Mucopolysaccharidosis type II in a female carrying a heterozygous stop mutation of the iduronate-2-sulfatase gene and showing a skewed X chromosome inactivation

Piña-Aguilar, Raúl E.; Zaragoza-Arévalo, Gerardo R.; Rau, Isabella; Gal, Andreas; Alcántara-Ortigoza, Miguel Ángel; López-Martı́nez, Mónica; Santillán-Hernández, Yuritzi

doi:10.1016/j.ejmg.2012.11.006

Cited by 17 publications

(19 citation statements)

References 18 publications

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“…In our results, 6 / 10 female carriers of MPS II showed skewed XCI pattern. This pattern was also described in previously published clinical case reports in females [9-18] and represents a higher rate than expected for healthy female population. As per Salsano et al investigation on X-linked adrenoleukodystrophy, moderately skewed XCI was found in 22.4% of healthy subjects in the control group [26] and Sharp et al obtained a rate of 16% in normal women over 60 years old [34].…”

Section: Discussionsupporting

confidence: 86%

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Clinical manifestations in female carriers of mucopolysaccharidosis type II: a spanish cross-sectional study

Guillén-Navarro

Domingo-Jiménez

Alcalde-Martin

et al. 2013

Orphanet Journal of Rare Diseases

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BackgroundMucopolysaccharidosis type II (MPS II) is an inherited X-linked disease associated with a deficiency in the enzyme iduronate 2-sulfatase due to iduronate 2-sulfatase gene (IDS) mutations. Recent studies in MPS II carriers did not find clinical involvement, but these were mainly performed by anamnesis and patients’ self-reported description of signs and symptoms. So although it is rare in heterozygous carriers, investigations in other types of inherited X-linked disorders suggest that some clinical manifestations may be a possibility. The aim of this study was to evaluate the clinical pattern in female carriers of MPS II and to determine whether clinical symptoms were associated with the X-chromosome inactivation (XCI) pattern and age.MethodsFemale carriers of MPS II were genetically identified by molecular analysis of IDS. The clinical evaluation protocol included pedigree analysis, a comprehensive anamnesis, complete physical examination, ophthalmological evaluation, brain-evoked auditory response, electrocardiogram, echocardiogram, pulmonary function tests, abdominal sonogram, skeletal survey, neurophysiological studies, blood cell counts and biochemistry, urine glycosaminoglycan (GAGs) quantification, karyotype and pattern of XCI.ResultsTen women were included in the study. The mean age of the participants was 40.2 ± 13.1 years. Six carriers presented a skewed XCI pattern, 3 of whom (aged 38, 42 and 52 years) had increased levels of GAGs in the urine and showed typical MPS II clinical manifestations, such as skeletal anomalies, liver abnormalities, carpal tunnel syndrome, recurrent ear infection, hypoacusia and more frequent severe odontological problems without coarse facial features.ConclusionsThis is the first study performing a comprehensive evaluation of heterozygous MPS II carriers. Our results provide evidence of possible progressive, age-dependent, mild clinical manifestations in MPS II female carriers with a skewed XCI pattern, most likely affecting the normal allele. Further comparative studies with systematized clinical examinations in larger age-stratified populations of MPS II female carriers are required.

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Section: Discussionsupporting

confidence: 86%

“…To date, 12 case reports of females affected with MPS II have been described in the literature; in 10 of these cases, the disease was associated with skewed XCI [9-18]. …”

Section: Introductionmentioning

confidence: 99%

Clinical manifestations in female carriers of mucopolysaccharidosis type II: a spanish cross-sectional study

Guillén-Navarro

Domingo-Jiménez

Alcalde-Martin

et al. 2013

Orphanet Journal of Rare Diseases

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“…A complete clinical MPSII picture in females is rare, with approximately 15 cases reported to date, including one of Mexican‐descent . The major implicated mechanism are skewed X‐inactivation in heterozygous females and translocations or large deletions of the X chromosome . None of the 24 mothers and 16 female relatives in this study was referred to have symptomatology of MPSII.…”

Section: Discussionmentioning

confidence: 80%

Wide allelic heterogeneity with predominance of large IDS gene complex rearrangements in a sample of Mexican patients with Hunter syndrome

et al. 2016

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Hunter syndrome or mucopolysaccharidosis type II (MPSII) is caused by pathogenic variants in the IDS gene. This is the first study that examines the mutational spectrum in 25 unrelated Mexican MPSII families. The responsible genotype was identified in 96% of the families (24/25) with 10 novel pathogenic variants: c.133G>C, c.1003C>T, c.1025A>C, c.463_464delinsCCGTATAGCTGG, c.754_767del, c.1132_1133del, c.1463del, c.508-1G>C, c.1006+1G>T and c.(-217_103del). Extensive IDS gene deletions were identified in four patients; using DNA microarray analysis two patients showed the loss of the entire AFF2 gene, and epilepsy developed in only one of them. Wide allelic heterogeneity was noted, with large gene alterations (e.g. IDS/IDSP1 gene inversions, partial to extensive IDS deletions, and one chimeric IDS-IDSP1 allele) that occurred at higher frequencies than previously reported (36% vs 18.9-29%). The frequency of carrier mothers (80%) is consistent with previous descriptions (>70%). Carrier assignment allowed molecular prenatal diagnoses. Notably, somatic and germline mosaicism was identified in one family, and two patients presented thrombocytopenic purpura and pancytopenia after idursulfase enzyme replacement treatment. Our findings suggest a wide allelic heterogeneity in Mexican MPSII patients; DNA microarray analysis contributes to further delineation of the resulting phenotype for IDS and neighboring loci deletions.

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“…Recently, female patients with mutations in X‐linked genes and presenting with predominant X‐inactivation of the apparent normal X chromosome have been reported for multiple disorders. These include MECP2 duplication [Fieremans et al., ], Wiskott‐Aldrich syndrome (MIM# 614493) [Boonyawat et al., ; Daza‐Cajigal et al., ], Duchenne muscular dystrophy (MIM# 310200) [Juan‐Mateu et al., ], Fabry disease (MIM# 301500) [Bouwman et al., ], and mucopolysaccharidosis type II (MIM# 309900) [Kloska et al., ; Pina‐Aguilar et al., ]. These findings strongly suggest that this “female X‐linked two‐hit model” can result in several X‐linked conditions.…”

Section: Discussionmentioning

confidence: 99%

Identification of Intellectual Disability Genes in Female Patients with a Skewed X-Inactivation Pattern

et al. 2016

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Intellectual disability (ID) is a heterogeneous disorder with an unknown molecular etiology in many cases. Previously, X-linked ID (XLID) studies focused on males due to the hemizygous state of their X chromosome. Carrier females are generally unaffected due to the presence of a second normal allele, or inactivation of the mutant X chromosome in most of their cells (skewing). However, in female ID patients, we hypothesized that the presence of skewing of X-inactivation would be an indicator for an X chromosomal ID cause. We analysed the X-inactivation patterns of 288 females with ID, and found that 22 (7.6%) had extreme skewing (>90%), which is significantly higher than observed in the general population (3.6%; p=0.029). Whole exome sequencing of 19 females with extreme skewing revealed causal variants in 6 females in the XLID genes DDX3X, NHS, WDR45, MECP2 and SMC1A. Interestingly, variants in genes escaping X-inactivation presumably cause both XLID and skewing of X-inactivation in 3 of these patients. Moreover, variants likely accounting for skewing only, were detected in MED12, HDAC8 and TAF9B. All tested candidate causative variants were de novo events. Hence, extreme skewing is a good indicator for the presence of X-linked variants in female patients.

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Mucopolysaccharidosis type II in a female carrying a heterozygous stop mutation of the iduronate-2-sulfatase gene and showing a skewed X chromosome inactivation

Cited by 17 publications

References 18 publications

Clinical manifestations in female carriers of mucopolysaccharidosis type II: a spanish cross-sectional study

Clinical manifestations in female carriers of mucopolysaccharidosis type II: a spanish cross-sectional study

Wide allelic heterogeneity with predominance of large IDS gene complex rearrangements in a sample of Mexican patients with Hunter syndrome

Identification of Intellectual Disability Genes in Female Patients with a Skewed X-Inactivation Pattern

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