Sulfatase Deficiency Research Articles

Development of disease-specific scale for multiple sulfatase deficiency

Development of disease-specific scale for multiple sulfatase deficiency

Screening of approved drugs identifies 3 generation retinoids as therapeutic agents in multiple sulfatase deficiency

Screening of approved drugs identifies 3 generation retinoids as therapeutic agents in multiple sulfatase deficiency

Efficacy of syngeneic bone marrow transplant for the treatment of multiple sulfatase deficiency

Efficacy of syngeneic bone marrow transplant for the treatment of multiple sulfatase deficiency

Biomarkers of disease severity in multiple sulfatase deficiency

Biomarkers of disease severity in multiple sulfatase deficiency

The effect of intravenous trehalose administration in a patient with multiple sulfatase deficiency.

We describe the case of a female child with multiple sulfatase deficiency (MSD) who received intravenous (IV) trehalose (15 g/week) for 3 months. The efficacy of trehalose was evaluated by comparing serum biomarkers, a quality-of-life questionnaire (HRQoL), and imaging (brain MRI and ultrasonography of liver and spleen) at weeks 0 (W0) and 12 (W12). The improvement in quality of life assessments along with a slight decrease in the spleen dimensions were observed after 3-month intervention. Future research with a larger MSD population and a longer-term follow-up is warranted to determine whether trehalose can improve MSD patient health and clinical outcomes.

Abstract 2603: Human steroid sulfatase deficiency induces keratinization of HaCaT cells by improving the expression level of E-cadherin

Abstract 2603: Human steroid sulfatase deficiency induces keratinization of HaCaT cells by improving the expression level of E-cadherin

New mouse models with hypomorphic SUMF1 variants mimic attenuated forms of multiple sulfatase deficiency.

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.

The Effects of N-Acetyl-L-Leucine on the Improvement of Symptoms in a Patient with Multiple Sulfatase Deficiency.

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 12years old, received NALL at a dose of 3g/day (1g in the morning, 1g in the afternoon, and 1g in the evening). A fasting blood sample was taken from the subject to evaluate side effects before the intervention and 4weeks 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 (3g/day) over 4weeks. 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 7.93s). 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 3g/day over 4weeks 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.

Unexpected Phenotype Reversion and Survival in a Zebrafish Model of Multiple Sulfatase Deficiency.

Multiple sulfatase deficiency (MSD) is a rare recessively inherited Mendelian disorder that manifests with developmental delay, neurodegeneration, skeletal deformities, facial dysmorphism, congenital growth retardation, and other clinical signs. The disorder is caused by mutations in the SUMF1 gene, which encodes the formylglycine-generating enzyme (FGE), and responsible for the activation of sulfatases. Mutations in SUMF1 result in reduced or absent FGE function with consequent compromised activities of its client sulfatases. This leads to an accumulation of enzyme substrates, such as glycosaminoglycans and sulfolipids, within lysosomes and subsequently impaired lysosome function and cellular pathology. Currently, there are no disease modifying therapeutic options for MSD patients, hence the need for more suitable animal models to investigate the disorder. Here, we describe the characterisation of a sumf1 null zebrafish model, which has negligible sulfatase activity. Our sumf1 −/− zebrafish model successfully recapitulates the pathology of MSD such as cranial malformation, altered bone development, an enlarged population of microglia, and growth retardation during early development but lacks early lethality of mouse Sumf1 −/− models. Notably, we provide evidence of recovery in MSD pathology during later developmental stages, resulting in homozygous mutants that are viable. Hence, our data suggest the possibility of a unique compensatory mechanism that allows the sumf1 −/− null zebrafish to survive better than human MSD patients and mouse Sumf1 −/− models.

Maternal plasma levels of vitamin D in postterm pregnancy

This study was conducted to examine the levels of vitamin D in postterm pregnancy. The study consisted of two groups: Group 1: women with postterm pregnancy in whom labour has not started (n = 40). Group 2: pregnant women with spontaneous labour between 37 and 41 weeks of gestation (n = 40). Demographic characteristics of individuals, age, body mass index, gravida, parity, living child, number of abortions and birth characteristics were recorded. Prepartum and postpartum haemoglobin (Hb) and haematocrit (Hct) values ​​and vitamin D levels of pregnant women were measured. We found no significant differences in vitamin D levels, smoking, mode of delivery, induction of labour, methods of cervical ripening and maternal and perinatal complications between the groups (p > .05). D vitamin in the model had a statistically significant effect on prepartum Hb (p < .05). Vitamin D levels seem not to be associated with postterm pregnancy. Vitamin D had a statistically significant effect on prepartum Hb. IMPACT STATEMENT What is already known on this subject? The aetiology of post term pregnancy is not clearly known, factors such as foetal anencephaly, foetal sex, placental sulfatase deficiency, genetic factors, and high pre-pregnancy body mass index play a role. What do the results of this study add? Vitamin D levels seem not to be associated with postterm pregnancy. Vitamin D had a statistically significant effect on prepartum Hb. What are the implications of these findings for clinical practice and/or further research? Further studies are needed to clarify the relationship between vitamin D levels and postterm pregnancy.

Multiple Sulfatase Deficiency: A Clinical Report with Neonatal Presentation

Multiple Sulfatase Deficiency: A Clinical Report with Neonatal Presentation

Myeloid Sulf Deletion and Immune Dysfunction in Multiple Sulfatase Deficiency

IntroductionMultiple sulfatase deficiency (MSD) is a rare autosomal recessive disease due to pathogenic mutations in the sulfatase‐modifying factor 1 (SUMF1) gene. SUMF1 encodes the formylglycine‐generating enzyme responsible for an activating posttranslational modification of all sulfatases (17 in humans), and deficiency in these sulfatases results in accumulation of sulfated sugars, lipids, and steroids. The heparan sulfate (HS) 6‐O‐endosulfatases, commonly referred to as the Sulfs (Sulf1 and Sulf2), are among the sulfatases affected by SUMF1mutation. Unlike other sulfatases which degrade sulfated molecules in lysosomes, the Sulfs remodel the 6‐O‐sulfation status of HS outside of cells and thus modulate the functions of HS binding growth factors and cytokines. Although the systemic symptoms of MSD can be variable due to varying degrees of deficiency across all sulfatases, common features of MSD include hepatosplenomegaly and recurrent pneumonia. As HS has been shown to play important regulatory roles in host immunity, the objective of the current study was to investigate the role of the Sulfs in myeloid lineage development and function and to examine how myeloid Sulf deficiency contributes to the symptomatology of MSD.MethodsTo generate a mouse model with myeloid specific deletion of the Sulfs, we crossed Sulf1 and Sulf2 double floxed mice with mice carrying the Cre recombinase under control of lysozyme 2 (Lyz2‐cre). The role of the Sulfs in macrophage function was examined both in vitro in bone marrow derived macrophages and in vivo using the lipopolysaccharide (LPS) lung injury and inflammation model. Finally, Western blotting was performed to evaluate how myeloid Sulf deficiency alters transforming growth factor (TGF)‐β signaling.ResultsThe myeloid specific Sulf deficient mice had enlarged spleens (231.0 ± 51.1 mg) compared to the control mice (Lyz2‐cre+/‐ alone with wildtype Sulfs, 95.4 ± 7.0 mg, P = 0.039), and some (5‐10%) died prematurely. Bone marrow derived macrophages from myeloid Sulf deficient mice exhibited increased proliferation but reduced ability to phagocytose Escherichia Coli (E. Coli) in vitrocompared to the control macrophages. Following intratracheal LPS (0.1 mg/kg) challenge (4 hours), myeloid Sulf deficient mice had significantly less neutrophils (1.8x105 ± 0.6x105cells) in the bronchoalveolar lavage fluid (BALF) compared to the control mice (6.3x105± 1.0x105cells, P = 0.0076). In contrast, coadministration of recombinant Sulf2 with LPS in wildtype mice lead to greater neutrophil recruitment in the airspace. Finally, enhanced phosphorylation of Smad2/3 (TGF‐β signal transducers) was found in spleens and lungs from myeloid specific Sulf deficient mice compared to the controls.ConclusionOur study reveals several important findings: the Sulfs play important roles in myeloid lineage development and function, myeloid Sulf deficiency contributes to the immune dysregulation observed in MSD, and enhanced TGF‐β signaling in the absence of the Sulfs might be responsible for the immune abnormality observed in myeloid Sulf deficient mice and in MSD. Our study builds on the foundation for targeting HS or the Sulfs in the treatment of MSD and potentially other myeloproliferative pathologies.

How to Manage Low Estriol Levels in Pregnancies, One Center Experience.

Objective:Low estriol (uE3) levels in the second-trimester screening for Down syndrome may be the result of fetal demise, congenital abnormalities, or some genetic hormonal disorders of the fetus. Although X-linked ichthyosis, a microdeletion syndrome with mild ichthyosis, which causes steroid sulfatase (STS) deficiency, is the most common genetic cause, second-trimester screening tests calculate the risk for a less common and severe disorder known as the Smith Lemli Opitz syndrome (SLOS). We aimed to investigate the outcomes of pregnancies with low uE3 levels in Down syndrome screening and emphasize the high prevalence of STS deficiency instead of SLOS in such cases.Methods:Fifteen pregnancies with very low uE3 levels and high risk for trisomy and/or SLOS in screening tests were evaluated and tested for STS deficiency and SLOS.Results:Seven of the pregnancies had STS microdeletion syndrome, while additional two cases were supposed to have STS gene mutation according to family and/or postnatal history. Although one fetal death was recorded, no chromosomal abnormality, SLOS, or congenital malformation was recorded in our series.Conclusions:SLOS is a very severe and rare syndrome. The risk estimation for SLOS in screening tests causes stress for pregnant women and healthcare givers. We recommend the addition of risk estimation for STS deficiency when a low uE3 level is detected in the screening test.

Efficacy of a scAAV9/SUMF1 viral vector for the treatment of multiple sulfatase deficiency

Efficacy of a scAAV9/SUMF1 viral vector for the treatment of multiple sulfatase deficiency

Early diagnosis of mucopolysaccharidosis type III (Sanfilippo syndrome) in the practice of a pediatrician

Mucopolysaccharidosis (MPS) type III (Sanfilippo syndrome) is a lysosomal storage disease inherited in an autosomal recessive manner, it is characterized by the accumulation of heparan sulfate in the cells of the body, which leads to the development of multiple organ failure. It occurs with a frequency of 1: 70 thousand newborns. There are 4 subtypes of the disease: A, B, C, D. Cognitive and neurological disorders are the earliest symptoms of the disease. Delay (loss) of speech development, regression of acquired skills, hyperreactivity, autistic character traits, mental retardation, sleep disturbance, epilepsy are noted; aggressive behavior is formed, the ability to move is impaired, hepatomegaly appears. There are observed the violations of other organs and systems – the organ of vision, bone, respiratory, cardiovascular systems, ENT organs, dental problems. Clinically, the subtypes of mucopolysaccharidosis III are practically indistinguishable. The average age at diagnosis is 2–6 years. Diagnostic search includes qualitative and quantitative determination of glycosaminoglycans in urine. It should be remembered that with mild variants of the disease, these indicators may be within the normal range. In the future, it is necessary to assess the activity of the corresponding enzymes in leukocytes, plasma or serum, in skin fibroblasts. Genetic testing is then performed to identify the mutation of the corresponding defective gene. Differential diagnosis should be carried out with other types of mucopolysaccharidosis, mucolipidosis, gangliosidosis, multiple sulfatase deficiency, some rheumatoid diseases.

Steroid sulfatase deficiency causes cellular senescence and abnormal differentiation by inducing Yippee-like 3 expression in human keratinocytes

Human steroid sulfatase (STS) is an enzyme that catalyzes the hydrolysis of dehydroepiandrosterone sulfate (DHEAS), estrone sulfate (E1S), and cholesterol sulfate. Abnormal expression of STS causes several diseases including colorectal, breast, and prostate cancer and refractory skin disease. In particular, accumulation of intracellular cholesterol sulfate by STS deficiency leads to a skin disorder with abnormal keratinization called X-linked ichthyosis (XLI). To determine the detailed mechanisms of XLI, we performed RNA sequencing (RNA-seq) analysis using human keratinocyte HaCaT cells treated with cholesterol and cholesterol sulfate. Of the genes with expression changes greater than 1.5-fold, Yippee-like 3 (YPEL3), a factor expected to affect cell differentiation, was found. Induction of YPEL3 causes permanent growth arrest, cellular senescence, and inhibition of metastasis in normal and tumor cells. In this study, we demonstrate that YPEL3 expression was induced by STS deficiency and, using the CRISPR/Cas9 system, a partial knock-out (STS+/−) cell line was constructed to establish a disease model for XLI studies. Furthermore, we show that increased expression of YPEL3 in STS-deficient cell lines promoted cellular senescence and expression of keratinization-related proteins such as involucrin and loricrin. Our results suggest that upregulation of YPEL3 expression by STS deficiency may play a crucial role in inducing cellular senescence and abnormal differentiation in human keratinocytes.

Natural disease history and characterization of SUMF1 molecular defects in multiple sulfatase deficiency: a case report

Multiple sulfatase deficiency (MSD) is a very rare lysosomal storage disease(LSD) caused by mutations in the SUMF1 gene. So far, about 143 patients with MSD have been reported in previous studies, although this figure is likely an underestimation due to under-reporting and under-recognition. This report showed the genetic and clinical aspects of a patient with MSD compared with previously reported patients.

182 Genetic heterogeneity of STS gene mutations in a Dutch patient cohort clinically suspected for X-linked recessive ichthyosis

X-linked ichthyosis (XLI) is after ichthyosis vulgaris (IV) the most frequent occurring genetic skin scaling disease (1 in 6,000). The disorder results from steroid sulfatase deficiency due to defects in the STS gene. Most patients (90%) have a genomic deletion encompassing the entire gene. Clinical distinction between XLI and IV may be difficult. Moreover, the incidence of FLG mutations causal to IV is high (5%) and therefore co-inheritance with STS mutations may occur, modifying the phenotype.

Chitotriosidase as a biomarker for gangliosidoses

Elevated serum chitotriosidase (CHITO) is an indication of macrophage activation, and its capacity have been explored as a marker of inflammation in a number of disease states. For over a decade, CHITO plasma levels have been used by clinicians as a biomarker of inflammation in the lysosomal disease, Gaucher disease, including monitoring response to therapies in patients with Gaucher disease type I. Although it is becoming increasingly recognized that inflammation is a prominent component of many lysosomal diseases, the relation of CHITO levels to disease burden has not been well-characterized in the large majority of lysosomal diseases. Moreover, the role of CHITO in lysosomal diseases that affect the central nervous system (CNS) has not been systematically studied. In this study, one hundred and thirty-four specimens of CSF and serum were collected from 34 patients with lysosomal diseases affecting the CNS. This study included patients with GM1-gangliosidosis, GM2-gangliosidosis, mucopolysaccharidoses (MPS), multiple sulfatase deficiency and Gaucher disease. CHITO levels in the CSF were significantly higher in patients with more rapidly progressing severe neurological impairment: GM1-gangliosidosis vs MPS (p < 0.0001); GM2-gangliosidosis vs MPS (p < 0.0001). CHITO levels were higher in patients with the more severe phenotypes compared to milder phenotypes in GM1-gangliosidosis and GM2-gangliosidosis (serum CHITO in GM1-gangliosidosis infantile vs juvenile p = 0.025; CSF CHITO in Tay-Sachs infantile vs Tay-Sachs late-onset p < 0.0001). Moreover, higher CHITO levels in the CSF were significantly associated with lower cognitive test scores in patients with GM1-gangliosidosis, GM2-gangliosidosis, and MPS (p = 1.12*10−5, R2 = 0.72). Patients with infantile GM1-gangliosidosis showed increasing CSF CHITO over time, suggesting that CSF CHITO reflects disease progression and a possible surrogate endpoint for future clinical trials with infantile GM1-gangliosidosis. In summary, these results support the use of CSF CHITO to diagnose between different disease phenotypes and as a valuable tool for monitoring disease progression in patients. These results necessitate the inclusion of CHITO as an exploratory biomarker for clinical trials.

Treatment of skeletal and non-skeletal alterations of Mucopolysaccharidosis type IVA by AAV-mediated gene therapy

Mucopolysaccharidosis type IVA (MPSIVA) or Morquio A disease, a lysosomal storage disorder, is caused by N-acetylgalactosamine-6-sulfate sulfatase (GALNS) deficiency, resulting in keratan sulfate (KS) and chondroitin-6-sulfate accumulation. Patients develop severe skeletal dysplasia, early cartilage deterioration and life-threatening heart and tracheal complications. There is no cure and enzyme replacement therapy cannot correct skeletal abnormalities. Here, using CRISPR/Cas9 technology, we generate the first MPSIVA rat model recapitulating all skeletal and non-skeletal alterations experienced by patients. Treatment of MPSIVA rats with adeno-associated viral vector serotype 9 encoding Galns (AAV9-Galns) results in widespread transduction of bones, cartilage and peripheral tissues. This led to long-term (1 year) increase of GALNS activity and whole-body correction of KS levels, thus preventing body size reduction and severe alterations of bones, teeth, joints, trachea and heart. This study demonstrates the potential of AAV9-Galns gene therapy to correct the disabling MPSIVA pathology, providing strong rationale for future clinical translation to MPSIVA patients.