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American Journal of Hematology May 2021
Topics: Abnormalities, Multiple; Adolescent; Basophils; Cytoplasmic Granules; Delayed Diagnosis; Eosinophils; Female; Flow Cytometry; Glycosaminoglycans; Humans; Mucopolysaccharidosis VII; Psychomotor Disorders; Staining and Labeling
PubMed: 32857898
DOI: 10.1002/ajh.25984 -
JIMD Reports Sep 2019Mucopolysaccharidoses VII, or Sly syndrome, is linked to mutations in the beta-glucuronidase encoding gene. Sly syndrome is a rare condition and presentation is highly...
Mucopolysaccharidoses VII, or Sly syndrome, is linked to mutations in the beta-glucuronidase encoding gene. Sly syndrome is a rare condition and presentation is highly variable, ranging from a prenatal form with severe, lethal fetal hydrops to more benign adolescent or adult forms with simple thoracic kyphosis. Molecular diagnosis of this adult male patient identified two missense mutations in the gene that led to a deficiency in beta-glucuronidase catalytic activity and the resulting accumulation of chondroitin sulfate glycosaminoglycans. During childhood, bilateral inguinal hernia was repaired at 1 year of age and gait abnormalities were noted, leading to a bilateral femoral varization osteotomy due to a bilateral coxa valga with hip subluxation at the age of 7.5. The patient suffered regular upper respiratory infections and required numerous orthopedic surgeries. Despite learning difficulties with visual and hearing deficits, the patient worked full-time and undertook regular leisure activities. At 33 years of age, the patient's health deteriorated; a hip replacement and glaucoma leading to reductions in his visual field limited his capacity to travel independently. The patient was hospitalized at 51. Although he remained self-sufficient for taking meals, he needed help with many daily activities. Following a period marked by major asthenia with a general loss of autonomy, the patient died at 52 years of age. With the advent of new enzyme replacement therapies, this medical history of this rare untreated attenuated patient may provide benchmarks to judge the efficacy of treatment in future patients.
PubMed: 31497474
DOI: 10.1002/jmd2.12039 -
Iranian Journal of Child Neurology 2020Mucopolysaccharidosis type VII (MPS VII) or Sly syndrome is a rare autosomal recessive disorder caused by deficiency of β-glucuronidase enzyme, which is involved in...
Mucopolysaccharidosis type VII (MPS VII) or Sly syndrome is a rare autosomal recessive disorder caused by deficiency of β-glucuronidase enzyme, which is involved in degradation of glycosaminoglycans. The lack of β-glucuronidase in this lysosomal storage disorder is characterized by various manifestations such as nonimmune hydrops fetalis, spinal deformity, organomegaly, dysostosis multiplex, intellectual disability, and eye involvement. It is caused by a mutation in gene located on chromosome 7 q11. The current study reported an Iranian female with MPS VII and a novel mutation (c.542G>T, p.Arg181Leu) in gene.
PubMed: 32256629
DOI: No ID Found -
Molecular Genetics and Metabolism... Dec 2020Bone elongation is driven by chondrocyte proliferation and hypertrophy in the growth plate. Both processes are modulated by multiple signaling pathways including the...
Bone elongation is driven by chondrocyte proliferation and hypertrophy in the growth plate. Both processes are modulated by multiple signaling pathways including the Indian Hedgehog (IHH) signaling pathway. Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders characterized by accumulation of glycosaminoglycans (GAGs) in multiple tissues and organs, leading to a range of clinical symptoms including bone shortening through mechanisms that are not fully understood. Using MPS VII mice, we previously observed a reduction in the number of proliferating and hypertrophic chondrocytes and a reduced gene expression of in the tibial growth plate. We further demonstrate here that IHH secretion by MPS VII chondrocytes was reduced both . While normal chondrocytes showed no response to exogenous IHH, proliferation of MPS VII chondrocytes was stimulated in response to exogenous IHH . This was accompanied by an elevated gene expression of patched receptor (). The results from this study suggested that reduced proliferation in MPS VII growth plate may be partially due to dysfunction of the IHH signaling pathway.
PubMed: 33117654
DOI: 10.1016/j.ymgmr.2020.100668 -
Current Issues in Molecular Biology Mar 2024Mucopolysaccharidoses (MPS) are a group of diseases caused by mutations in genes encoding lysosomal enzymes that catalyze reactions of glycosaminoglycan (GAG)...
Mucopolysaccharidoses (MPS) are a group of diseases caused by mutations in genes encoding lysosomal enzymes that catalyze reactions of glycosaminoglycan (GAG) degradation. As a result, GAGs accumulate in lysosomes, impairing the proper functioning of entire cells and tissues. There are 14 types/subtypes of MPS, which are differentiated by the kind(s) of accumulated GAG(s) and the type of a non-functional lysosomal enzyme. Some of these types (severe forms of MPS types I and II, MPS III, and MPS VII) are characterized by extensive central nervous system disorders. The aim of this work was to identify, using transcriptomic methods, organelle-related genes whose expression levels are changed in neuronopathic types of MPS compared to healthy cells while remaining unchanged in non-neuronopathic types of MPS. The study was conducted with fibroblast lines derived from patients with neuronopathic and non-neuronopathic types of MPS and control (healthy) fibroblasts. Transcriptomic analysis has identified genes related to cellular organelles whose expression is altered. Then, using fluorescence and electron microscopy, we assessed the morphology of selected structures. Our analyses indicated that the genes whose expression is affected in neuronopathic MPS are often associated with the structures or functions of the cell nucleus, endoplasmic reticulum, or Golgi apparatus. Electron microscopic studies confirmed disruptions in the structures of these organelles. Special attention was paid to up-regulated genes, such as and , and down-regulated genes, such as , , , , and . Of particular interest is also the () gene, which encodes golgin A2, which revealed an increased expression in neuronopathic MPS types. We propose to consider the levels of mRNAs of these genes as candidates for biomarkers of neurodegeneration in MPS. These genes may also become potential targets for therapies under development for neurological disorders associated with MPS and candidates for markers of the effectiveness of these therapies. Although fibroblasts rather than nerve cells were used in this study, it is worth noting that potential genetic markers characteristic solely of neurons would be impractical in testing patients, contrary to somatic cells that can be relatively easily obtained from assessed persons.
PubMed: 38534785
DOI: 10.3390/cimb46030169 -
International Journal of Molecular... Oct 2019We report the case of a boy who was diagnosed with mucopolysaccharidosis (MPS) VII at two weeks of age. He harbored three missense β-glucuronidase ( variations in exon...
We report the case of a boy who was diagnosed with mucopolysaccharidosis (MPS) VII at two weeks of age. He harbored three missense β-glucuronidase ( variations in exon 3: two novel, c.422A>C and c.424C>T, inherited from his mother, and the rather common c.526C>T, inherited from his father. Expression of these variations in transfected HEK293T cells demonstrated that the double mutation c.422A>C;424C>T reduces β-glucuronidase enzyme activity. Enzyme replacement therapy (ERT), using UX003 (vestronidase alfa), was started at four months of age, followed by a hematopoietic stem cell allograft transplantation (HSCT) at 13 months of age. ERT was well tolerated and attenuated visceromegaly and skin infiltration. After a severe skin and gut graft-versus-host disease, ERT was stopped six months after HSCT. The last follow-up examination (at the age of four years) revealed a normal psychomotor development, stabilized growth curve, no hepatosplenomegaly, and no other organ involvement. Intriguingly, enzyme activity had normalized in leukocytes but remained low in plasma. This case report illustrates: (i) The need for an early diagnosis of MPS, and (ii) the possible benefit of a very early enzymatic and/or cellular therapy in this rare form of lysosomal storage disease.
Topics: Combined Modality Therapy; Enzyme Replacement Therapy; Glucuronidase; HEK293 Cells; Hematopoietic Stem Cell Transplantation; Hepatomegaly; Humans; Infant, Newborn; Leukocytes; Male; Mucopolysaccharidosis VII; Mutation; Splenomegaly
PubMed: 31661765
DOI: 10.3390/ijms20215345 -
Molecular Genetics and Metabolism... Mar 2024Non-immune hydrops fetalis (NIHF) is a common and severe manifestation of many genetic disorders. The ultrasound is an ideal method for diagnosing hydrops fetalis during...
A homozygous missense mutation of the GUSB gene leads to mucopolysaccharidosis type VII identification in a family with twice adverse pregnancy outcomes due to non-immune hydrops fetalis.
Non-immune hydrops fetalis (NIHF) is a common and severe manifestation of many genetic disorders. The ultrasound is an ideal method for diagnosing hydrops fetalis during pregnancy. Since most NIHFs do not have an identifiable cause, determining the underlying etiology remains a challenge for prenatal counseling. Due to advancements in exome sequencing, the diagnostic rates of NIHF have recently increased. As reported here, DNA was extracted from the amniotic fluid of a pregnant woman who was prenatally diagnosed with a NIHF type of unclear origin. Amniocentesis sampling demonstrated a normal female karyotype and copy number variation(CNVs) without alterations. Tri-whole exome sequencing (WES) was conducted to identify possible causative variants. In the fetus, a genetic mutation was identified as a homozygous form. The mutation was located on the glucuronidase beta (GUSB) gene: NM_000181.3: c.1324G > A; p. Ala442Thr; Chr7:65439349, which leads to mucopolysaccharidosis type VII. This mutation was inherited from the parents and was first reported to be related to NIHF. We conclude that the use of WES is beneficial for NIHF cases whose prognosis has not been explained by standard genetic testing.
PubMed: 38149215
DOI: 10.1016/j.ymgmr.2023.101033