed a large increase in sulfatide excretion in a second laboratory. Measurement of arylsulfatase A in that laboratory showed a partial decrease in arylsulfatase A activity measured under typical conditions (about 37% of the normal mean). When the concentration of substrate in the assay was lowered to one quarter of that normally used, this individual had activity \u3c10% of controls. The patient was found to be homozygous for an unusual missense mutation in the arylsulfatase A gene confirming the diagnosis of MLD. This case illustrates the importance of careful biochemical and molecular testing for MLD if there is suspicion of this diagnosis

Accumulation of lysosulfatide in the brain of arylsulfatase A-deficient mice

Lysosomal storage diseases are a group of disorders where accumulation of catabolites is manifested in the lysosomes of different cell types. In metachromatic leukodystrophy (Arylsulfatase A [EC.3.1.6.8] deficiency) storage of the glycosphingolipid sulfatide in the brain leads to demyelination, resulting in neuromotor co-ordination deficits and regression. In a mouse model for metachromatic leukodystrophy, the ASA null mutant mouse, the accumulation of sulfatide in correlation to phenotype has been thoroughly investigated. Another lipid species reported to accumulate in patients with metachromatic leukodystrophy is the sulfatide related lipid lysosulfatide. Lysosulfatide was shown to be a cytotoxic compound in cell culture experiments and thus suggested to be involved in the pathology of metachromatic leukodystrophy. In this study, we further investigated the developmental profile of lysosulfatide in the brain of ASA null mutant mice by using high performance liquid chromatography. Lysosulfatide could be detected in the brain of normal mice (ASA +/+) from 1.8 months up to 23.1 months of age. From the age of 8.8 months the lysosulfatide levels remained constant at 1 pmol/mg wet tissue. The developmental change (< 20 months) of brain lysosulfatide showed an accumulation in ASA null mutant mice at ages above one month compared to its normal counterpart (ASA +/+). Thus, the ASA null mutant mouse might be a suitable model to further investigate the role of lysosulfatide in the pathogenesis of metachromatic leukodystrophy

Atidarsagene autotemcel for metachromatic leukodystrophy

Metachromatic leukodystrophy (MLD) is a rare autosomal recessive disorder of sphingolipid metabolism, due to a deficiency of the enzyme arylsulfatase A (ARSA). The main clinical signs of the disease are secondary to central and peripheral nervous system demyelination. MLD is subdivided into early and lateonset subtypes based upon the onset of neurological disease. The earlyonset subtype is associated with a more rapid progression of the disease that leads to death within the first decade of life. Until recently, no effective treatment was available for MLD. The blood–brain barrier (BBB) prevents systemically administered enzyme replacement therapy from reaching target cells in MLD. The evidence for the efficacy of hematopoietic stem cell transplantation is limited to the lateonset MLD subtype. Here, we review the preclinical and clinical studies that facilitated the approval of the ex vivo gene therapy atidarsagene autotemcel for earlyonset MLD by the European Medicines Agency (EMA) in December 2020. This approach was studied in an animal model first and then in a clinical trial, eventually proving its efficacy in preventing disease manifestations in presymptomatic patients and stabilizing its progression in paucisymptomatic subjects. This new therapeutic consists of patients’ CD34+ hematopoietic stem/progenitor cells (HSPCs) transduced with a lentiviral vector encoding functional ARSA cDNA. The genecorrected cells get reinfused into the patients after a cycle of chemotherapy conditioning

Kinetika i aktivnost leukocitne arilsulfataze A u osoba s dijagnozom cerebralne paralize

Activity and kinetics of arylsulfatase A (ASA, EC 3.1.6.8) were analyzed in leukocyte homogenates derived from patients suffering from cerebral palsy. Lower ASA activity was found in the patients\u27 leukocytes than in controls, as determined by spectrophotometry using chromogenic substrate p-nitrocatechol sulfate (p-NCS). Kinetic parameters, Km and vmax, for leukocyte ASA were determined from the dependence of initial reaction velocities on the p-NCS concentrations. A slight difference in Km values was found for leukocyte enzyme in cerebral palsy (0.26 mmol L-1) compared to the control (0.21 mmol L-1), whereas max-1 value for leukocyte ASA in disease reached only 58% of the control value. In addition, the presence of the most common mutations associated with ASA pseudodeficiency (N350S, 1524+95 A>G) and metachromatic leukodystrophy (P426L) was detected in all investigated patients. Changes in activity and kinetic parameters of leukocyte ASA in cerebral palsy are most probably related to the decrease of enzyme concentration; the detected mutations might at least partially contribute to the observed changes.Analizirane su aktivnost i kinetika arilsulfataze A (ASA, EC 3.1.6.8) u leukocitnim homogenatima osoba oboljelih od cerebralne paralize. Spektrofotometrijskim određivanjem aktivnosti ASA prema kromogenom supstratu p-nitrokatehol sulfatu (p-NCS) utvrđene su manje aktivnosti enzima u leukocitima oboljelih osoba. Kinetički parametri, Km i vmax, leukocitne ASA određeni su iz ovisnosti početne brzine reakcije o koncentraciji p-NCS. Utvrđena je manja razlika između Km vrijednosti enzima zdravih (0,21 mmol L-1) i oboljelih osobal (0.26 mmol L-1), dok je vrijednost vmax enzima iznosila 58% vrijednosti vmax enzima zdravih osoba. Također je u svih ispitanika s dijagnozom cerebralne paralize utvrđeno prisustvo najčešći mutacija povezanih s ASA pseudodeficijencijom (N350S, 1524+95 A>G) i metakromatskom leukodistrofijom (P426L). promjene aktivnosti i kinetičkih parametara leukocitne ASA u cerebralnoj parealizi najvjerojatnije su posljedica snižene koncentracije enzima; moguće je da nađene mutacije barem djelomično doprinose zapaženim promjenama

Population Carrier Rates of Pathogenic ARSA Gene Mutations: Is Metachromatic Leukodystrophy Underdiagnosed?

BACKGROUND: Metachromatic leukodystrophy (MLD) is a severe neurometabolic disease caused mainly by deficiency of arylsulfatase A encoded by the ARSA gene. Based on epidemiological surveys the incidence of MLD per 100,000 live births varied from 0.6 to 2.5. Our purpose was to estimate the birth prevalence of MLD in Poland by determining population frequency of the common pathogenic ARSA gene mutations and to compare this estimate with epidemiological data. METHODOLOGY: We studied two independently ascertained cohorts from the Polish background population (N∼3000 each) and determined carrier rates of common ARSA gene mutations: c.459+1G>A, p.P426L, p.I179S (cohort 1) and c.459+1G>A, p.I179S (cohort 2). PRINCIPAL FINDINGS: Taking into account ARSA gene mutation distribution among 60 Polish patients, the expected MLD birth prevalence in the general population (assuming no selection against homozygous fetuses) was estimated as 4.0/100,000 and 4.1/100,000, respectively for the 1(st) and the 2(nd) cohort with a pooled estimate of 4.1/100,000 (CI: 1.8-9.4) which was higher than the estimate of 0.38 per 100,000 live births based on diagnosed cases. The p.I179S mutation was relatively more prevalent among controls than patients (OR = 3.6, P = 0.0082, for a comparison of p.I179S frequency relative to c.459+1G>A between controls vs. patients). CONCLUSIONS/SIGNIFICANCE: The observed discrepancy between the measured incidence of metachromatic leukodystrophy and the predicted carriage rates suggests that MLD is substantially underdiagnosed in the Polish population. The underdiagnosis rate may be particularly high among patients with p.I179S mutation whose disease is characterized mainly by psychotic symptoms

Modified Delphi procedure-based expert consensus on endpoints for an international disease registry for Metachromatic Leukodystrophy:The European Metachromatic Leukodystrophy initiative (MLDi)

BACKGROUND: Metachromatic Leukodystrophy (MLD) is a rare lysosomal disorder. Patients suffer from relentless neurological deterioration leading to premature death. Recently, new treatment modalities, including gene therapy and enzyme replacement therapy, have been developed. Those advances increase the need for high-quality research infrastructure to adequately compare treatments, execute post-marketing surveillance, and perform health technology assessments (HTA). To facilitate this, a group of MLD experts started the MLD initiative (MLDi) and initiated an academia-led European MLD registry: the MLDi. An expert-based consensus procedure, namely a modified Delphi procedure, was used to determine the data elements required to answer academic, regulatory, and HTA research questions. RESULTS: Three distinct sets of data elements were defined by the 13-member expert panel. The minimal set (n = 13) contained demographics and basic disease characteristics. The core set (n = 55) included functional status scores in terms of motor, manual, speech and eating abilities, and causal and supportive treatment characteristics. Health-related quality of life scores were included that were also deemed necessary for HTA. The optional set (n = 31) contained additional clinical aspects, such as findings at neurological examination, detailed motor function, presence of peripheral neuropathy, gall bladder involvement and micturition. CONCLUSION: Using a modified Delphi procedure with physicians from the main expert centers, consensus was reached on a core set of data that can be collected retrospectively and prospectively. With this consensus-based approach, an important step towards harmonization was made. This unique dataset will support knowledge about the disease and facilitate regulatory requirements related to the launch of new treatments. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13023-022-02189-w

The clinical features and diagnosis of Metachromatic leukodystrophy: A case series of Iranian Pediatric patients

How to Cite This Article: Jabbehdari S, Rahimian E, Jafari N, Sanii S, Khayatzadeh Kakhki S, Nejad Biglari H. The Clinical Features and Diagnosis of Metachromatic Leukodystrophy: A Case Series of Iranian Pediatric Patients. Iran J Child Neurol. Summer 2015;9(3):57-61.AbstractObjectiveMetachromatic leukodystrophy disorder (MLD) is one of the rare neurometabolicdiseases caused due to lack of saposin B and arylsulfatase A enzyme deficiency.Materials &amp; MethodsEighteen patients diagnosed as metachromatic leukodystrophy in the NeurologyDepartment of Mofid Children’s Hospital in Tehran, Iran between 2010 and2014 were included in our study. The disorder was confirmed by clinical,EMG-NCV, arylsulfatase A enzyme checking and neuroimaging findings alongwith neurometabolic and genetic assessment from reference laboratory in Iran.We assessed age, gender, past medical history, developmental status, clinicalmanifestations, and neuroimaging findings of 18 patients with metachromaticleukodystrophy.ResultsFrom 18 patients, 80% were offspring from consanguineous marriages. A familyhistory of metachromatic leukodystrophy disease was positive for four patients.Twelve patients had late infantile form of this disorder and six patients had juvenile form. A history of tonic type seizure was positive in 20% of the patients and tonic spasm was confirmed with clinical information. Electromyographgraphy (EMG) in 96% of patients was abnormal with demyelinating sensorimotor neuropathy pattern. MRI in all patients showed the leukodystrophic pattern as arcuate fibers sparing and subcortical rim in white matter and periventricular involvement. Our diagnosis was confirmed by EMG-NCV findings with sensorimotor neuropathy pattern and the assessment of arylsulfatase A enzyme function. ConclusionMLD is an inheritance metabolic disorder, which was confirmed by theassessment of arylsulfatase A enzyme function, peripheral blood leukocyte thatassessed in a referral laboratory in Iran

Animal models of leukodystrophy : a new perspective for the development of therapies

The leukodystrophies are a family of heritable disorders characterised by white matter degeneration, accompanied by variable clinical symptoms including loss of motor function and cognitive decline. Now thought to include over fifty distinct disorders, there are a vast array of mechanisms underlying the pathology of these monogenic conditions and, accordingly, a range of animal models relating to each disorder. While both murine and zebrafish models continue to aid in the development of potential therapies, many of these models fail to truly recapitulate the human condition—thus leaving substantial weaknesses in our understanding of leukodystrophy pathogenesis. Additionally, the heterogeneity in leukodystrophy presentation—both in patients and in vivo models—often results in a narrow focus on single disorders in isolation across much of the literature. Thus, this review aims to synthesise prominent research regarding the most common leukodystrophies in order to provide an overview of key animal models and their utility in developing novel treatments. We begin by discussing the ongoing revolution across the leukodystrophy field following the rise of next generation sequencing, before focusing more extensively on existing animal models from the mouse and zebrafish fields. Finally, we explore how these pre‐clinical models have shaped the development of therapeutic strategies currently in development. We propose future directions for the field and suggest a more critical view of the dogma which has underpinned leukodystrophy research for decades

Gallbladder polyps in association with metachromatic leukodystrophy

Polypoid lesions of the gallbladder (PLG) are rare in the paediatric population. Growth in technology with the availability of high-quality ultrasonography and in the experience of radiologists in detecting such lesions, has led to an increase in incidental detection of PLG. In children, the occur either as a primary disorder or in association with other conditions, including metachromatic leukodystrophy, Peutz- Jeghers syndrome, or pancreatobiliary malunion [1]. Due the rarity of these lesions in the paediatric age group, accurate management algorithms are inherited from the adult population. In these, PLG is a more common pathology, occurring in 4\u20137% of patients undergoing ultrasonography, with clinical significance relating largely to their malignant potential [2,3]