Sexual behaviour in a murine model of mucopolysaccharidosis type I (MPS I)

AbstractMucopolysaccharidosis Type I (MPS I) is a rare genetic lysosomal storage disease caused by a mutation of IDUA gene. IDUA codes for α-L-iduronidase (IDUA), a lysosomal hydrolase that degrades glycosaminoglycans (GAGs): heparan sulphate and dermatan sulphate. GAGs are structural and signalling molecules that have a crucial role in controlling a variety of cell functions and their interaction with extracellular matrix. Because of GAG’s widespread action in cellular metabolism, MPS I is a progressive and disabling multisystemic disorder. Nowadays, the therapies availability allowed patients to reach the adult life and the consequences of the disease in their reproductive system is still little known. We aimed to investigate whether IDUA disruption influences sexual behaviour and sexual steroid production in male and female MPS I mice. We used 3 and 6-month-old male and 3-month-old female Idua+/_ and Idua−/− mice to evaluate typical rodent copulatory behaviours. In males we observed the frequency and latency of mounts, intromissions and ejaculations. In females we evaluated the lordosis quotient. We also analysed the locomotor capacity of mice in the open field test, since copulatory behaviour requires mobility. We also quantified steroidal hormonal levels in plasmatic samples. We detected an increase in the latencies of intromissions in male copulatory behaviour of Idua−/− males when compared to Idua+/_. However, the number of intromissions was not statistically different between groups. No parameter of female sexual behaviour was statistically different between control and knockout females. In both sexes, we detected diminished mobility in Idua−/− mice. Plasma hormone levels did not differ between Idua+/_ and Idua−/− mice, both in males and females. We concluded that in the considered time point of MPS I progression, mice are able to perform sexual behaviour, but the male performance may be influenced due to the motor disability predicted to MPS I.

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69. Gene therapy of mucopolysaccharidosis type I: Intraventricular administration of adeno-associated virus vector transducing the human alpha-l-iduronidase gene in a murine model of the disease

Molecular Genetics and Metabolism ◽

10.1016/j.ymgme.2007.10.081 ◽

2008 ◽

Vol 93 (2) ◽

pp. 31

Author(s):

R. Scott McIvor ◽

Daniel A. Wolf ◽

Zhenhong Nan ◽

Mayra Quito ◽

Kelly Podetz-Pedersen ◽

...

Keyword(s):

Gene Therapy ◽

Murine Model ◽

Virus Vector ◽

Type I ◽

Intraventricular Administration ◽

Mucopolysaccharidosis Type ◽

Mucopolysaccharidosis Type I ◽

Adeno Associated Virus

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Mucopolysaccharidosis type I - Clinical and genetic characteristics of Romanian patients

Revista Romana de Medicina de Laborator ◽

10.2478/rrlm-2020-0030 ◽

2020 ◽

Vol 28 (3) ◽

pp. 279-286

Author(s):

Camelia Alkhzouz ◽

Cecilia Lazea ◽

Diana Miclea ◽

Carmen Asavoaie ◽

Ioana Nascu ◽

...

Keyword(s):

Severe Form ◽

The Other ◽

Compound Heterozygous ◽

Type I ◽

Ophthalmological Examination ◽

Mucopolysaccharidosis Type ◽

Hurler Syndrome ◽

Mucopolysaccharidosis Type I ◽

Genetic Characteristics ◽

Mps I

AbstractBackground: Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder caused by a deficiency of α-L-iduronidase (IDUA), which leads to the accumulation of partially digested glycosaminoglycans (dermatan sulfate and heparan sulfate) in the lysosomes and induces multisystemic alteration. Hurler (severe), Scheie (mild), and Hurler/Scheie (intermediate) syndromes are clinical subtypes of MPS-I. To date, more than 290 IDUA mutations have been reported. The purpose of this study was to present the clinical and genetic characteristics of Romanian MPS I syndrome patients and their genotype-phenotype correlation.Patients and methods: Seven patients (5 girls and 2 boys) with MPS type I, belonging to 4 unrelated families, aged 0,75-17.9 years, were enrolled. The study methods consisted in: clinical and standard auxological assessment, bone radiographs, joint ultrasonography, goniometry, neurological and psychological evaluation, hepatic and splenic ultrasonography, cardiological evaluation, otorhinolaryngology examination, ophthalmological examination, spirometry, α-L-iduronidase enzyme activity assay and molecular analysis.Results: The seven patients originated from 4 unrelated families, three patients with severe, two patients with intermediate and two with attenuated clinical phenotype. Each patient presented the classical picture of MPS type I picture, represented by: variable coarse facial features, arthropathy, hepatosplenomegaly, cardiac involvement, respiratory dysfunction and neurological impairment. Five patological variants, three point mutations (p.Q70 *, p.I238Q and p.K324R), two deletion c.1045_1047delGAC, c.46_57delTCGCTCCTG) and an insertion (c.1389 insC) were identified in both alleles of the ADUA gene in homozygous or heterozygous form. Two novel mutations (p.K324R and c.1389 insC) were reported. The p.Q70*(c.208C>T) variant was identified in 2 families with severe form of disease (Hurler syndrome) in homozygous status in one family and in compound heterozygous status in the other family.Conclusion: The p.Q70* missense variant was the most frequent, correlated in all the cases who presented it with severe form, Hurler syndrome, the other mutations being usually isolated and particular for each patient, associated in our patients with less severe MPS I phenotype, as Hurler-Scheie or Scheie syndrome. The results of this study indicated the mutational heterogeneity of the IDUA gene and the difficulty to indicate some correlation between the genotype and phenotype in MPS I patients.

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Incorporation of Second-Tier Biomarker Testing Improves the Specificity of Newborn Screening for Mucopolysaccharidosis Type I

International Journal of Neonatal Screening ◽

10.3390/ijns6010010 ◽

2020 ◽

Vol 6 (1) ◽

pp. 10 ◽

Cited By ~ 5

Author(s):

Dawn S. Peck ◽

Jean M. Lacey ◽

Amy L. White ◽

Gisele Pino ◽

April L. Studinski ◽

...

Keyword(s):

Newborn Screening ◽

False Positive ◽

Dermatan Sulfate ◽

False Positive Rate ◽

False Negative ◽

Type I ◽

Mucopolysaccharidosis Type ◽

Mucopolysaccharidosis Type I ◽

Second Tier ◽

Mps I

Enzyme-based newborn screening for Mucopolysaccharidosis type I (MPS I) has a high false-positive rate due to the prevalence of pseudodeficiency alleles, often resulting in unnecessary and costly follow up. The glycosaminoglycans (GAGs), dermatan sulfate (DS) and heparan sulfate (HS) are both substrates for α-l-iduronidase (IDUA). These GAGs are elevated in patients with MPS I and have been shown to be promising biomarkers for both primary and second-tier testing. Since February 2016, we have measured DS and HS in 1213 specimens submitted on infants at risk for MPS I based on newborn screening. Molecular correlation was available for 157 of the tested cases. Samples from infants with MPS I confirmed by IDUA molecular analysis all had significantly elevated levels of DS and HS compared to those with confirmed pseudodeficiency and/or heterozygosity. Analysis of our testing population and correlation with molecular results identified few discrepant outcomes and uncovered no evidence of false-negative cases. We have demonstrated that blood spot GAGs analysis accurately discriminates between patients with confirmed MPS I and false-positive cases due to pseudodeficiency or heterozygosity and increases the specificity of newborn screening for MPS I.

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