Clinical characterization and mutation identification for multiple sulfatase deficiency patients in China / 中华儿科杂志

<p><b>OBJECTIVE</b>Multiple sulfatase deficiency is a rare autosomal recessively inherited lysosomal storage disorder characterized by the accumulation of sulfated lipids and acid mucopolysaccharides. The aim of this study was to explore the clinical manifestations, enzyme activities and SUMF1 gene mutations in two Chinese patients with multiple sulfatase deficiency.</p><p><b>METHOD</b>One boy and one girl from two families were studied. Both patients presented with mental retardation, mild coarse facial features, a neurodegenerative course of disease with loss of sensory and motor function after 2 years of age, ichthyosis and skeletal abnormalities (kyphosis or/and scoliosis). Clinical characteristics indicate multiple sulfatase deficiency.Sulfatases activities in blood leucocytes, plasma or cultured fibroblast of the patients were measured.Genomic DNAs were extracted from peripheral blood leukocytes from the patients and their parents. All SUMF1 gene exons and intron-exon boundaries were amplified by PCR and subjected for direct sequencing.</p><p><b>RESULT</b>In case 1, five sulfatases activities of blood leucocytes and four sulfatases of cultured skin-fibroblasts were analyzed.In case 2, three sulfatases activities of blood leucocytes were tested.Significantly decreased sulfatases activities confirmed the diagnosis of multiple sulfatase deficiency.On SUMF1 gene, c.793_794 insATG (p. P265X)/ c.1045C>T (p.R349W) in case 1 and c.451A>G (p.K151E)/ c.1046G>C (p.R349Q) in case 2 were detected, respectively. Three novel mutations c.793_794insAGT, c.1046G>C and c.451A>G were identified.</p><p><b>CONCLUSIONS</b>Multiple sulfatase deficiency usually results in multi-organ damage, especially neurologic, skeletal and skin.Sulfatases assay and SUMF1 gene analysis are necessary for the diagnosis. Two Chinese cases with multiple sulfatase deficiency were firstly reported. Three novel mutations were found.It should be considered that the mutation profile of SUMF1 gene in Chinese patients is different from other populations.</p>

Mutation analysis of 11 Chinese patients with attenuated mucopolysaccharidosis type / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease resulting from the deficiency in the lysosomal enzyme alpha-L-iduronidase (IDUA). The present study was conducted to identify IDUA gene mutations in attenuated (MPS I H/S and MPS I S) patients with MPS I in northern China.</p><p><b>METHODS</b>Fourteen exons with adjacent intronic sequences of the IDUA gene in 11 MPS I patients were amplified by polymerase chain reaction (PCR), and the PCR products were sequenced directly and origin analysis was conducted.</p><p><b>RESULTS</b>Seven mutations were detected in the 11 MPS I patients, i.e., c.236 C to T (p. A79V), c.266 G to A (p.R89Q), c.265 C to T (p.R89W), c.532G to A (p.E178K), c.589G to A (p.G197S), c.1037T to G (p.L346R), and c.1877 G to A (p.W626X). All of them were known mutations. Six patients were homozygotes and 1 was heterozygote with nonsense mutation. In addition, 9 reported single nucleotide polymorphism (SNP) were detected, i.e., p.A8, p.A20, p.H33Q, p.R105Q, p.A314, p. A361T, p.T388, p.T410 and p.V454I.</p><p><b>CONCLUSION</b>The mutation spectrum of the IDUA gene in attenuated MPS I Chinese patients may be different from that in patients from other countries.</p>

Mutation analysis and prenatal diagnosis of 2 cases with mucopolysaccharidosis type I / 中华儿科杂志

<p><b>OBJECTIVE</b>Mucopolysaccharidosis type I (MPS I; MIM# 252800) is an autosomal recessive disease that results from the deficiency in the lysosomal enzyme α-L-iduronidase(IDUA). IDUA is one of the enzymes involved in degradation of glycosaminoglycans heparan sulphate and dermatan sulphate. The deficiency of IDUA leads to widespread accumulation of partially degraded mucopolysaccharides inside lysosomes, resulting in progressive cellular and multiorgan dysfunction. Up to now there is no definitely effective treatment for this disorder, therefore it is important to provide an accurate genetic diagnosis and prenatal diagnosis for the MPSI families. This study was conducted to detect IDUA gene mutation in patients with MPSIand make a definite diagnosis of homozygote or heterozygote and make first trimester prenatal diagnosis.</p><p><b>METHOD</b>The 2 male probands included in this study were diagnosed as MPSI patients in Peking Union Medical College Hospital, case 1 was 2 years old and case 2 was 5 years old. Genomic DNA was extracted from leucocytes in the 2 patients and 2 mothers' cultured amniocytes. IDUA gene DNA sequence was amplified by polymerase chain reaction (PCR) and the PCR products were sequenced directly. Novel mutations were analyzed in 100 normal chromosomes.</p><p><b>RESULT</b>The genotype of case 1 was p.L238R/c.883InsC, while of case 2 was c.531InsT/p.L346R. The fetal case 1 did not inherit the same pathogenic mutations as proband 1, the activity of the IDUA in amniocytes was 9.0 nmol/(h·mg pr). The fetal case 2 inherited the same pathogenic mutations with the proband, the genotype of fetal 2 was c.531InsT/p.L346R, the activity of the IDUA in amniocytes was 0.5 nmol/(h·mg pr).</p><p><b>CONCLUSION</b>Of the 4 mutations found in 2 MPS I patients, p. L238R, c.883InsC, c.531InsT were novel. The fetal case 1 was diagnosed as normal fetus while the fetus 2 was diagnosed as affected. The results of the two kinds of prenatal diagnostic methods were correspondent with each other.</p>

The power of linkage analysis on PAH gene in prenatal gene diagnosis is improved with three additional short tandem repeat markers / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To increase the success rate of prenatal diagnosis for classical phenylketonuria(PKU).</p><p><b>METHODS</b>Three new short tandem repeat (STR) markers (PAH26, PAH32 and PAH9) within and surrounding phenylalanine hydroxylase(PAH) gene were selected for amplified fragment length polymorphism. The allele frequencies and polymorphism information contests (PIC) were determined in Chinese population.</p><p><b>RESULTS</b>The PIC of these three new STR markers was 0.518 (PAH26), 0.413 (PAH32) and 0.362 (PAH9) respectively. There was linkage disequilibrium between PAH9 marker and PAH-STR marker (TCTA)n in the intron 3 of PAH gene. The linkage phase of the mutant genes and the markers was established using the combination of PAH-STR, PAH26 and PAH32 in 95% families. Prenatal diagnosis was performed successfully with these markers in four cases.</p><p><b>CONCLUSION</b>By selecting or combining the three STR markers, the mutant genes could be distinguished from the normal allele in up to 95% of families with classical PKU.</p>