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Orphanet Journal of Rare Diseases Apr 2024Mucopolysaccharidoses (MPSs) are caused by a deficiency in the enzymes needed to degrade glycosaminoglycans (GAGs) in the lysosome. The storage of GAGs leads to the... (Review)
Review
Mucopolysaccharidoses (MPSs) are caused by a deficiency in the enzymes needed to degrade glycosaminoglycans (GAGs) in the lysosome. The storage of GAGs leads to the involvement of several systems and even to the death of the patient. In recent years, an increasing number of therapies have increased the treatment options available to patients. Early treatment is beneficial in improving the prognosis, but children with MPSs are often delayed in their diagnosis. Therefore, there is an urgent need to develop a method for early screening and diagnosis of the disease. Tandem mass spectrometry (MS/MS) is an analytical method that can detect multiple substrates or enzymes simultaneously. GAGs are reliable markers of MPSs. MS/MS can be used to screen children at an early stage of the disease, to improve prognosis by treating them before symptoms appear, to evaluate the effectiveness of treatment, and for metabolomic analysis or to find suitable biomarkers. In the future, MS/MS could be used to further identify suitable biomarkers for MPSs for early diagnosis and to detect efficacy.
Topics: Humans; Mucopolysaccharidoses; Tandem Mass Spectrometry; Biomarkers; Glycosaminoglycans
PubMed: 38685110
DOI: 10.1186/s13023-024-03195-w -
Journal of Communication Disorders 2024To investigate the peripheral and central auditory pathways in mucopolysaccharidosis (MPS) individuals.
OBJECTIVE
To investigate the peripheral and central auditory pathways in mucopolysaccharidosis (MPS) individuals.
METHOD
The research sample comprised 15 individuals (one female and 14 males), aged 8 to 46 years. The following procedures were used: medical history survey, otoscopy, speech and pure-tone threshold audiometry, acoustic immittance measures, and central auditory pathway assessment with brainstem auditory evoked potentials (BAEP) and long-latency auditory evoked potentials (LLAEP).
RESULTS
The pure-tone audiometry identified hearing loss in 13 individuals, and more than 90 % of the hearing loss was sensorineural. The degree of hearing loss was between mild to moderately severe with descendent configuration. Type A tympanogram predominated, and acoustic reflexes were present according to the types and degrees of hearing loss. Among the individuals with abnormal BAEP, longer wave III and V absolute latencies were the main findings. In addition, the unilateral absence of wave I was observed in two cases. In the LLAEP, longer latencies were observed in 14 individuals, and the most impaired components were the P1 and P3 in children and adolescents and the P2, N2 and P3 in adult individuals.
CONCLUSION
The peripheral auditory pathway assessment revealed a predominantly sensorineural hearing loss, affecting mainly high frequencies, and in the central pathway was observed abnormal brainstem and cortical auditory processing in individuals with MPS.
Topics: Male; Adult; Child; Adolescent; Humans; Female; Auditory Pathways; Evoked Potentials, Auditory, Brain Stem; Evoked Potentials, Auditory; Auditory Perception; Hearing Loss, Sensorineural; Deafness
PubMed: 38096654
DOI: 10.1016/j.jcomdis.2023.106402 -
American Journal of Physiology. Lung... Jun 2024Mucopolysaccharidosis type IIIA (MPS IIIA) is characterized by neurological and skeletal pathologies caused by reduced activity of the lysosomal hydrolase, sulfamidase,...
Mucopolysaccharidosis type IIIA (MPS IIIA) is characterized by neurological and skeletal pathologies caused by reduced activity of the lysosomal hydrolase, sulfamidase, and the subsequent primary accumulation of undegraded heparan sulfate (HS). Respiratory pathology is considered secondary in MPS IIIA and the mechanisms are not well understood. Changes in the amount, metabolism, and function of pulmonary surfactant, the substance that regulates alveolar interfacial surface tension and modulates lung compliance and elastance, have been reported in MPS IIIA mice. Here we investigated changes in lung function in 20-wk-old control and MPS IIIA mice with a closed and open thoracic cage, diaphragm contractile properties, and potential parenchymal remodeling. MPS IIIA mice had increased compliance and airway resistance and reduced tissue damping and elastance compared with control mice. The chest wall impacted lung function as observed by an increase in airway resistance and a decrease in peripheral energy dissipation in the open compared with the closed thoracic cage state in MPS IIIA mice. Diaphragm contractile forces showed a decrease in peak twitch force, maximum specific force, and the force-frequency relationship but no change in muscle fiber cross-sectional area in MPS IIIA mice compared with control mice. Design-based stereology did not reveal any parenchymal remodeling or destruction of alveolar septa in the MPS IIIA mouse lung. In conclusion, the increased storage of HS which leads to biochemical and biophysical changes in pulmonary surfactant also affects lung and diaphragm function, but has no impact on lung or diaphragm structure at this stage of the disease. Heparan sulfate storage in the lungs of mucopolysaccharidosis type IIIA (MPS IIIA) mice leads to changes in lung function consistent with those of an obstructive lung disease and includes an increase in lung compliance and airway resistance and a decrease in tissue elastance. In addition, diaphragm muscle contractile strength is reduced, potentially further contributing to lung function impairment. However, no changes in parenchymal lung structure were observed in mice at 20 wk of age.
Topics: Animals; Diaphragm; Lung Compliance; Airway Resistance; Mice; Pulmonary Alveoli; Mucopolysaccharidosis III; Muscle Contraction; Mice, Inbred C57BL; Disease Models, Animal; Muscle Strength; Lung; Male
PubMed: 38469649
DOI: 10.1152/ajplung.00445.2022 -
American Journal of Medical Genetics.... May 2024Mucopolysaccharidosis type IIIA (MPS IIIA or Sanfilippo syndrome type A) is an autosomal recessive lysosomal storage disorder caused by pathogenic variants in the SGSH...
Mucopolysaccharidosis type IIIA (MPS IIIA or Sanfilippo syndrome type A) is an autosomal recessive lysosomal storage disorder caused by pathogenic variants in the SGSH gene encoding N-sulfoglucosamine sulfohydrolase, an enzyme involved in the degradation of heparan sulfate. MPS IIIA is typically characterized by neurocognitive decline and hepatosplenomegaly with childhood onset. Here, we report on a 53-year-old male subject initially diagnosed with Usher syndrome for the concurrence of retinitis pigmentosa and sensorineural hearing loss. Clinical exome sequencing identified biallelic missense variants in SGSH, and biochemical assays showed complete deficiency of sulfamidase activity and increased urinary glycosaminoglycan excretion. Reverse phenotyping revealed left ventricle pseudo-hypertrophy, hepatosplenomegaly, bilateral deep white matter hyperintensities upon brain MRI, and decreased cortical metabolic activity by PET-CT. On neuropsychological testing, the proband presented only partial and isolated verbal memory deficits. This case illustrates the power of unbiased, comprehensive genetic testing for the diagnosis of challenging mild or atypical forms of MPS IIIA.
Topics: Male; Humans; Child; Middle Aged; Mucopolysaccharidosis III; Hydrolases; Positron Emission Tomography Computed Tomography; Usher Syndromes; Genetic Testing; Hepatomegaly
PubMed: 38149346
DOI: 10.1002/ajmg.a.63517 -
AJNR. American Journal of Neuroradiology Aug 2023Posterior fossa "horns" caused by internal hypertrophy of the occipitomastoid sutures are one of the more recently defined cranial abnormalities described in...
Posterior fossa "horns" caused by internal hypertrophy of the occipitomastoid sutures are one of the more recently defined cranial abnormalities described in mucopolysaccharidoses, especially in Hurler Syndrome. However, details of this finding, including the development and natural history, are not well-understood. Two hundred eighty-six brain MR imaging studies of 61 patients with mucopolysaccharidosis I-Hurler syndrome treated at single institution between 1996 and 2015 were studied. Posterior fossa horn height was measured as the perpendicular distance from the tip of the horn to the expected curvature of the occipital inner table. Fifty-seven of the 61 patients (93.4%) had evidence of posterior fossa horns on at least one occasion. The initial average height of the right horn was 4.5 mm, and the left horn, 4.7 mm. Most of the posterior horns regressed before transplantation in our cohort, though the exact age was variable among the patients. Nearly all patients in our cohort had posterior fossa horns, and these horns regressed with age. The regression of the horns frequently started before transplantation. This trend has not been previously described, and it may suggest unknown effects of mucopolysaccharidosis on skull development.
Topics: Humans; Mucopolysaccharidosis I; Prevalence; Skull; Brain; Head; Cranial Fossa, Posterior
PubMed: 37414449
DOI: 10.3174/ajnr.A7931 -
American Journal of Medical Genetics.... Sep 2023Mucopolysaccharidosis type III (MPS III) is a rare autosomal recessive lysosomal storage disorder characterized by progressive neurocognitive deterioration. There are...
Mucopolysaccharidosis type III (MPS III) is a rare autosomal recessive lysosomal storage disorder characterized by progressive neurocognitive deterioration. There are four MPS III subtypes (A, B, C, and D) that are clinically indistinguishable with variable rates of progression. A retrospective analysis was carried out on 34 patients with MPS III types at Cairo University Children's Hospital. We described the clinical, biochemical, and molecular spectrum of MPS III patients. Of 34 patients, 22 patients had MPS IIIB, 7/34 had MPS IIIC, 4/34 had MPS IIIA, and only 1 had MPS IIID. All patients presented with developmental delay/intellectual disability, and speech delay. Ataxia was reported in a patient with MPS IIIC, and cerebellar atrophy in a patient with MPS IIIA. We reported 25 variants in the 4 MPS III genes, 11 of which were not previously reported. This is the first study to analyze the clinical and genetic spectrum of MPS III patients in Egypt. This study explores the genetic map of MPS III in the Egyptian population. It will pave the way for a national registry for rare diseases in Egypt, a country with a high rate of consanguineous marriage and consequently a high rate of autosomal recessive disorders.
Topics: Child; Humans; Mucopolysaccharidosis III; Egypt; Retrospective Studies; Lysosomal Storage Diseases; Ataxia
PubMed: 37596900
DOI: 10.1002/ajmg.a.63342 -
Neurology Oct 2023Mucopolysaccharidosis IIID (MPS IIID/Sanfilippo syndrome D, OMIM # 252940) is an autosomal recessive lysosomal storage disorder (LSD) and the rarest form of the...
Mucopolysaccharidosis IIID (MPS IIID/Sanfilippo syndrome D, OMIM # 252940) is an autosomal recessive lysosomal storage disorder (LSD) and the rarest form of the mucopolysaccharidosis (MPS) III subtypes. It is caused by sequence variations in the gene encoding lysosomal enzyme N-acetyl glucosamine-6-sulphatase (GNS). Deficiency of GNS impairs catabolism of glycosaminoglycans causing accumulation of heparan sulphate within lysosomes of various tissues, which is visualized as membranous cytoplasmic bodies (MCBs) on electron microscopy. The recognition of this ultrastructural feature in a muscle biopsy instigated genetic evaluation for LSD in our case resulting in the detection of a novel pathogenic gene variant. The patient also exhibited intellectual disability since childhood, reduced vision due to pigmentary retinopathy, and behavioral abnormalities without other systemic features of MPS. In this study, we report a patient of Indian origin with MPS IIID based on a novel pathogenic variant c.1078 G>T (p.G360C) in the and the presence of MCBs in muscle biopsy, characterized by several novel findings including the occurrence of pigmentary retinopathy, which extends the clinical spectrum of MPS IIID.
Topics: Humans; Child; Mucopolysaccharidosis III; Glycosaminoglycans; Genomics; Recognition, Psychology; Retinitis Pigmentosa
PubMed: 37487748
DOI: 10.1212/WNL.0000000000207647 -
Journal, Genetic Engineering &... Nov 2023One of the 11 recognized mucopolysaccharidosis (MPS) diseases is Sanfilippo. It is autosomal recessive in its mode of transmission. There are four subtypes of Sanfilippo...
BACKGROUND
One of the 11 recognized mucopolysaccharidosis (MPS) diseases is Sanfilippo. It is autosomal recessive in its mode of transmission. There are four subtypes of Sanfilippo (A, B, C, and D). The most worldwide prevalent subtypes of mucopolysaccharidosis type III (MPS III) are A and B followed by C and D subtypes. To estimate the frequency of MPS IIIA among MPS III patients, we diagnose and compare their clinical features with those of MPS IIIB and also compare the prevalence of MPS IIIB versus MPS IIIA among diagnosed cases at the Biochemical Genetic Department at NRC. For every case that was referred, the quantitative determination of urine Glycosaminoglycans (GAGs) was assessed. Two-dimensional electrophoresis (2DE) of GAGs extracted from urine was performed on all cases with high urinary GAG levels. Both N-sulphoglucosamine sulphohydrolase (MPS IIIA) and N-alpha-acetylglucosaminidase (MPS IIIB) enzyme activity were determined fluorometrically.
RESULTS
From November 2019 to May 2022, 535 cases were referred to the National Research Centre's Biochemical Genetics Department. 233 (43%) MPS cases were diagnosed with high urinary GAG levels for their ages. 73 (31.3%) MPS III cases were diagnosed by 2DE out of the 233 MPS cases. Plasma N-alpha-acetylglucosaminidase enzyme assay was insufficient in 36 (49.3%) patients (Sanfilippo type B), while N-sulphoglucosamine sulphohydrolase enzyme activity was deficient in 15 (20.6%) patients. The other 22 (30.1%) patients are either Sanfilippo type C or D.
CONCLUSION
N-sulphoglucosamine sulphohydrolase enzyme activity was measured for the first time in Egypt. Thirty-one percent of all diagnosed MPS cases during the last 3 years were MPS type III, making Sanfilippo the most common MPS type among the referred cases to our Biochemical Genetics Department. MPS IIIA accounts for 20.6% of MPSIII cases in this study. Still, MPS type IIIB is the commonest type among diagnosed patients.
PubMed: 37947910
DOI: 10.1186/s43141-023-00586-7 -
Clinical Chemistry Jun 2024Mucopolysaccharidosis (MPS) and glycoproteinosis are 2 groups of heterogenous lysosomal storage disorders (LSDs) caused by defective degradation of glycosaminoglycans...
Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry Analysis of Urinary Oligosaccharides and Glycoamino Acids for the Diagnosis of Mucopolysaccharidosis and Glycoproteinosis.
BACKGROUND
Mucopolysaccharidosis (MPS) and glycoproteinosis are 2 groups of heterogenous lysosomal storage disorders (LSDs) caused by defective degradation of glycosaminoglycans (GAGs) and glycoproteins, respectively. Oligosaccharides and glycoamino acids have been recognized as biomarkers for MPS and glycoproteinosis. Given that both groups of LSDs have overlapping clinical features, a multiplexed assay capable of unambiguous subtyping is desired for accurate diagnosis, and potentially for severity stratification and treatment monitoring.
METHODS
Urinary oligosaccharides were derivatized with 3-methyl-1-phenyl-2-pyrazoline-5-one (PMP) and analyzed by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) together with the underivatized glycoamino acids. Novel biomarkers were identified with a semi-targeted approach with precursor mass scanning, the fragmentation pattern (if applicable), and the biochemical basis of the condition.
RESULTS
A UPLC-MS/MS analysis with improved chromatographic separation was developed. Novel biomarkers for MPS-IIIA, IIIB, IIIC, and VII were identified and validated. A total of 28 oligosaccharides, 2 glycoamino acids, and 2 ratios were selected as key diagnostic biomarkers. Validation studies including linearity, lower limit of quantitation (LLOQ), and precision were carried out with the assay performance meeting the required criteria. Age-specific reference ranges were collected. In the 76 untreated patients, unambiguous diagnosis was achieved with 100% sensitivity and specificity. Additionally, the levels of disease-specific biomarkers were substantially reduced in the treated patients.
CONCLUSIONS
A multiplexed UPLC-MS/MS assay for urinary oligosaccharides and glycoamino acids measurement was developed and validated. The assay is suitable for the accurate diagnosis and subtyping of MPS and glycoproteinosis, and potentially for severity stratification and monitoring response to treatment.
Topics: Humans; Tandem Mass Spectrometry; Oligosaccharides; Child; Chromatography, High Pressure Liquid; Child, Preschool; Biomarkers; Mucopolysaccharidoses; Adolescent; Glycoproteins; Infant; Male; Female; Adult; Amino Acids; Young Adult
PubMed: 38597162
DOI: 10.1093/clinchem/hvae043 -
Molecular Genetics and Metabolism 2023We describe our experience with population-based newborn screening for mucopolysaccharidosis type II (MPS II) in 586,323 infants by measurement of iduronate-2-sulfatase...
We describe our experience with population-based newborn screening for mucopolysaccharidosis type II (MPS II) in 586,323 infants by measurement of iduronate-2-sulfatase activity in dried blood spots between December 12, 2017 and April 30, 2022. A total of 76 infants were referred for diagnostic testing, 0.01% of the screened population. Of these, eight cases of MPS II were diagnosed for an incidence of 1 in 73,290. At least four of the eight cases detected had an attenuated phenotype. In addition, cascade testing revealed a diagnosis in four extended family members. Fifty-three cases of pseudodeficiency were also identified, for an incidence of 1 in 11,062. Our data suggest that MPS II may be more common than previously recognized with a higher prevalence of attenuated cases.
Topics: Infant; Infant, Newborn; Humans; Mucopolysaccharidosis II; Neonatal Screening; Incidence; Family; Iduronate Sulfatase
PubMed: 36907694
DOI: 10.1016/j.ymgme.2023.107557