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BMC Medical Genomics Jun 2024Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disease caused by biallelic variants in the N-acetylgalactosamine-6-sulfatase (GALNS) gene and is...
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.
Topics: Humans; Male; Mucopolysaccharidosis IV; Child; Female; Delayed Diagnosis; Child, Preschool; Adolescent; Chondroitinsulfatases; Mutation
PubMed: 38831290
DOI: 10.1186/s12920-024-01910-x -
Biochemical and Biophysical Research... Feb 2024The Lysosomal Storage disease known as Mucopolysaccharidosis type II, is caused by mutations affecting the iduronate-2-sulfatase required for heparan and dermatan...
The Lysosomal Storage disease known as Mucopolysaccharidosis type II, is caused by mutations affecting the iduronate-2-sulfatase required for heparan and dermatan sulfate catabolism. The central nervous system (CNS) is mostly and severely affected by the accumulation of both substrates. The complexity of the CNS damage observed in MPS II patients has been limitedly explored. The use of mass spectrometry (MS)-based proteomics tools to identify protein profiles may yield valuable information about the pathological mechanisms of Hunter syndrome. In this further study, we provide a new comparative proteomic analysis of MPS II models by using a pipeline consisting of the identification of native protein complexes positioned selectively by using a specific antibody, coupled with mass spectrometry analysis, allowing us to identify changes involving in a significant number of new biological functions, including a specific brain antioxidant response, a down-regulated autophagic, the suppression of sulfur catabolic process, a prominent liver immune response and the stimulation of phagocytosis among others.
Topics: Humans; Mucopolysaccharidosis II; Proteomics; Iduronate Sulfatase; Glycosaminoglycans; Brain
PubMed: 38241811
DOI: 10.1016/j.bbrc.2024.149490 -
Metabolites Dec 2023Recent data described that patients with lysosomal storage disorders (LSDs) may have clinical schizophrenia (SCZ) features. Disruption of lipid metabolism in SCZ...
Recent data described that patients with lysosomal storage disorders (LSDs) may have clinical schizophrenia (SCZ) features. Disruption of lipid metabolism in SCZ pathogenesis was found. Clinical features of schizophrenia (SCZ) have been demonstrated in patients with several lysosomal storage disorders (LSDs). Taking into account the critical role of lysosomal function for neuronal cells' lysosomal dysfunction could be proposed in SCZ pathogenesis. The current study analyzed lysosomal enzyme activities and the alpha-synuclein level in the blood of patients with late-onset SCZ. In total, 52 SCZ patients with late-onset SCZ, 180 sporadic Parkinson's disease (sPD) patients, and 176 controls were recruited. The enzymatic activity of enzymes associated with mucopolysaccharidosis (alpha-L-Iduronidase ()), glycogenosis (acid alpha-glucosidase (GAA)) and sphingolipidosis (galactosylceramidase (), glucocerebrosidase (GCase), alpha-galactosidase (GLA), acid sphingomyelinase (ASMase)) and concentration of lysosphingolipids (hexosylsphingosine (HexSph), globotriaosylsphingosine (LysoGb3), and lysosphingomyelin (LysoSM)) were measured using LC-MS/MS. The alpha-synuclein level was estimated in magnetically separated CD45+ blood cells using the enzyme-linked immunosorbent assay (ELISA). Additionally, NGS analysis of 11 LSDs genes was conducted in 21 early-onset SCZ patients and 23 controls using the gene panel PGRNseq-NDD. Decreased ASMase, increased GLA activities, and increased HexSpn, LysoGb3, and LysoSM concentrations along with an accumulation of the alpha-synuclein level were observed in late-onset SCZ patients in comparison to the controls ( < 0.05). Four rare deleterious variants among LSDs genes causing mucopolysaccharidosis type I ( (rs532731688, rs74385837) and type III ( (rs766835582)) and sphingolipidosis (metachromatic leukodystrophy ( (rs201251634)) were identified in five patients from the group of early-onset SCZ patients but not in the controls. Our findings supported the role of sphingolipid metabolism in SCZ pathogenesis. Aberrant enzyme activities and compounds of sphingolipids associated with ceramide metabolism may lead to accumulation of alpha-synuclein and may be critical in SCZ pathogenesis.
PubMed: 38248833
DOI: 10.3390/metabo14010030 -
PloS One 2023Heparan sulfate (HS), an abundant component of the apical cell surface and basement membrane, belongs to the glycosaminoglycan family of carbohydrates covalently linked...
Effects of Heparan sulfate acetyl-CoA: Alpha-glucosaminide N-acetyltransferase (HGSNAT) inactivation on the structure and function of epithelial and immune cells of the testis and epididymis and sperm parameters in adult mice.
Heparan sulfate (HS), an abundant component of the apical cell surface and basement membrane, belongs to the glycosaminoglycan family of carbohydrates covalently linked to proteins called heparan sulfate proteoglycans. After endocytosis, HS is degraded in the lysosome by several enzymes, including heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT), and in its absence causes Mucopolysaccharidosis III type C (Sanfilippo type C). Since endocytosis occurs in epithelial cells of the testis and epididymis, we examined the morphological effects of Hgsnat inactivation in these organs. In the testis, Hgsnat knockout (Hgsnat-Geo) mice revealed statistically significant decrease in tubule and epithelial profile area of seminiferous tubules. Electron microscopy (EM) analysis revealed cross-sectional tubule profiles with normal and moderately to severely altered appearances. Abnormalities in Sertoli cells and blood-testis barrier and the absence of germ cells in some tubules were noted along with altered morphology of sperm, sperm motility parameters and a reduction in fertilization rates in vitro. Along with quantitatively increased epithelial and tubular profile areas in the epididymis, EM demonstrated significant accumulations of electrolucent lysosomes in the caput-cauda regions that were reactive for cathepsin D and prosaposin antibodies. Lysosomes with similar storage materials were also found in basal, clear and myoid cells. In the mid/basal region of the epithelium of caput-cauda regions of KO mice, large vacuolated cells, unreactive for cytokeratin 5, a basal cell marker, were identified morphologically as epididymal mononuclear phagocytes (eMPs). The cytoplasm of the eMPs was occupied by a gigantic lysosome suggesting an active role of these cells in removing debris from the epithelium. Some eMPs were found in proximity to T-lymphocytes, a feature of dendritic cells. Taken together, our results reveal that upon Hgsnat inactivation, morphological alterations occur to the testis affecting sperm morphology and motility parameters and abnormal lysosomes in epididymal epithelial cells, indicative of a lysosomal storage disease.
PubMed: 37756356
DOI: 10.1371/journal.pone.0292157 -
International Ophthalmology Apr 2024This review examined existing literature to determine various ocular manifestations of liver pathologies, with a focus on metabolic deficiencies as well as viral and... (Review)
Review
PURPOSE
This review examined existing literature to determine various ocular manifestations of liver pathologies, with a focus on metabolic deficiencies as well as viral and immune liver conditions.
METHODS
Recent data were compiled from PubMed from 2000 to 2020 using keywords that were relevant to the assessed pathologies. Ocular presentations of several liver pathologies were researched and then summarized in a comprehensive form.
RESULTS
Several ocular manifestations of liver disease were related to vitamin A deficiency, as liver disease is associated with impaired vitamin A homeostasis. Alcoholic liver cirrhosis can result in vitamin A deficiency, presenting with Bitot spots, xerosis, and corneal necrosis. Congenital liver diseases such as mucopolysaccharidoses and peroxisomal disorders are also linked with ocular signs. Viral causes of liver disease have associations with conditions like retinal vasculitis, keratoconjunctivitis sicca, retinopathies, Mooren's ulcer, and Sjogren's syndrome. Autoimmune hepatitis has been linked to peripheral ulcerative keratitis and uveitis.
CONCLUSIONS
Building strong associations between ocular and liver pathology will allow for early detection of such conditions, leading to the early implementation of management strategies. While this review outlines several of the existing connections between hepatic and ophthalmic disease, further research is needed in the area in order to strengthen these associations.
Topics: Humans; Vitamin A Deficiency; Keratoconjunctivitis Sicca; Corneal Ulcer; Sjogren's Syndrome; Dry Eye Syndromes; Liver Diseases; Retinal Vasculitis
PubMed: 38622271
DOI: 10.1007/s10792-024-03103-y -
Journal of Thrombosis and Haemostasis :... Sep 2023Transplacental delivery of maternal immunoglobulin G (IgG) provides humoral protection during the first months of life until the newborn's immune system reaches...
BACKGROUND
Transplacental delivery of maternal immunoglobulin G (IgG) provides humoral protection during the first months of life until the newborn's immune system reaches maturity. The maternofetal interface has been exploited therapeutically to replace missing enzymes in the fetus, as shown in experimental mucopolysaccharidoses, or to shape adaptive immune repertoires during fetal development and induce tolerance to self-antigens or immunogenic therapeutic molecules.
OBJECTIVES
To investigate whether proteins that are administered to pregnant mice or endogenously present in their circulation may be delivered through the placenta.
METHODS
We engineered monovalent immunoglobulin G (FabFc) specific for different domains of human factor VIII (FVIII), a therapeutically relevant model antigen. FabFc was injected with exogenous FVIII into pregnant severe hemophilia A mice or pregnant mice expressing human FVIII following AAV8-mediated gene therapy. FabFc and FVIII were detected in the pregnant mice and/or fetuses by enzyme-linked immunosorbent assay and immunohistochemistry.
RESULTS
Administration of FabFc to pregnant mice allowed the maternofetal delivery of FVIII in a FcRn-dependent manner. FVIII antigen levels achieved in the fetuses represented 10% of normal plasma levels in the human. We identified antigen/FabFc complex stability, antigen size, and shielding of promiscuous protein patches as key parameters to foster optimal antigen delivery.
CONCLUSION
Our results pave the way toward the development of novel strategies for the in utero delivery of endogenous maternal proteins to replace genetically deficient fetal proteins or to educate the immune system and favor active immune tolerance upon protein encounter later in life.
Topics: Pregnancy; Female; Mice; Humans; Animals; Immunoglobulin G; Factor VIII; Hemophilia A; Placenta; Genetic Therapy; Immune Tolerance
PubMed: 37271431
DOI: 10.1016/j.jtha.2023.05.021 -
Annals of Medicine and Surgery (2012) Oct 2023Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI; MPS VI) is a chronic illness that causes progressive enlargement, inflammation, or scarring of several tissues...
BACKGROUND
Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI; MPS VI) is a chronic illness that causes progressive enlargement, inflammation, or scarring of several tissues and organs until their collapse. In most cases, an infant with MPS VI shows no symptoms. The early signs and symptoms of MPS VI in children often develop in the first few months of life. MPS VI affects various systems in the body, including the skeletal, cardiac, and respiratory systems. The authors aim in our study to describe the clinical and genotypic-phenotypic findings of MPS VI patients in 'children Welfare Teaching Hospital, Medical City Complex.'
METHODS
The single-center study was conducted at the 'children Welfare Teaching Hospital, Medical City Complex' from November 2016 to May 2022. The research recruited 72 MPS VI patients from Iraq, all under 20. The authors investigated the sociodemographic characteristics, hematological lab results, gene-phenotype findings, and clinical features and evaluated the severity and progression of the MPS 6 disease.
RESULTS
Seventy-two Iraqi MPS VI patients were involved in the study, and the average age of the study sample was 6.38±3.4 (0.3-19). The consanguinity rate was 94.4%. In the research, females comprised 56.9% of the patients, and the -scores for body mass index and occipital-frontal head circumference were -2.66 and 1.2. The fascial features at diagnosis, 'coarse facies' (90.3%), dysostosis multiplex (93%), short stature (94.4%), and recurrent respiratory infections (91.6%), were the most common clinical features among the enrolled patients. The most frequent mutation was (complementary DNA: c.753C>G, protein effect: p.(Tyr2*) or p.(Tyr251Term), and the codon cross-tabulation: premature stop codon, or homozygous stop nonsense mutation/exon N.3) (33/69 (47.82%)). Furthermore, a statistically significant correlation existed between lower weight and height readings and the progressed and severe stages of the MPS VI illness.
CONCLUSION
As the first research in Iraq with a sufficient sample size of MPS VI patients, the investigation presented important clinical and gene-phenotype findings and revealed the necessity for enhancing the diagnosis of MPS VI, including the updated molecular analysis and monitoring the multisystem parameters, aberrant comorbidities, and the progression and severity.
PubMed: 37811045
DOI: 10.1097/MS9.0000000000001272 -
The Indian Journal of Radiology &... Apr 2024Skeletal dysplasias or osteochondrodysplasias comprise a large heterogeneous group of genetic disorders and possess significant overlap on imaging, which adds to the... (Review)
Review
Skeletal dysplasias or osteochondrodysplasias comprise a large heterogeneous group of genetic disorders and possess significant overlap on imaging, which adds to the dilemma of the reporting radiologist. These entities are routinely evaluated with a detailed skeletal survey and hand radiographs form a crucial part of a complete survey. Certain conditions have characteristic imaging findings that enable a diagnosis be made on hand radiograph alone. Additionally, hand radiographs may also demonstrate findings that may be suggestive of a particular diagnosis/differential diagnoses and would warrant further assessment for proving the same. We aim to demonstrate the use of hand radiographs in diagnosis of various such entities through this review. Although they cannot replace a complete skeletal survey in the diagnosis, hand radiographs performed for other indications might alert a radiologist to the diagnosis of an unsuspected skeletal dysplasia.
PubMed: 38549896
DOI: 10.1055/s-0043-1777320 -
International Journal of Molecular... Sep 2023Morquio disease, also called mucopolysaccharidosis IV (MPS IV), belongs to the group of lysosomal storage diseases (LSD). Due to deficiencies in the activities of...
Morquio disease, also called mucopolysaccharidosis IV (MPS IV), belongs to the group of lysosomal storage diseases (LSD). Due to deficiencies in the activities of galactose-6-sulfate sulfatase (in type A) or β-galactosidase (in type B), arising from mutations in or , respectively, keratan sulfate (one of glycosaminoglycans, GAGs) cannot be degraded efficiently and accumulates in lysosomes. This primary defect leads to many cellular dysfunctions which then cause specific disease symptoms. Recent works have indicated that different secondary effects of GAG accumulation might significantly contribute to the pathomechanisms of MPS. Apoptosis is among the cellular processes that were discovered to be affected in MPS cells on the basis of transcriptomic studies and some cell biology experiments. However, Morquio disease is the MPS type which is the least studied in light of apoptosis dysregulation, while RNA-seq analyses suggested considerable changes in the expression of genes involved in apoptosis in MPS IVA and IVB fibroblasts. Here we demonstrate that cytochrome release from mitochondria is more efficient in MPS IVA and IVB fibroblasts relative to control cells, both under the standard cultivation conditions and after treatment with staurosporine, an apoptosis inducer. This indication of apoptosis stimulation was corroborated by measurements of the levels of caspases 9, 3, 6, and 7, as well as PARP, cleaved at specific sites, in Morquio disease and control fibroblasts. The more detailed analyses of the transcriptomic data revealed which genes related to apoptosis are down- and up-regulated in MPS IVA and IVB fibroblasts. We conclude that apoptosis is stimulated in Morquio disease under both standard cell culture conditions and after induction with staurosporine which may contribute to the pathomechanism of this disorder. Dysregulation of apoptosis in other MPS types is discussed.
Topics: Humans; Mucopolysaccharidosis IV; Staurosporine; Keratan Sulfate; Fibroblasts; Apoptosis; Chondroitinsulfatases
PubMed: 37762422
DOI: 10.3390/ijms241814119 -
Science Translational Medicine May 2024Mucopolysaccharidosis type I Hurler (MPSIH) is characterized by severe and progressive skeletal dysplasia that is not fully addressed by allogeneic hematopoietic stem...
Mucopolysaccharidosis type I Hurler (MPSIH) is characterized by severe and progressive skeletal dysplasia that is not fully addressed by allogeneic hematopoietic stem cell transplantation (HSCT). Autologous hematopoietic stem progenitor cell-gene therapy (HSPC-GT) provides superior metabolic correction in patients with MPSIH compared with HSCT; however, its ability to affect skeletal manifestations is unknown. Eight patients with MPSIH (mean age at treatment: 1.9 years) received lentiviral-based HSPC-GT in a phase 1/2 clinical trial (NCT03488394). Clinical (growth, measures of kyphosis and genu velgum), functional (motor function, joint range of motion), and radiological [acetabular index (AI), migration percentage (MP) in hip x-rays and MRIs and spine MRI score] parameters of skeletal dysplasia were evaluated at baseline and multiple time points up to 4 years after treatment. Specific skeletal measures were retrospectively compared with an external cohort of HSCT-treated patients. At a median follow-up of 3.78 years after HSPC-GT, all patients treated with HSPC-GT exhibited longitudinal growth within WHO reference ranges and a median height gain greater than that observed in patients treated with HSCT after 3-year follow-up. Patients receiving HSPC-GT experienced complete and earlier normalization of joint mobility compared with patients treated with HSCT. Mean AI and MP showed progressive decreases after HSPC-GT, suggesting a reduction in acetabular dysplasia. Typical spine alterations measured through a spine MRI score stabilized after HSPC-GT. Clinical, functional, and radiological measures suggested an early beneficial effect of HSPC-GT on MPSIH-typical skeletal features. Longer follow-up is needed to draw definitive conclusions on HSPC-GT's impact on MPSIH skeletal dysplasia.
Topics: Humans; Mucopolysaccharidosis I; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Male; Female; Child, Preschool; Infant; Treatment Outcome; Hematopoietic Stem Cells; Child; Bone and Bones; Magnetic Resonance Imaging
PubMed: 38691622
DOI: 10.1126/scitranslmed.adi8214