[IDUA gene mutation analysis and prenatal diagnosis of two families affected with mucopolysaccharidosis type I].

OBJECTIVE: To analyze mutations of IDUA gene in two pedigrees affected with mucopolysaccharidosis type I and provide prenatal diagnosis for them. METHODS: The 14 exons of the IDUA gene were subjected to PCR amplification and Sanger sequencing. RESULTS: For pedigree 1, the proband was found to harbor compound heterozygous mutations c.46-57delTCGCTCCTGGCC (p.Ser16_Ala19del) of exon 1 and c.1147delC (p.Arg383Alafs*57) of exon 8 of the IDUA gene, which were inherited from his father and mother, respectively. The latter was unreported previously. Prenatal diagnosis suggested that the fetus has carried a heterozygous c.46-57delTCGCTCCTGGCC mutation. For family 2, the proband was also found to carry compound mutations of the IDUA gene, namely c.721T to C (p.Cys241Arg) of exon 6 and c.1491delG (p.Thr497fs27) of exon 8, which were inherited from her mother and father, respectively. Neither mutation was reported previously. Prenatal diagnosis suggested that the fetus has carried a heterozygous c.721T to C mutation. CONCLUSION: Mutations of the IDUA gene probably underlie the MPS-I in both pedigrees. Above results have enriched the spectrum of IDUA gene mutations and facilitated prenatal diagnosis for both families.

Congenital deformities and developmental abnormalities of the mandibular condyle in the temporomandibular joint.

The temporomandibular joint (TMJ) consists of the mandibular condyle and the articular eminence of the temporal bone. The morphological development of the TMJ during prenatal life lags behind other joints in terms of both the timing of its appearance and its progress. At birth, the joint is still largely underdeveloped. There are many causes of the various growth disturbances and abnormalities of the mandibular condyle and related structures. Growth disturbances in the development of the mandibular condyle may occur in utero late in the first trimester and may result in disorders such as aplasia or hypoplasia of the mandibular condyle. Meanwhile, hyperplasia of the mandibular condyle is not visible at birth and seems to be gradually acquired during growth. In the present review article, the congenital abnormalities of the mandibular condyle are classified morphologically into three major groups and two subgroups from a clinical standpoint: (1) hypoplasia or aplasia of the mandibular condyle, including (i) primary condylar aplasia and hypoplasia, (ii) secondary condylar hypoplasia; (2) hyperplasia; and (3) bifidity. In addition, the molecular-based etiology of anomalies of the mandibular condyle is also discussed.

In utero injection of alpha-L-iduronidase-carrying retrovirus in canine mucopolysaccharidosis type I: infection of multiple tissues and neonatal gene expression.

Canine alpha-L-iduronidase (alpha-ID) deficiency is caused by a single base pair mutation in the alpha-ID gene, resulting in no enzyme activity in homozygous affected pups. The disease clinically resembles human mucopolysaccharidosis type I (MPSI). We used the canine MPSI model system to address the efficacy of a new retroviral vector, MND-MFG, containing the human alpha-ID cDNA (MND-MFG-alpha-ID) for direct in utero gene delivery to MPSI cells. In vitro, the MND-MFG-alpha-ID vector showed high-level, long-term expression of the transgene in both canine and human alpha-ID-deficient fibroblasts. The effectiveness of this vector for in utero gene transfer and expression in multiple tissues was assessed by injecting viral supernatants into MPSI fetuses and evaluating transduction efficiency and enzyme expression at various times after birth. Transduction of a spectrum of cell types and tissues was observed in all seven live-born pups and in one stillborn pup. Although enzyme activity was not detected in adult tissues from the seven surviving pups, significant alpha-ID enzyme activity was detected in both the liver and kidney of the deceased pup. Our combined gene delivery vector and in utero transfer approach, while encouraging in terms of overall gene transfer efficiency to multiple tissues and successful short-term gene expression, was unable to meet the important requirement of sustained in vivo gene expression.

[Fetal pathology in Fabry's disease and mucopolysaccharidosis type I]. / Fetální patologie Fabryho nemoci a mukopolysacharidózy I.

Fetal Fabry disease (defect of alfa galactosidase) and mucopolysaccharidosis I (defect of alfa iduronidase, family with IH phenotype) were diagnosed by biochemistry in two risk gravidities subsequently interrupted according to mother's demand. Fetus with Fabry disease (gestation age 19 weeks) had rudimentary storage in kidney and myenteric plexuses cells, cardiocytes were normal. Biopsy of chorionic villi showed a bit more conspicuous storage in single trophoblastic elements. Much more striking storage was observed in MPS I (gestational age 14-15 weeks) especially in liver (hepatocytes and sinus cells), spleen (sinus endothelial cells and pulp macrophages) and fibroblasts of skin and placenta. Skin peripheral nerves and cerebral cortical gangliocytes did not show any lysosomal storage. Different manifestation of storage in fetal age may reflex the speed of lysosomal storage development in both lysosomal enzymopathies.