CRISPR/Cas9 technology in the modeling of and treatment of mucopolysaccharidosis.

Mucopolysaccharidosis (MPS) syndromes are a group of heterogeneous genetic disorders in terms of genetic basis and clinical manifestations, ranging from mild to fatal forms. There are a number of applied or prospective treatment modalities for MPS, including bone marrow transplantation, enzyme replacement therapy, targeted gene therapy and substrate reduction therapy. Recently, CRISPR/Cas9 technology has emerged as a novel tool for several metabolic disorders, such as MPS. This review concentrates on the application of this technique in the treatment of MPS, particularly MPS I, and modeling of disease-causing mutations.

Hypomyelinated vps16 Mutant Zebrafish Exhibit Systemic and Neurodevelopmental Pathologies.

Homotypic Fusion and Protein Sorting (HOPS) and Class C-core Vacuole/Endosome Tethering (CORVET) complexes regulate the correct fusion of endolysosomal bodies. Mutations in core proteins (VPS11, VPS16, VPS18, and VPS33) have been linked with multiple neurological disorders, including mucopolysaccharidosis (MPS), genetic leukoencephalopathy (gLE), and dystonia. Mutations in human Vacuolar Protein Sorting 16 (VPS16) have been associated with MPS and dystonia. In this study, we generated and characterized a zebrafish vps16(-/-) mutant line using immunohistochemical and behavioral approaches. The loss of Vps16 function caused multiple systemic defects, hypomyelination, and increased neuronal cell death. Behavioral analysis showed a progressive loss of visuomotor response and reduced motor response and habituation to acoustic/tap stimuli in mutants. Finally, using a novel multiple-round acoustic/tap stimuli test, mutants showed intermediate memory deficits. Together, these data demonstrate that zebrafish vps16(-/-) mutants show systemic defects, neurological and motor system pathologies, and cognitive impairment. This is the first study to report behavior abnormalities and memory deficiencies in a zebrafish vps16(-/-) mutant line. Finally, we conclude that the deficits observed in vps16(-/-) zebrafish mutants do not mimic pathologies associated with dystonia, but more align to abnormalities associated with MPS and gLE.

Endodontic management of taurodontism in a patient with Morquio syndrome: Case report of a 16-year-old girl.

BACKGROUND AND AIM: Mucopolysaccharidosis (MPS) type IV, referred to as Morquio A syndrome (MAS), is a rare genetic disorder characterized by an insufficient level in the storage of glycosaminoglycans within lysosomes. Diagnosis generally depends on clinical examination, skeletal radiographs, and histochemical tests. The condition is characterized by prominent skeletal deformities, limited joint mobility, significant growth impairment, abnormalities in tooth alignment, and defects in tooth enamel. The present clinical case report aims to provide details of a MAS case with peculiar dental findings, including multiple taurodonts where emergency dental treatment was rendered. CASE REPRESENTATION: A 16-year-old girl with short stature and prominent facial characteristics reported severe pain in the right maxillary back region. Clinical examination revealed multiple areas of alveolar bone loss, decayed #36, and temporary restoration on #16. Radiographic examination indicated multiple posterior teeth with taurodontism. Past medical history was confirmative of Morquio syndrome. Treating taurodonts endodontically is challenging due to the enlarged pulp chamber, shortened roots, and constricted root canal anatomy. Motorized canal preparation and the use of bioceramic sealer with single cone obturation were done to achieve the best results. CONCLUSION: The present case report encountered difficulty locating and negotiating the root canals and establishing the glide path. Using a dental operating microscope and stiff hand files for glide path and short-length Niti rotary files helped achieve the desired results. Although MPS IV is not frequently seen in dental practice, persons with this syndrome can continue to have good oral and overall health if their dental and medical condition if appropriately managed.

Design and validation of a GMP stem cell manufacturing protocol for MPSII hematopoietic stem cell gene therapy.

Hematopoietic stem cell gene therapy (HSCGT) is a promising therapeutic strategy for the treatment of neurodegenerative, metabolic disorders. The approach involves the ex vivo introduction of a missing gene into patients' own stem cells via lentiviral-mediated transduction (TD). Once transplanted back into a fully conditioned patient, these genetically modified HSCs can repopulate the blood system and produce the functional protein, previously absent or non-functional in the patient, which can then cross-correct other affected cells in somatic organs and the central nervous system. We previously developed an HSCGT approach for the treatment of Mucopolysaccharidosis type II (MPSII) (Hunter syndrome), a debilitating pediatric lysosomal disorder caused by mutations in the iduronate-2-sulphatase (IDS) gene, leading to the accumulation of heparan and dermatan sulfate, which causes severe neurodegeneration, skeletal abnormalities, and cardiorespiratory disease. In HSCGT proof-of-concept studies using lentiviral IDS fused to a brain-targeting peptide ApoEII (IDS.ApoEII), we were able to normalize brain pathology and behavior of MPSII mice. Here we present an optimized and validated good manufacturing practice hematopoietic stem cell TD protocol for MPSII in preparation for first-in-man studies. Inclusion of TEs LentiBOOST and protamine sulfate significantly improved TD efficiency by at least 3-fold without causing adverse toxicity, thereby reducing vector quantity required.

AAV gene replacement therapy for treating MPS IIIC: Facilitating bystander effects via EV-mRNA cargo.

MPS IIIC is a lysosomal storage disease caused by mutations in heparan-α-glucosaminide N-acetyltransferase (HGSNAT), for which no treatment is available. Because HGSNAT is a trans-lysosomal-membrane protein, gene therapy for MPS IIIC needs to transduce as many cells as possible for maximal benefits. All cells continuously release extracellular vesicles (EVs) and communicate by exchanging biomolecules via EV trafficking. To address the unmet need, we developed a rAAV-hHGSNATEV vector with an EV-mRNA-packaging signal in the 3'UTR to facilitate bystander effects, and tested it in an in vitro MPS IIIC model. In human MPS IIIC cells, rAAV-hHGSNATEV enhanced HGSNAT mRNA and protein expression, EV-hHGSNAT-mRNA packaging, and cleared GAG storage. Importantly, incubation with EVs led to hHGSNAT protein expression and GAG contents clearance in recipient MPS IIIC cells. Further, rAAV-hHGSNATEV transduction led to the reduction of pathological EVs in MPS IIIC cells to normal levels, suggesting broader therapeutic benefits. These data demonstrate that incorporating the EV-mRNA-packaging signal into a rAAV-hHGSNAT vector enhances EV packaging of hHGSNAT-mRNA, which can be transported to non-transduced cells and translated into functional rHGSNAT protein, facilitating cross-correction of disease pathology. This study supports the therapeutic potential of rAAVEV for MPS IIIC, and broad diseases, without having to transduce every cell.

Initiation of fluoxetine in a pediatric patient with Mucopolysaccharidosis IIIA: Early observations.

Fluoxetine has been identified as a potential treatment for mucopolysaccharidosis IIIA (MPS IIIA), a debilitating and progressive lysosomal storage disorder for which no treatments are approved. In the MPS IIIA mouse model, fluoxetine decreases the accumulation of glycosaminoglycans and aggregated autophagic substrates, reducing inflammation, and slowing cognitive deterioration. 1 We treated a single patient, 6 years old, under off-label prescription of fluoxetine, a selective serotonin reuptake inhibitor (SSRI). The primary endpoint was safety. Secondary exploratory assessments included urine quantitative heparan sulfate. Fluoxetine was well-tolerated in this patient and the patient continued treatment following the 12-month monitoring period. The patient experienced an increase in daytime somnolence which resolved with rescheduling fluoxetine administration to bedtime. Quantitative heparan sulfate levels remained elevated during treatment. Parents reported improved sleep latency time and less nighttime waking. These findings support general tolerability and further study of fluoxetine as a potential therapy for MPS IIIA.

Anesthetic and Airway Management in a Pediatric Patient with Morquio Syndrome: A Case Report.

Morquio syndrome is a subtype of mucopolysaccharidoses, wherein the accumulation of glycosaminoglycans (GAGs) in various organ systems lead to alteration of anatomy and physiology. Most prominent features are extensive bony abnormalities, which normally require surgical correction. This paper reports the case of a 7-year-old child with Morquio syndrome who successfully underwent correction of genu valgum under general endotracheal anesthesia via asleep induction and videolaryngoscopy, with supplemental peripheral nerve block. The precautions and anesthetic care done to ensure a safe procedure are discussed, especially with anticipation of a possible difficult airway.

Clinical and Molecular Characterization of Mucopolysaccharidosis Type 3A and 3B in a Turkish Series.

Introduction: Sanfilippo syndrome or mucopolysaccharidosis type 3 (MPS-3) is a rare condition and its epidemiological data are still not defined. MPS-3 is linked to a deficiency in enzymes involved in heparan sulfate degradation. This biomolecule is neurotoxic and its accumulation underlies the severe central nervous system degeneration observed in this disease. Methods: Here, we describe 15 Turkish patients with MPS-3A or MPS-3B subtypes. Clinical data upon the diagnosis and during the follow-up as well as molecular characterization are reported. Results: Two and ten distinct variants were identified in SGSH and NAGLU gene sequences, respectively. Six variants (NAGLU NM_000263.3:c.532-?_c.764+?del, NAGLU NM_000263.3: c.509G>T, NAGLU NM_000263.3: c.700C>G, NAGLU NM_000263.3:c.507_516 del, NAGLU NM dises_000263.3: c.1354 G>A, NAGLU NM_000263.3: c.200T>C) have been previously published and 6 are novel (SGSH NM_000199.4: c.80T>G, SGSH NM_000199.4: c.7_16del, NAGLU NM_000263.3: c.224_235del, NAGLU NM_000263.3: c.904G>T, NAGLU NM_000263.3: c.626C>T, NAGLU NM_000263.3: c.1241A>G). SGSH NM_000199.4:c.7_16del variation might be caused by a founder effect. Conclusion: Due to the high rate of consanguinity in Turkey, the incidence of Sanfilippo syndrome might be higher compared to other populations worldwide. Our results contribute to the characterization of rare diseases in Turkey and to improve our knowledge of the clinical, molecular, and epidemiological aspects of MPS-3 disease.

Delayed diagnosis of mild mucopolysaccharidosis type IVA.

BACKGROUND: Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disease caused by biallelic variants in the N-acetylgalactosamine-6-sulfatase (GALNS) gene and is characterized by progressive and multi-system involvements, dominantly with skeletal deformities. A mild form of MPS IVA often presents with atypical symptoms and can go unrecognized for years. METHODS: The diagnosis of MPS IVA was confirmed via GALNS enzyme activity testing in leukocytes. Clinical features were collected. Molecular analysis was performed by next generation sequence and Sanger sequencing of the GALNS gene. The pathogenicity of the deep intron variant was verified by mRNA analyses. RESULTS: Thirteen patients with mild MPS IVA from six families were included. All probands first visit pediatric orthopedists and it took 5.6 years to be diagnosed after the disease onset. The most common symptoms in our series were waddling gait (85%), short neck (69%) and flat feet (62%). Radiologic findings indicated skeletal abnormalities in all patients, especially modification of the vertebral bodies (100%) and acetabular and femoral head dysplasia (100%). Five novel GALNS variants, including c.121-2_121-1insTTTGCTGGCATATGCA, E2 deletion, c.569 A > G, c.898 + 2 T > A, and c.1139 + 2 T > C, were identified. The most common variant, a deep intron variant NM_000512.5: c.121-210 C > T (NM_001323544.2: c.129 C > T, p.G43G), was revealed to result in an 11 bp deletion (c.128_138delGCGATGCTGAG, p.Gly43Aspfs*5) on GALNS mRNA in the GALNS transcript of NM_001323544.2. CONCLUSIONS: This study provides significant insights into the clinical features and molecular characteristics that contribute to the early diagnosis of mild MPS IVA. On the basis of our cohort, orthopedists need to be able to recognize signs and symptoms of mild MPS IVA as well as the molecular and biochemical diagnosis so that an early diagnosis and treatment can be instituted.

Molecular therapy and nucleic acid adeno-associated virus-based gene therapy delivering combinations of two growth-associated genes to MPS IVA mice.

Mucopolysaccharidosis type IVA (MPS IVA) is caused by a deficiency of the galactosamine (N-acetyl)-6-sulfatase (GALNS) enzyme responsible for the degradation of specific glycosaminoglycans (GAGs). The progressive accumulation of GAGs leads to various skeletal abnormalities (short stature, hypoplasia, tracheal obstruction) and several symptoms in other organs. To date, no treatment is effective for patients with bone abnormalities. To improve bone pathology, we propose a novel combination treatment with the adeno-associated virus (AAV) vectors expressing GALNS enzyme and a natriuretic peptide C (CNP; NPPC gene) as a growth-promoting agent for MPS IVA. In this study, an MPS IVA mouse model was treated with an AAV vector expressing GALNS combined with another AAV vector expressing NPPC gene, followed for 12 weeks. After the combination therapy, bone growth in mice was induced with increased enzyme activity in tissues (bone, liver, heart, lung) and plasma. Moreover, there were significant changes in bone morphology in CNP-treated mice with increased CNP activity in plasma. Delivering combinations of CNP and GALNS gene therapies enhanced bone growth in MPS IVA mice more than in GALNS gene therapy alone. Enzyme expression therapy alone fails to reach the bone growth region; our results indicate that combining it with CNP offers a potential alternative.

Laronidase-loaded liposomes reach the brain and other hard-to-treat organs after noninvasive nasal administration.

Mucopolysaccharidosis type I (MPS I) is caused by a lack of the lysosomal enzyme α-L-iduronidase (IDUA), responsible for the degradation of the glycosaminoglycans (GAGs) dermatan and heparan sulfate, leading to multisystemic signs and symptoms. Enzyme replacement therapy (ERT) is a treatment that consists of weekly intravenous administrations of laronidase, a recombinant version of IDUA. However, ERT has limited access to certain tissues, such as bone, cartilage, and brain, and laronidase fails to trespass the BBB. In this sense, this study reports the development and characterization of laronidase-loaded liposomes for the treatment of MPS I mice. Liposomal complexes were obtained by the thin film formation method followed by microfluidization. The main characterization results showed mean vesicle size of 103.0 ± 3.3 nm, monodisperse populations of vesicles, zeta potential around + 30.0 ± 2.1 mV, and mucoadhesion strength of 5.69 ± 0.14 mN. Treatment of MPS I mice fibroblasts showed significant increase in enzyme activity. Nasal administration of complexes to MPS I mice resulted in significant increase in laronidase activity in the brain cortex, heart, lungs, kidneys, eyes, and serum. The overall results demonstrate the feasibility of nasal administration of laronidase-loaded liposomes to deliver enzyme in difficult-to-reach tissues, circumventing ERT issues and bringing hope as a potential treatment for MPS I.

Systemic immune challenge exacerbates neurodegeneration in a model of neurological lysosomal disease.

Mucopolysaccharidosis type IIIA (MPS IIIA) is a rare paediatric lysosomal storage disorder, caused by the progressive accumulation of heparan sulphate, resulting in neurocognitive decline and behavioural abnormalities. Anecdotal reports from paediatricians indicate a more severe neurodegeneration in MPS IIIA patients, following infection, suggesting inflammation as a potential driver of neuropathology. To test this hypothesis, we performed acute studies in which WT and MPS IIIA mice were challenged with the TLR3-dependent viral mimetic poly(I:C). The challenge with an acute high poly(I:C) dose exacerbated systemic and brain cytokine expression, especially IL-1ß in the hippocampus. This was accompanied by an increase in caspase-1 activity within the brain of MPS IIIA mice with concomitant loss of hippocampal GFAP and NeuN expression. Similar levels of cell damage, together with exacerbation of gliosis, were also observed in MPS IIIA mice following low chronic poly(I:C) dosing. While further investigation is warranted to fully understand the extent of IL-1ß involvement in MPS IIIA exacerbated neurodegeneration, our data robustly reinforces our previous findings, indicating IL-1ß as a pivotal catalyst for neuropathological processes in MPS IIIA.

Safe and effective liver-directed AAV-mediated homology-independent targeted integration in mouse models of inherited diseases.

Liver-directed adeno-associated viral (AAV) vector-mediated homology-independent targeted integration (AAV-HITI) by CRISPR-Cas9 at the highly transcribed albumin locus is under investigation to provide sustained transgene expression following neonatal treatment. We show that targeting the 3' end of the albumin locus results in productive integration in about 15% of mouse hepatocytes achieving therapeutic levels of systemic proteins in two mouse models of inherited diseases. We demonstrate that full-length HITI donor DNA is preferentially integrated upon nuclease cleavage and that, despite partial AAV genome integrations in the target locus, no gross chromosomal rearrangements or insertions/deletions at off-target sites are found. In line with this, no evidence of hepatocellular carcinoma is observed within the 1-year follow-up. Finally, AAV-HITI is effective at vector doses considered safe if directly translated to humans providing therapeutic efficacy in the adult liver in addition to newborn. Overall, our data support the development of this liver-directed AAV-based knockin strategy.

Successful treatment of corneal hypertrophic scar in Hurler syndrome.

In Hurler syndrome, corneal opacification is a common finding but rarely manifests as hypertrophic scars. A 6-year-old boy with Hurler syndrome had a hypertrophic scar on his left eye, which was successfully treated with superficial keratectomy.

Lung Diseases and Rare Disorders: Is It a Lysosomal Storage Disease? Differential Diagnosis, Pathogenetic Mechanisms and Management.

Pulmonologists may be involved in managing pulmonary diseases in children with complex clinical pictures without a diagnosis. Moreover, they are routinely involved in the multidisciplinary care of children with rare diseases, at baseline and during follow-up, for lung function monitoring. Lysosomal storage diseases (LSDs) are a group of genetic diseases characterised by a specific lysosomal enzyme deficiency. Despite varying pathogen and organ involvement, they are linked by the pathological accumulation of exceeding substrates, leading to cellular toxicity and subsequent organ damage. Less severe forms of LSDs can manifest during childhood or later in life, sometimes being underdiagnosed. Respiratory impairment may stem from different pathogenetic mechanisms, depending on substrate storage in bones, with skeletal deformity and restrictive pattern, in bronchi, with obstructive pattern, in lung interstitium, with altered alveolar gas exchange, and in muscles, with hypotonia. This narrative review aims to outline different pulmonary clinical findings and a diagnostic approach based on key elements for differential diagnosis in some treatable LSDs like Gaucher disease, Acid Sphingomyelinase deficiency, Pompe disease and Mucopolysaccharidosis. Alongside their respiratory clinical aspects, which might overlap, we will describe radiological findings, lung functional patterns and associated symptoms to guide pediatric pulmonologists in differential diagnosis. The second part of the paper will address follow-up and management specifics. Recent evidence suggests that new therapeutic strategies play a substantial role in preventing lung involvement in early-treated patients and enhancing lung function and radiological signs in others. Timely diagnosis, driven by clinical suspicion and diagnostic workup, can help in treating LSDs effectively.

Evaluation of aortic elasticity properties in mucopolysaccharidosis patients; effect of enzyme replacement therapy (ERT) on aortic stiffness.

OBJECTIVES: We aimed to cardiologically evaluate the consequences of glycosaminoglycan (GAG) accumulation in the large vessels of patients with mucopolysaccharidosis (MPS). METHODS: The left ventricular wall thickness, left ventricular mass (LVmass) were evaluated and aortic annulus diameter (AA), aortic sinus valsalva diameter (SV), sinotubular junction diameter (STJ), systolic aortic diameter (ADs), diastolic aortic diameter (ADd) body indices were obtained by dividing by the surface area. Aortic distensibility and stiffness index were obtained using aortic strain. Ejection fraction, mitral E and A velocities, mitral early diastolic tissue velocity (e'), E/A ratio, and E/e' ratio were evaluated. RESULTS: The LVED-i, LVmass-i, AA-i, SV-i, STJ-i, ADs-i, and ADd-i values were significantly higher in the MPS group. While the E and e' velocities and E/A ratio were significantly low in the MPS group, the A velocity and E/e' ratio were significantly high. While the stiffness index, SBP, and PP values were significantly higher in the MPS group, the aortic strain and distensibility were significantly lower. There was a correlation between the stiffness index and the aortic strain, distensibility, SBP, PP, and ventricular function. Cardiac function, aortic diameter, and aortic elasticity characteristics were similar between patients with MPS who received ERT and those who did not. CONCLUSIONS: In the MPS group, aortic elasticity properties were impaired, and aortic stiffness increased. ERT has positive effects on cardiac function, aortic diameter, and aortic stiffness in MPS patients. An increased LVmass-i and impaired ventricular geometric structure in patients with MPS may be associated with increased aortic stiffness.

Atypical Mongolian Spots With Hurler's Disease: A Case Report.

Mongolian spots are bluish-grey, irregular, hyperpigmented macules present at birth or that appear in the first few weeks of life. They are classified as atypical if they occur in unusual locations without spontaneous disappearance after infancy; or if new lesions continue to appear beyond early infancy. Although they are generally considered benign, recent studies have shown that atypical Mongolian spots may be associated with inborn errors of metabolism, such as lysosomal storage disorders and neurocristopathies. An 11-month-old male presented with multiple aberrant Mongolian spots on the abdomen, back, buttocks, arms, and legs, with the largest patch measuring 10x10 cm. Additionally, the child exhibited coarse facial features, a high-arched palate, low-set ears, and a depressed nasal bridge. Systemic examination revealed hepatosplenomegaly, fundus examination showed a hazy cornea, and the urine glycosaminoglycan test was positive, prompting us to conduct further research prioritising lysosomal storage disorders. The mucopolysaccharidosis (MPS) spot test was positive, and electrophoresis for MPS revealed bands for chondroitin sulfate and dermatan sulfate, confirming the diagnosis of MPS. Enzyme assay revealed no alpha-iduronidase activity and normal beta-galactosidase activity, thus confirming Hurler's disease. This case report highlights the importance of considering atypical Mongolian spots as a potential indicator of underlying storage disorders, enabling early intervention.

Heterologous HSPC Transplantation Rescues Neuroinflammation and Ameliorates Peripheral Manifestations in the Mouse Model of Lysosomal Transmembrane Enzyme Deficiency, MPS IIIC.

Mucopolysaccharidosis III type C (MPS IIIC) is an untreatable neuropathic lysosomal storage disease caused by a genetic deficiency of the lysosomal N-acetyltransferase, HGSNAT, catalyzing a transmembrane acetylation of heparan sulfate. HGSNAT is a transmembrane enzyme incapable of free diffusion between the cells or their cross-correction, which limits development of therapies based on enzyme replacement and gene correction. Since our previous work identified neuroinflammation as a hallmark of the CNS pathology in MPS IIIC, we tested whether it can be corrected by replacement of activated brain microglia with neuroprotective macrophages/microglia derived from a heterologous HSPC transplant. Eight-week-old MPS IIIC (HgsnatP304L) mice were transplanted with HSPC from congenic wild type mice after myeloablation with Busulfan and studied using behavior test battery, starting from the age of 6 months. At the age of ~8 months, mice were sacrificed to study pathological changes in the brain, heparan sulfate storage, and other biomarkers of the disease. We found that the treatment corrected several behavior deficits including hyperactivity and reduction in socialization, but not memory decline. It also improved several features of CNS pathology such as microastroglyosis, expression of pro-inflammatory cytokine IL-1ß, and accumulation of misfolded amyloid aggregates in cortical neurons. At the periphery, the treatment delayed development of terminal urinary retention, potentially increasing longevity, and reduced blood levels of heparan sulfate. However, we did not observe correction of lysosomal storage phenotype in neurons and heparan sulfate brain levels. Together, our results demonstrate that neuroinflammation in a neurological lysosomal storage disease, caused by defects in a transmembrane enzyme, can be effectively ameliorated by replacement of microglia bearing the genetic defect with cells from a normal healthy donor. They also suggest that heterologous HSPC transplant, if used together with other methods, such as chaperone therapy or substrate reduction therapy, may constitute an effective combination therapy for MPS IIIC and other disorders with a similar etiology.

Current Concepts in the Management of Sanfilippo Syndrome (MPS III): A Narrative Review.

Sanfilippo syndrome is a childhood-onset (1-4 years) autosomal recessive lysosomal storage disease that presents as a neurodegenerative disease by targeting the brain and spinal cord. It is also known as mucopolysaccharidosis III. Mucopolysaccharidosis III is divided into four subtypes (A, B, C, or D). It can cause delayed speech, behavior problems, and features of autism spectrum disorder. Sanfilippo syndrome is of a higher prevalence within consanguineous families that carry its gene alteration. If both parents have a nonfunctional copy of a gene linked to this condition, their children will have a 25% (1 in 4) chance of developing the disease. In Saudi Arabia, the incidence rate is estimated at 2 per 100,000 live births. Recent research focused on promising treatment approaches, such as gene therapy, modified enzyme replacement therapy, and stem cells. These approaches work by exogenous administration of the proper version of the mutant enzyme (enzyme replacement therapy), cleaning the defective enzyme in individuals with glycolipid storage disorders (substrate reduction therapy), or using a pharmacological chaperone to target improperly folded proteins. However, there is currently no approved curative medication for Sanfilippo syndrome that can effectively halt or reverse the disorder.

[Importance of lysosomal storage diseases in rheumatology]. / Bedeutung lysosomaler Speicherkrankheiten in der Rheumatologie.

Lysosomal storage diseases are a group of rare hereditary metabolic diseases. Due to a deficiency of lysosomal enzymes, complex substrates accumulate in the lysosomes of various organs. Depending on the affected enzyme, this results in clinically variable and chronic progressive multiorgan diseases. Diagnosis is often delayed. As clinical symptoms include the musculoskeletal system, an awareness of lysosomal storage diseases is of relevance to (pediatric) rheumatologists. This article is focused on Mucopolysaccharidosis type I­S, Mucolipidosis type III, Gaucher disease and Fabry disease. When suspecting a lysosomal storage disease, enzyme activity should be determined in dried blood spots or leukocytes. For some diseases, specific biomarkers can additionally be analyzed. Diagnosis should be confirmed by genetic testing. As causal treatment options are available for three of the presented diseases, a timely diagnosis is very important.