RESUMEN
Biallelic variants in SUMF1 are associated with multiple sulfatase deficiency (MSD), a rare lysosomal storage disorder typically diagnosed in early infancy or childhood, marked by severe neurodegeneration and early mortality. We present clinical and molecular characterisation of three unrelated patients aged 13 to 58 years with milder clinical manifestations due to SUMF1 disease variants, including two adult patients presenting with apparent non-syndromic retinal dystrophy. Whole genome sequencing identified biallelic SUMF1 variants in all three patients; Patient 1 homozygous for a complex allele c.[290G>T;293T>A]; p.[(Gly97Val);(Val98Glu)], Patient 2 homozygous for c.866A>G; p.(Tyr289Cys), and Patient 3 compound heterozygous for c.726-1G>C and p.(Tyr289Cys). Electroretinography indicated a rod-cone dystrophy with additional possible inner retinal dysfunction in all three patients. Biochemical studies confirmed reduced, but not absent, sulfatase enzyme activity in the absence of extra-ocular disease (Patient 1) or only mild systemic disease (Patients 2, 3). These cases are suggestive that non-null SUMF1 genotypes can cause an attenuated clinical phenotype, including retinal dystrophy without systemic complications, in adulthood.
Asunto(s)
Alelos , Distrofias Retinianas , Sulfatasas , Humanos , Masculino , Femenino , Adulto , Adolescente , Distrofias Retinianas/genética , Distrofias Retinianas/patología , Persona de Mediana Edad , Sulfatasas/genética , Sulfatasas/deficiencia , Leucocitos/patología , Leucocitos/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética , Enfermedad por Deficiencia de Múltiples Sulfatasas/genética , Enfermedad por Deficiencia de Múltiples Sulfatasas/patología , Mutación , Fenotipo , Adulto Joven , Secuenciación Completa del Genoma , GenotipoRESUMEN
Sulfatases catalyze essential cellular reactions, including degradation of glycosaminoglycans (GAGs). All sulfatases are post-translationally activated by the formylglycine generating enzyme (FGE) which is deficient in multiple sulfatase deficiency (MSD), a neurodegenerative lysosomal storage disease. Historically, patients were presumed to be deficient of all sulfatase activities; however, a more nuanced relationship is emerging. Each sulfatase may differ in their degree of post-translational modification by FGE, which may influence the phenotypic spectrum of MSD. Here, we evaluate if residual sulfatase activity and accumulating GAG patterns distinguish cases from controls and stratify clinical severity groups in MSD. We quantify sulfatase activities and GAG accumulation using three complementary methods in MSD participants. Sulfatases differed greatly in their tolerance of reduction in FGE-mediated activation. Enzymes that degrade heparan sulfate (HS) demonstrated lower residual activities than those that act on other GAGs. Similarly, HS-derived urinary GAG subspecies preferentially accumulated, distinguished cases from controls, and correlated with disease severity. Accumulation patterns of specific sulfatase substrates in MSD provide fundamental insights into sulfatase regulation and will serve as much-needed biomakers for upcoming clinical trials. This work highlights that biomarker investigation of an ultra-rare disease can simultaneously inform our understanding of fundamental biology and advance clinical trial readiness efforts.
Asunto(s)
Enfermedades por Almacenamiento Lisosomal , Enfermedad por Deficiencia de Múltiples Sulfatasas , Humanos , Enfermedad por Deficiencia de Múltiples Sulfatasas/genética , Sulfatasas , Glicosaminoglicanos , Heparitina Sulfato , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro , Gravedad del PacienteRESUMEN
Multiple sulfatase deficiency (MSD) is an ultra-rare, inherited lysosomal storage disease caused by mutations in the gene sulfatase modifying factor 1 (SUMF1). MSD is characterized by the functional deficiency of all sulfatase enzymes, leading to the storage of sulfated substrates including glycosaminoglycans (GAGs), sulfolipids, and steroid sulfates. Patients with MSD experience severe neurological impairment, hearing loss, organomegaly, corneal clouding, cardiac valve disease, dysostosis multiplex, contractures, and ichthyosis. Here, we generated a novel human model of MSD by reprogramming patient peripheral blood mononuclear cells to establish an MSD induced pluripotent stem cell (iPSC) line (SUMF1 p.A279V). We also generated an isogenic control iPSC line by correcting the pathogenic variant with CRISPR/Cas9 gene editing. We successfully differentiated these iPSC lines into neural progenitor cells (NPCs) and NGN2-induced neurons (NGN2-iN) to model the neuropathology of MSD. Mature neuronal cells exhibited decreased SUMF1 gene expression, increased lysosomal stress, impaired neurite outgrowth and maturation, reduced sulfatase activities, and GAG accumulation. Interestingly, MSD iPSCs and NPCs did not exhibit as severe of phenotypes, suggesting that as neurons differentiate and mature, they become more vulnerable to loss of SUMF1. In summary, we demonstrate that this human iPSC-derived neuronal model recapitulates the cellular and biochemical features of MSD. These cell models can be used as tools to further elucidate the mechanisms of MSD pathology and for the development of therapeutics.
Asunto(s)
Células Madre Pluripotentes Inducidas , Enfermedad por Deficiencia de Múltiples Sulfatasas , Humanos , Leucocitos Mononucleares/metabolismo , Neuronas/patología , Sulfatasas , Oxidorreductasas actuantes sobre Donantes de Grupos SulfuroRESUMEN
BACKGROUND: Multiple sulfatase deficiency (MSD) is a rare lysosomal storage disorder caused due to pathogenic variants in the SUMF1 gene. The SUMF1 gene encodes for formylglycine generating enzyme (FGE) that is involved in the catalytic activation of the family of sulfatases. The affected patients present with a wide spectrum of clinical features including multi-organ involvement. To date, almost 140 cases of MSD have been reported worldwide, with only four cases reported from India. The present study describes two cases of late infantile form of MSD from India and the identification of a novel missense variant in the SUMF1 gene. CASE PRESENTATION: In case 1, a male child presented to us at the age of 6 years. The remarkable presenting features included ichthyosis, presence of irritability, poor social response, thinning of corpus callosum on MRI and, speech regression. Clinical suspicion of MSD was confirmed by enzyme analysis of two sulfatase enzymes followed by gene sequencing. We identified a novel missense variant c.860A > T (p.Asn287Ile) in exon 7 of the SUMF1 gene. In case 2, a two and a half years male child presented with ichthyosis, leukodystrophy and facial dysmorphism. We performed an enzyme assay for two sulfatases, which showed significantly reduced activities thereby confirming MSD diagnosis. CONCLUSION: Overall, present study has added to the existing data on MSD from India. Based on the computational analysis, the novel variant c.860A > T identified in this study is likely to be associated with a milder phenotype and prolonged survival.
Asunto(s)
Ictiosis , Enfermedad por Deficiencia de Múltiples Sulfatasas , Masculino , Humanos , Enfermedad por Deficiencia de Múltiples Sulfatasas/diagnóstico , Enfermedad por Deficiencia de Múltiples Sulfatasas/genética , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética , Mutación Missense , Sulfatasas/genéticaRESUMEN
Multiple sulfatase deficiency (MSD, MIM #272200) results from pathogenic variants in the SUMF1 gene that impair proper function of the formylglycine-generating enzyme (FGE). FGE is essential for the posttranslational activation of cellular sulfatases. MSD patients display reduced or absent sulfatase activities and, as a result, clinical signs of single sulfatase disorders in a unique combination. Up to date therapeutic options for MSD are limited and mostly palliative. We performed a screen of FDA-approved drugs using immortalized MSD patient fibroblasts. Recovery of arylsulfatase A activity served as the primary readout. Subsequent analysis confirmed that treatment of primary MSD fibroblasts with tazarotene and bexarotene, two retinoids, led to a correction of MSD pathophysiology. Upon treatment, sulfatase activities increased in a dose- and time-dependent manner, reduced glycosaminoglycan content decreased and lysosomal position and size normalized. Treatment of MSD patient derived induced pluripotent stem cells (iPSC) differentiated into neuronal progenitor cells (NPC) resulted in a positive treatment response. Tazarotene and bexarotene act to ultimately increase the stability of FGE variants. The results lay the basis for future research on the development of a first therapeutic option for MSD patients.
Asunto(s)
Enfermedad por Deficiencia de Múltiples Sulfatasas , Humanos , Enfermedad por Deficiencia de Múltiples Sulfatasas/diagnóstico , Enfermedad por Deficiencia de Múltiples Sulfatasas/genética , Enfermedad por Deficiencia de Múltiples Sulfatasas/patología , Bexaroteno , Evaluación Preclínica de Medicamentos , Sulfatasas/genética , Oxidorreductasas actuantes sobre Donantes de Grupos SulfuroRESUMEN
Multiple sulfatase deficiency (MSD) is an ultrarare lysosomal storage disorder due to deficiency of all known sulfatases. MSD is caused by mutations in the Sulfatase Modifying Factor 1 (SUMF1) gene encoding the enzyme responsible for the post-translational modification and activation of all sulfatases. Most MSD patients carry hypomorph SUMF1 variants resulting in variable degrees of residual sulfatase activities. In contrast, Sumf1 null mice with complete deficiency in all sulfatase enzyme activities, have very short lifespan with significant pre-wean lethality, owing to a challenging preclinical model. To overcome this limitation, we genetically engineered and characterized in mice two commonly identified patient-based SUMF1 pathogenic variants, namely p.Ser153Pro and p.Ala277Val. These pathogenic missense variants correspond to variants detected in patients with attenuated MSD presenting with partial-enzyme deficiency and relatively less severe disease. These novel MSD mouse models have a longer lifespan and show biochemical and pathological abnormalities observed in humans. In conclusion, mice harboring the p.Ser153Pro or the p.Ala277Val variant mimic the attenuated MSD and are attractive preclinical models for investigation of pathogenesis and treatments for MSD.
Asunto(s)
Enfermedades por Almacenamiento Lisosomal , Enfermedad por Deficiencia de Múltiples Sulfatasas , Humanos , Animales , Ratones , Enfermedad por Deficiencia de Múltiples Sulfatasas/genética , Mutación , Sulfatasas , Mutación Missense , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genéticaRESUMEN
Multiple Sulfatase Deficiency (MSD) is a rare autosomal recessive disease with specific clinical findings such as psychomotor retardation and neurological deterioration. No therapy is available for this genetic disorder. Previous studies have shown that N-acetyl-L-leucine (NALL) can improve the neurological inflammation in the cerebellum.In the current study, the effects of NALL on ataxia symptoms and quality of life were explored in a patient with MSD.This study was a crossover case study. The subject, a girl aged 12 years old, received NALL at a dose of 3 g/day (1 g in the morning, 1 g in the afternoon, and 1 g in the evening). A fasting blood sample was taken from the subject to evaluate side effects before the intervention and 4 weeks after taking supplement/placebo in every study stage. The ataxia moving symptoms were evaluated using the Scale for the Assessment and Rating of Ataxia (SARA) score in every study stage. Dietary intake was measured using 24-h dietary recall before and after the intervention. The diet compositions were assessed by Nutritionist IV software. Serum IL-6 level was measured using an ELISA kit.There was no significant change in complete blood count (CBC) and serum biochemical factors in the patient with MSD after receiving NALL (3 g/day) over 4 weeks. The SARA score was reduced by 25%. The gait whose maximum score accounts for approximately one-fifth of the maximum total SARA score (8/40) was decreased. The heel-to-shin slide, the only SARA item performed without visual control, was also improved after therapy. Furthermore, there was a downward trend in the 8MWT (8.71 to 7.93 s). Regarding quality of life assessments, the parent and child reported improved quality of life index, physical health, and emotional function after taking NALL. Moreover, total energy intake was increased with NALL treatment through the study period.Supplementation with NALL at a dose of 3 g/day over 4 weeks was well tolerated and improved ataxia symptoms, quality of life measure, and serum IL-6 levels in the patient with MSD. Further proof-of-concept trials are warranted to confirm the present findings.
Asunto(s)
Ataxia Cerebelosa , Enfermedad por Deficiencia de Múltiples Sulfatasas , Niño , Femenino , Humanos , Calidad de Vida , Interleucina-6/uso terapéutico , Ataxia Cerebelosa/tratamiento farmacológico , AtaxiaRESUMEN
BACKGROUND: Multiple sulfatase deficiency (MSD) (MIM#272200) is an ultra-rare autosomal recessive lysosomal storage disorder caused by mutation of the Sulfatase Modifying Factor 1 (SUMF1) gene. METHODS: Herein, we report an eight-year-old boy with a late infantile form of multiple sulfatase deficiency. A combination of copy-number variation sequencing (CNV-seq) and whole-exome sequencing (WES) were used to analyze the genetic cause for the MSD patient. RESULTS: Our results, previously not seen in China, show a novel compound heterozygous mutation with one allele containing a 240.55 kb microdeletion on 3p26.1 encompassing the SETMAR gene and exons 4-9 of the SUMF1 gene, and the other allele containing a novel missense mutation of c.671G>A (p.Arg224Gln) in the SUMF1 gene. Both were inherited from the proband's unaffected parents, one from each. Bioinformatics analyses show the novel variation to be "likely pathogenic." SWISS-MODEL analysis shows that the missense mutation may alter the three-dimensional (3D) structure. CONCLUSIONS: In summary, this study reported a novel compound heterozygous with microdeletion in SUMF1 gene, which has not been reported in China. The complex clinical manifestations of MSD may delay diagnosis; however, molecular genetic analysis of the SUMF1 gene can be performed to help obtain an early diagnosis.
Asunto(s)
Enfermedad por Deficiencia de Múltiples Sulfatasas , Masculino , Humanos , Niño , Enfermedad por Deficiencia de Múltiples Sulfatasas/genética , Enfermedad por Deficiencia de Múltiples Sulfatasas/diagnóstico , Sulfatasas/genética , Mutación/genética , Mutación Missense , Biología Computacional , N-Metiltransferasa de Histona-Lisina/genética , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genéticaRESUMEN
Multiple sulfatase deficiency (MSD) is an ultra-rare neurodegenerative disorder caused by pathogenic variants in SUMF1. This gene encodes formylglycine-generating enzyme (FGE), a protein required for sulfatase activation. The clinical course of MSD results from additive effect of each sulfatase deficiency, including metachromatic leukodystrophy (MLD), several mucopolysaccharidoses (MPS II, IIIA, IIID, IIIE, IVA, VI), chondrodysplasia punctata, and X-linked ichthyosis. While it is known that affected individuals demonstrate a complex and severe phenotype, the genotype-phenotype relationship and detailed clinical course is unknown. We report on 35 cases enrolled in our retrospective natural history study, n = 32 with detailed histories. Neurologic function was longitudinally assessed with retrospective scales. Biochemical and computational modeling of novel SUMF1 variants was performed. Genotypes were classified based on predicted functional change, and each individual was assigned a genotype severity score. The median age at symptom onset was 0.25 years; median age at diagnosis was 2.7 years; and median age at death was 13 years. All individuals demonstrated developmental delay, and only a subset of individuals attained ambulation and verbal communication. All subjects experienced an accumulating systemic symptom burden. Earlier age at symptom onset and severe variant pathogenicity correlated with poor neurologic outcomes. Using retrospective deep phenotyping and detailed variant analysis, we defined the natural history of MSD. We found that attenuated cases can be distinguished from severe cases by age of onset, attainment of ambulation, and genotype. Results from this study can help inform prognosis and facilitate future study design.
Asunto(s)
Leucodistrofia Metacromática/genética , Mucopolisacaridosis/genética , Enfermedad por Deficiencia de Múltiples Sulfatasas/genética , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética , Adolescente , Niño , Preescolar , Femenino , Genotipo , Glicina/análogos & derivados , Glicina/genética , Glicina/metabolismo , Humanos , Lactante , Internacionalidad , Leucodistrofia Metacromática/patología , Masculino , Mucopolisacaridosis/patología , Enfermedad por Deficiencia de Múltiples Sulfatasas/patología , Mutación , Fenotipo , Enfermedades Raras , Estudios Retrospectivos , Sulfatasas/deficiencia , Sulfatasas/genéticaRESUMEN
Multiple Sulfatase Deficiency (MSD) is an inborn error of metabolism caused by pathogenic variants in the SUMF1 gene encoding the formylglycine-generating enzyme (FGE) that activates all known sulfatases. FGE deficiency results in widespread tissue accumulation of multiple sulphated substrates. Through a systematic analysis of published cases, we retrieved 80 MSD cases and reviewed the disease clinical, biochemical, and genetic findings. Leukodystrophy, neurosensorial hearing loss, and ichthyosis were the most frequent findings at diagnosis. Of 51 reported pathogenic variants, 20 were likely gene disruptive and the remaining were missense variants. No correlations between class of variants and clinical severity or degree of enzyme deficiency were detected. However, cases harboring variants located at N-terminal always had severe neonatal presentations. Moreover, cases with neonatal onset showed the lowest overall survival rate compared to late-infantile and juvenile onsets. Using GnomAD, carrier frequency for pathogenic SUMF1 variants was estimated to be ~1/700 and the disease prevalence was approximately 1/2,000,000. In summary, MSD is an ultra-rare multisystem disorder with mainly neurologic, hearing and skin involvements. Although the collected data were retrospective and heterogenous, the quantitative data inform the disease natural history and are important for both counseling and design of future interventional studies.
Asunto(s)
Enfermedad por Deficiencia de Múltiples Sulfatasas/diagnóstico , Mutación , Sulfatasas/deficiencia , Sulfatasas/genética , Adolescente , Niño , Preescolar , Estudios Transversales , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Masculino , Enfermedad por Deficiencia de Múltiples Sulfatasas/enzimología , Enfermedad por Deficiencia de Múltiples Sulfatasas/genética , Pronóstico , Tasa de Supervivencia , Revisiones Sistemáticas como AsuntoRESUMEN
Multiple Sulfatase Deficiency (MSD, MIM#272200) is an ultra-rare lysosomal storage disorder arising from mutations in the SUMF1 gene, which encodes the formylglycine-generating enzyme (FGE). FGE is necessary for the activation of sulfatases, a family of enzymes that are involved in the degradation of sulfated substrates such as glycosaminoglycans and sulfolipids. SUMF1 mutations lead to functionally impaired FGE and individuals with MSD demonstrate clinical signs of single sulfatase deficiencies, including metachromatic leukodystrophy (MLD) and several mucopolysaccharidosis (MPS) subtypes. Comprehensive information related to the natural history of MSD is missing. We completed a systematic literature review and a meta-analysis on data from published cases reporting on MSD. As available from these reports, we extracted clinical, genetic, biochemical, and brain imaging information. We identified 75 publications with data on 143 MSD patients with a total of 53 unique SUMF1 mutations. The mean survival was 13 years (95% CI 9.8-16.2 years). Seventy-five clinical signs and 11 key clusters of signs were identified. The most frequently affected organs systems were the nervous, skeletal, and integumentary systems. The most frequent MRI features were abnormal myelination and cerebral atrophy. Individuals with later onset MSD signs and survived longer than those with signs at birth. Less severe mutations, low disease burden and achievement of independent walking positively correlated with longer survival. Despite the limitations of our approach, we were able to define clinical characteristics and disease outcomes in MSD. This work will provide the foundation of natural disease history data needed for future clinical trial design.
Asunto(s)
Leucodistrofia Metacromática/genética , Mucopolisacaridosis/genética , Enfermedad por Deficiencia de Múltiples Sulfatasas/genética , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética , Glicina/análogos & derivados , Glicina/genética , Glicina/metabolismo , Humanos , Leucodistrofia Metacromática/patología , Mucopolisacaridosis/patología , Enfermedad por Deficiencia de Múltiples Sulfatasas/patología , Procesamiento Proteico-Postraduccional/genética , Sulfatasas/deficiencia , Sulfatasas/genéticaRESUMEN
Multiple sulfatase deficiency (MSD, MIM #272200) is an ultra-rare disease comprising pathophysiology and clinical features of mucopolysaccharidosis, sphingolipidosis and other sulfatase deficiencies. MSD is caused by impaired posttranslational activation of sulfatases through the formylglycine generating enzyme (FGE) encoded by the sulfatase modifying factor 1 (SUMF1) gene, which is mutated in MSD. FGE is a highly conserved, non-redundant ER protein that activates all cellular sulfatases by oxidizing a conserved cysteine in the active site of sulfatases that is necessary for full catalytic activity. SUMF1 mutations result in unstable, degradation-prone FGE that demonstrates reduced or absent catalytic activity, leading to decreased activity of all sulfatases. As the majority of sulfatases are localized to the lysosome, loss of sulfatase activity induces lysosomal storage of glycosaminoglycans and sulfatides and subsequent cellular pathology. MSD patients combine clinical features of all single sulfatase deficiencies in a systemic disease. Disease severity classifications distinguish cases based on age of onset and disease progression. A genotype- phenotype correlation has been proposed, biomarkers like excreted storage material and residual sulfatase activities do not correlate well with disease severity. The diagnosis of MSD is based on reduced sulfatase activities and detection of mutations in SUMF1. No therapy exists for MSD yet. This review summarizes the unique FGE/ sulfatase physiology, pathophysiology and clinical aspects in patients and their care and outlines future perspectives in MSD.
Asunto(s)
Mucopolisacaridosis/genética , Enfermedad por Deficiencia de Múltiples Sulfatasas/genética , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética , Esfingolipidosis/genética , Glicina/análogos & derivados , Glicina/genética , Glicina/metabolismo , Humanos , Mucopolisacaridosis/patología , Enfermedad por Deficiencia de Múltiples Sulfatasas/patología , Mutación/genética , Procesamiento Proteico-Postraduccional/genética , Esfingolipidosis/patología , Sulfatasas/deficiencia , Sulfatasas/genéticaRESUMEN
BACKGROUND: Multiple sulfatase deficiency (MSD, MIM #272200) is an ultrarare congenital disorder caused by SUMF1 mutation and often misdiagnosed due to its complex clinical presentation. Impeded by a lack of natural history, knowledge gained from individual case studies forms the source for a reliable diagnosis and consultation of patients and parents. METHODS: We collected clinical records as well as genetic and metabolic test results from two MSD patients. The functional properties of a novel SUMF1 variant were analyzed after expression in a cell culture model. RESULTS: We report on two MSD patients-the first neonatal type reported in Israel-both presenting with this most severe manifestation of MSD. Our patients showed uniform clinical symptoms with persistent pulmonary hypertension, hypotonia, and dysmorphism at birth. Both patients were homozygous for the same novel SUMF1 mutation (c.1043C>T, p.A348V). Functional analysis revealed that the SUMF1-encoded variant of formylglycine-generating enzyme is highly instable and lacks catalytic function. CONCLUSION: The obtained results confirm genotype-phenotype correlation in MSD, expand the spectrum of clinical presentation and are relevant for diagnosis including the extremely rare neonatal severe type of MSD.
Asunto(s)
Enfermedad por Deficiencia de Múltiples Sulfatasas/genética , Mutación Missense , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética , Fenotipo , Línea Celular Tumoral , Preescolar , Estabilidad de Enzimas , Homocigoto , Humanos , Lactante , Masculino , Enfermedad por Deficiencia de Múltiples Sulfatasas/patología , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/metabolismoRESUMEN
Liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays were developed to measure arylsulfatase A (ARSA) activity in leukocytes and dried blood spots (DBS) using deuterated natural sulfatide substrate. These new assays were highly specific and sensitive. Patients with metachromatic leukodystrophy (MLD) and multiple sulfatase deficiency (MSD) displayed a clear deficit in the enzymatic activity and could be completely distinguished from normal controls. The leukocyte assay reported here will be important for diagnosing MLD and MSD patients and for monitoring the efficacy of therapeutic treatments. ARSA activity was measured in DBS for the first time without an antibody. This new ARSA DBS assay can serve as a second-tier test following the sulfatide measurement in DBS for newborn screening of MLD. This leads to an elimination of most of the false positives identified by the sulfatide assay.
Asunto(s)
Cerebrósido Sulfatasa/análisis , Pruebas con Sangre Seca , Leucocitos/enzimología , Leucodistrofia Metacromática/sangre , Enfermedad por Deficiencia de Múltiples Sulfatasas/sangre , Cerebrósido Sulfatasa/metabolismo , Cromatografía Liquida , Humanos , Leucodistrofia Metacromática/diagnóstico , Leucodistrofia Metacromática/enzimología , Estructura Molecular , Enfermedad por Deficiencia de Múltiples Sulfatasas/diagnóstico , Enfermedad por Deficiencia de Múltiples Sulfatasas/enzimología , Sulfoglicoesfingolípidos/química , Espectrometría de Masas en TándemRESUMEN
Metachromatic Leukodystrophy (MLD) and Multiple Sulfatase Deficiency (MSD) are rare and ultra-rare lysosomal storage diseases. Due to enzyme defects, patients are unable to split the sulfategroup from the respective substrates. In MSD all sulfatases are affected due to a defect of the Sulfatase Modifying Factor 1 (SUMF1) gene coding for the formylglycine generating enzyme (FGE) necessary for the modification of the active site of sulfatases. In MLD mutations in the arylsulfatase A (ARSA) gene cause ARSA deficiency with subsequent accumulation of 3-sulfogalactocerebroside especially in oligodendrocytes. The clinical consequence is demyelination and a devastating neurological disease. Enzyme replacement therapy (ERT) with recombinant human arylsulfatase A (rhARSA), gene therapy, and stem cell transplantation are suggested as new therapeutic options. The aim of our study was to characterize rhARSA concerning its substrate specificity using analytical isotachophoresis (ITP). Substrate specificity could be demonstrated by sulfate splitting from the natural substrates 3-sulfogalactocerebroside and ascorbyl-2-sulfate and the artificial substrate p-nitrocatecholsulfate, whereas galactose-6-sulfate, a substrate of galactose-6sulfurylase, was totally resistant. In contrast, leukocyte extracts of healthy donors were able to split sulfate also from galactose-6-sulfate. The ITP method allows therefore a rapid and simple differentiation between samples of MLD and MSD patients and healthy donors. Therefore, the isotachophoretic diagnostic assay from leukocyte extracts described here provides a fast and efficient way for the diagnosis of MLD and MSD patients and an elegant system to differentiate between these diseases in one assay.
Asunto(s)
Cerebrósido Sulfatasa/química , Pruebas de Enzimas/métodos , Isotacoforesis/métodos , Leucocitos/enzimología , Leucodistrofia Metacromática/enzimología , Enfermedad por Deficiencia de Múltiples Sulfatasas/enzimología , Sulfatasas/química , Cerebrósido Sulfatasa/genética , Cerebrósido Sulfatasa/metabolismo , Humanos , Cinética , Leucodistrofia Metacromática/diagnóstico , Leucodistrofia Metacromática/genética , Enfermedad por Deficiencia de Múltiples Sulfatasas/diagnóstico , Enfermedad por Deficiencia de Múltiples Sulfatasas/genética , Proteínas Recombinantes/análisis , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Sulfatasas/genética , Sulfatasas/metabolismo , Sulfatos/química , Sulfatos/metabolismoRESUMEN
Multiple sulfatase deficiency is an autosomal recessive lysosomal storage disorder due to a deficiency in formylglycine-generating enzyme, which is encoded by the Sulfatase Modifying Factor 1 ( SUMF1) gene. Clinically, the disorder is variable. The most common characteristics are developmental regression, intellectual disability, ichthyosis, and periventricular white matter disease. Herein, we report 6 Saudi patients with multiple sulfatase deficiency caused by a novel homozygous missense mutation in the SUMF1 gene (NM_182760.3; c.785A>G [p.Gln262Arg]). The patients are 2 females and 4 males between 5 and 13 years of age, with an age of onset of 1 to 3 years. All patients are consanguineous and suffer from developmental regression, intellectual disability, ichthyosis, and periventricular white matter disease. This cohort differs from previous cohorts because of the absence of organomegaly and skeletal abnormalities.
Asunto(s)
Enfermedad por Deficiencia de Múltiples Sulfatasas/genética , Mutación/genética , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética , Adolescente , Encéfalo/diagnóstico por imagen , Niño , Preescolar , Estudios de Cohortes , Consanguinidad , Electroencefalografía , Femenino , Humanos , Ictiosis/complicaciones , Ictiosis/genética , Discapacidad Intelectual/etiología , Imagen por Resonancia Magnética , Masculino , Enfermedad por Deficiencia de Múltiples Sulfatasas/complicaciones , Enfermedad por Deficiencia de Múltiples Sulfatasas/diagnóstico por imagen , Arabia Saudita , Tomografía Computarizada por Rayos XRESUMEN
Multiple sulfatase deficiency (MSD) is a fatal, inherited lysosomal storage disorder characterized by reduced activities of all sulfatases in patients. Sulfatases require a unique post-translational modification of an active-site cysteine to formylglycine that is catalyzed by the formylglycine-generating enzyme (FGE). FGE mutations that affect intracellular protein stability determine residual enzyme activity and disease severity in MSD patients. Here, we show that protein disulfide isomerase (PDI) plays a pivotal role in the recognition and quality control of MSD-causing FGE variants. Overexpression of PDI reduces the residual activity of unstable FGE variants, whereas inhibition of PDI function rescues the residual activity of sulfatases in MSD fibroblasts. Mass spectrometric analysis of a PDI+FGE variant covalent complex allowed determination of the molecular signature for FGE recognition by PDI. Our findings highlight the role of PDI as a disease modifier in MSD, which may also be relevant for other ER-associated protein folding pathologies.
Asunto(s)
Retículo Endoplásmico/metabolismo , Glicina/análogos & derivados , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/metabolismo , Proteína Disulfuro Isomerasas/química , Proteína Disulfuro Isomerasas/metabolismo , Pliegue de Proteína , Secuencia de Aminoácidos , Disulfuros/metabolismo , Estabilidad de Enzimas , Glicina/biosíntesis , Humanos , Enfermedad por Deficiencia de Múltiples Sulfatasas/enzimología , Proteínas Mutantes/metabolismo , Mutación/genética , Péptidos/químicaAsunto(s)
Enfermedad por Deficiencia de Múltiples Sulfatasas/complicaciones , Enfermedad por Deficiencia de Múltiples Sulfatasas/genética , Sulfatasas/genética , Preescolar , Femenino , Humanos , Lactante , Masculino , Mutación Missense , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro , Enfermedades de la Piel/etiologíaRESUMEN
Multiple sulfatase deficiency (MSD) is an ultra-rare neurodegenerative disorder that results in defective sulfatase post-translational modification. Sulfatases in the body are activated by a unique protein, formylglycine-generating enzyme (FGE) that is encoded by SUMF1. When FGE is absent or insufficient, all 17 known human sulfatases are affected, including the enzymes associated with metachromatic leukodystrophy (MLD), several mucopolysaccharidoses (MPS II, IIIA, IIID, IVA, VI), chondrodysplasia punctata, and X-linked ichthyosis. As such, individuals demonstrate a complex and severe clinical phenotype that has not been fully characterized to date. In this report, we describe two individuals with distinct clinical presentations of MSD. Also, we detail a comprehensive systems-based approach to the management of individuals with MSD, from the initial diagnostic evaluation to unique multisystem issues and potential management options. As there have been no natural history studies to date, the recommendations within this report are based on published studies and consensus opinion and underscore the need for future research on evidence-based outcomes to improve management of children with MSD.