Identification of 17 novel mutations in 40 Argentinean unrelated families with mucopolysaccharidosis type II (Hunter syndrome)

Amartino, Hernán; Ceci, Romina; Masllorens, Francisca; Gal, Andreas; Arberas, Claudia; Bay, Luisa; Ilari, Rita; Dipierri, José Edgardo; Spécola, Norma; Cabrera, A. Suarez; Rozenfeld, Paula

doi:10.1016/j.ymgmr.2014.08.006

Cited by 11 publications

(7 citation statements)

References 12 publications

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“…(Pro120Arg)–[27]Likely pathogenicc.592G>Ap. (Asp198Asn)ClinVar ID: 221210[1]Likely pathogenicc.589_592delp. (Pro197Thrfs*15)–NovelPathogenicc.708G>Ap.…”

Section: Resultsmentioning

confidence: 99%

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Molecular diagnosis of patients affected by mucopolysaccharidosis: a multicenter study

et al. 2019

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Mucopolysaccharidoses (MPS) are a subgroup of 11 monogenic lysosomal storage disorders due to the deficit of activity of the lysosomal hydrolases deputed to the degradation of mucopolysaccharides. Although individually rare, all together they account for at least 1:25,000 live births. In this study, we present the genetic analysis of a population of 71 MPS patients enrolled in a multicenter Italian study. We re-annotated all variants, according to the latest recommendations, and re-classified them as suggested by the American College of Medical Genetics and Genomics. Variant distribution per type was mainly represented by missense mutations. Overall, 10 patients had received no molecular diagnosis, although 6 of them had undergone either HSCT or ERT, based on clinical and enzymatic evaluations. Moreover, nine novel variants are reported. Conclusions : Our analysis underlines the need to complete the molecular diagnosis in patients previously diagnosed only on a biochemical basis, suggests a periodical re-annotation of the variants and solicits their deposition in public databases freely available to clinicians and researchers. We strongly recommend a molecular diagnosis based on the analysis of the “trio” instead of the sole proband. These recommendations will help to obtain a complete and correct diagnosis of mucopolysaccharidosis, rendering also possible genetic counseling. What is known • MPS are a group of 11 metabolic genetic disorders due to deficits of enzymes involved in the mucopolysaccharides degradation. • Molecular analysis is commonly performed to confirm enzymatic assays. What is new • Eighty-six percent of the 71 patients we collected received a molecular diagnosis; among them, 9 novel variants were reported. • We stress the importance of molecular diagnosis in biochemically diagnosed patients, encourage a periodical re-annotation of variants according to the recent nomenclature and their publication in open databases. Electronic supplementary material The online version of this article (10.1007/s00431-019-03341-8) contains supplementary material, which is available to authorized users.

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“…(Pro120Arg)–[27]Likely pathogenicc.592G>Ap. (Asp198Asn)ClinVar ID: 221210[1]Likely pathogenicc.589_592delp. (Pro197Thrfs*15)–NovelPathogenicc.708G>Ap.…”

Section: Resultsmentioning

confidence: 99%

“…(Pro120Arg)Severe (P13)Severe to intermediate [27]; severe [33]c.592G>Ap. (Asp198Asn)Severe (P22)Severe [1]c.708G>Ap. (Lys236Lys)Mild (P21)Intermediate [49]c.1264 T>Cp.…”

Section: Resultsmentioning

confidence: 99%

Molecular diagnosis of patients affected by mucopolysaccharidosis: a multicenter study

et al. 2019

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“…There is a high allelic heterogeneity among genes associated with MPS, which is the main cause of the wide spectrum observed in these disorders and cannot always be correlated with residual enzyme activity [108]. To date, more than 2200 mutations have been reported in all 11 genes related to MPS, with the majority of individuals showing private mutations (~70%) [109,110]. This broad mutational spectrum is composed mostly by missense/nonsense variants (64.6%), followed by small deletion/insertions/indels (19.6%), splicing defects (8.1%), complex rearrangements (4%), gross deletion/insertion/indels (3.6%) and defects in regulatory regions (0.2%) (http://www.hgmd.cf.ac.uk/ac) ( Table 4).…”

Section: Molecular Genetics Analysesmentioning

confidence: 99%

Diagnosis of Mucopolysaccharidoses

et al. 2020

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The mucopolysaccharidoses (MPSs) include 11 different conditions caused by specific enzyme deficiencies in the degradation pathway of glycosaminoglycans (GAGs). Although most MPS types present increased levels of GAGs in tissues, including blood and urine, diagnosis is challenging as specific enzyme assays are needed for the correct diagnosis. Enzyme assays are usually performed in blood, with some samples (as leukocytes) providing a final diagnosis, while others (such as dried blood spots) still being considered as screening methods. The identification of variants in the specific genes that encode each MPS-related enzyme is helpful for diagnosis confirmation (when needed), carrier detection, genetic counseling, prenatal diagnosis (preferably in combination with enzyme assays) and phenotype prediction. Although the usual diagnostic flow in high-risk patients starts with the measurement of urinary GAGs, it continues with specific enzyme assays and is completed with mutation identification; there is a growing trend to have genotype-based investigations performed at the beginning of the investigation. In such cases, confirmation of pathogenicity of the variants identified should be confirmed by measurement of enzyme activity and/or identification and/or quantification of GAG species. As there is a growing number of countries performing newborn screening for MPS diseases, the investigation of a low enzyme activity by the measurement of GAG species concentration and identification of gene mutations in the same DBS sample is recommended before the suspicion of MPS is taken to the family. With specific therapies already available for most MPS patients, and with clinical trials in progress for many conditions, the specific diagnosis of MPS as early as possible is becoming increasingly necessary. In this review, we describe traditional and the most up to date diagnostic methods for mucopolysaccharidoses.

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“…Kosuga et al [ 9 ] and a host of other authors [ [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] , [23] , [24] , [25] , [26] ] have found that deletions, recombination, frameshift and in most but not all cases, nonsense mutations are associated with severe forms of the disease. This literature also points to a subset of missense mutations that also lead to severe forms, while the majority of missense mutations result in attenuated disease.…”

Section: Introductionmentioning

confidence: 99%

Natural history of cognitive development in neuronopathic mucopolysaccharidosis type II (Hunter syndrome): Contribution of genotype to cognitive developmental course

Seo

Okuyama

Shapiro

et al. 2020

Molecular Genetics and Metabolism Reports

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The natural history of cognitive growth in the neuronopathic form of Mucopolysaccharidosis type II (MPS II) is not well defined especially their patterns of development and decline. The ability to predict the developmental course of the neurologically impaired patient is necessary to assess treatment outcomes aimed at the brain. Thirteen intravenous enzyme replacement therapy-treated Japanese patients with neuronopathic MPSII who had mutation analysis were followed on one standard measure of cognitive development over time. Six children in Group MS had missense mutations and 7 children in Group NT had null type mutations such as deletions, recombination with the pseudogene, and nonsense mutations. The patients as a whole demonstrated cognitive growth until about 36–42 months of age, followed by a plateau in development. The mean age equivalent score at age 3 was similar to that at age 6. While the decline was slow for the entire group, the patients in Group NT showed a more rapid decline than those in Group MS. Two patients with deletions showed decline to a very low level by age 5. The long plateau in cognitive development in patents with MPS II was substantiated and was consistent with other studies. This is the first demonstration that different mutation types within the neuronopathic MPS II patients are associated with different rates of decline. We also were able to identify the chronological age before which a trial would need to start in order to maintain cognitive growth and a ceiling beyond which a relatively normal outcome would not be likely.

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Identification of 17 novel mutations in 40 Argentinean unrelated families with mucopolysaccharidosis type II (Hunter syndrome)

Cited by 11 publications

References 12 publications

Molecular diagnosis of patients affected by mucopolysaccharidosis: a multicenter study

Molecular diagnosis of patients affected by mucopolysaccharidosis: a multicenter study

Diagnosis of Mucopolysaccharidoses

Natural history of cognitive development in neuronopathic mucopolysaccharidosis type II (Hunter syndrome): Contribution of genotype to cognitive developmental course

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