Humans ; Mucopolysaccharidosis I/therapy* ; Consensus

PURPOSE: The mucopolysaccharidoses (MPSs) are a heterogeneous group of lysosomal storage disorders. They are caused by a deficiency of the enzymes involved in the degradation of glycosaminoglycans. Early recognition is important because recombinant enzyme replacement therapy is now available for MPS. We studied the clinical characteristics of 80 MPS children with the object of determining the epidemiological, clinical and radiological features in Korean MPS children. METHODS: Diagnosis of MPS was confirmed by skin fibroblast enzyme analysis in 80 patients between February 1995 and December 2004. Charts were retrospectively reviewed for clinical and radiological findings, as well as for intelligence and speech evaluations. RESULTS: Hunter syndrome (MPS type II) was the most prevalent type, appearing in 51/80 cases (64 %), followed by Sanfilippo syndrome (MPS III-18%), Hurler syndrome (MPS I-15%), and Morquio syndrome (MPS IV-4%). The average age at diagnosis was 5.5 years (range 1 to 20), and the male-to-female ratio was 4.7: 1. Typical radiographic changes were observed in 45/54 cases (83%). Mitral regurgitation was the most common cardiac defect. Moderate to profound mental retardation and hearing loss were present in 14/35 cases (56%) and 33/38 cases (82%), respectively. Four MPS II patients had bone marrow transplantation, with mixed outcomes. Five MPS I patients are currently on enzyme replacement therapy. CONCLUSION: Our study showed a high proportion of MPS II cases (64%), which may represent population variability. By studying the clinical features of these patients, we hope to alert pediatricians of the warning signs of MPS.
Bone Marrow Transplantation ; Child ; Diagnosis ; Enzyme Replacement Therapy ; Fibroblasts ; Glycosaminoglycans ; Hearing Loss ; Hope ; Humans ; Incidence ; Intellectual Disability ; Intelligence ; Korea ; Mitral Valve Insufficiency ; Mucopolysaccharidoses* ; Mucopolysaccharidosis I ; Mucopolysaccharidosis II ; Mucopolysaccharidosis III ; Mucopolysaccharidosis IV ; Retrospective Studies ; Skin

OBJECTIVE: To analyze the clinical and genetic characteristics of a child with mucopolysaccharidoses type I. METHODS: Enzymatic and genetic testing were carried out for the child who was admitted due to contraction of fingers and flexion deformity of lower limbs. The child was subjected to target exome capture sequencing. Candidate variants were verified by Sanger sequencing of the child, her parents and two sisters. RESULTS: The child had featured facial dysmorphism, short stature, round head, short neck, corneal turbidity and skeletal deformity. Enzyme test was positive, and genetic testing revealed that she had harbored c.1049delA (p.N350Mfs*4) and c.1815dupT (p.V606Cfs*53) compound heterozygous variants of the IDUA gene, which were inherited from her mother and father, respectively. Her two sisters had each carried one of above variants. c.1815dupT was known to be pathogenic, whilst c.1049delA was not reported in Human Gene Mutation Database. CONCLUSION The compound heterozygous variants of the IDUA gene probably underlay the disease in this child, among which the c.1049delA (p.N350Mfs*4) is unreported previously.
Child ; Dwarfism ; Female ; Genetic Testing ; Humans ; Iduronidase ; Mucopolysaccharidosis I ; Mutation ; Exome Sequencing

Osteogenesis imperfecta is one of the groups of hereditary disorders of connective tissue which includes the Ehlers-Danlos syndrome, the Marfan syndrome, pseudoxanthoma elasticum, and Hurler syndrome. While cardiovascular involvement is associated with each of these disorders, it is least common in osteogenesis imperfecta and is overshadowed by the bony, ocular, otologic, cutaneous, and dental manifestations that are characteristic of the disorder. In evaluating patients with osteogenesis imperfecta, careful attention should be paid to cardiovascular findings and if valvular lesions are noted, patients should be instructed regarding the need for antibiotic prophylaxis for dental and surgical procedures. We report a case of osteogenesis imperfecta associated with aortic regurgitation.
Antibiotic Prophylaxis ; Aortic Valve Insufficiency* ; Connective Tissue ; Ehlers-Danlos Syndrome ; Humans ; Marfan Syndrome ; Mucopolysaccharidosis I ; Osteogenesis Imperfecta* ; Osteogenesis* ; Pseudoxanthoma Elasticum

BACKGROUND: We developed an analytical method to measure alpha-L-iduronidase (IDUA) activity in dried blood spots. This was achieved by using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) with electrospray ionization in the positive ion mode. METHODS: Chromatographic separation was completed using mobile phase involving water-formic acid and acetonitrile-formic acid over 2.8 min of run time on a column with a Kinetex XB-C18 (Phenomenex, USA). The detection of column effluent was performed using a Xevo TQ-S triple quadrupole mass spectrometer (Waters, USA) in the multiple-reaction monitoring mode. This method was verified with blank and control samples at four activity levels: base, low, medium, and high. Control materials were provided from Centers for Disease Control and Prevention (CDC). RESULTS: Intra- and inter-day precisions were between 2.6% and 16.5% and between 7.9% and 17.0%, respectively. A correlative regression study on the IDUA activity in CDC-control samples performed to assess the validity of the developed method showed a highly significant linear association (r2=0.9976) between the calculated and CDC-reported values and an obvious difference in activity among the four levels. This reliable analytical method was applied to mucopolysaccharidosis I (Hurler) screening of patients under treatment (n=4) and in normal controls (n=129). IDUA activity ranged from 8.98 to 77.12 micromol/hr/L) in normal controls, and patients undergoing medical treatment showed low IDUA activity. CONCLUSIONS: This method had advantages of simplicity, rapid sample preparation, and liquid chromatographic separation, which efficiently inhibited ionization suppression induced by matrix effects in mass spectrometric detection.
*Chromatography, High Pressure Liquid ; Dried Blood Spot Testing/*instrumentation ; Humans ; Iduronidase/*analysis/metabolism ; Mucopolysaccharidosis I/blood/*diagnosis ; Regression Analysis ; Substrate Specificity ; *Tandem Mass Spectrometry

Adequate growth is the most importment and principal factor in the fields of pediatrics and also it is great concern to all parents. There are many causes of short stature, secondary to a variety of causes. Clinical evaluation of short stature requires a wide variety of clinical, radiographic, pathologic, and biochemical tools. The most important thing is early and accurate diagnosis of disease. As a first step to do so, we performed the clinical analysis of 25 short statured children who had been admitted to Severance Hospital in recent 10 years. Results were as follows; 1) In 25 cases, male were 11 and female were 14 cases. Etiologically, contitutional slow growth 2, mongolism 1, gargoylism 3, achondroplasia 3, spondylometaphyseal dsplasia 1, cretinism 12, and pitutary dwarfism 3 cases.2) Chronological age at the beginning of diagnostic approach were generally delayed. 3) Height age and bone age of dwarfism were markedly retarded than chronological age wheras weight age showed no specific relationship except in case of malnutrition. 4) skeletal dysplasia and endocrine dwarfism, bone age was retarded than height age. But in constitutional slow growth, discrepancy was not marked. 5) Head circumference in each type of short stature was variable. 6) Diagnostic methods include measurement of height and bone age, X-ray, thyroid function test, growth hormone stimulation test and chromosome study.
Achondroplasia ; Child ; Congenital Hypothyroidism ; Diagnosis ; Down Syndrome ; Dwarfism ; Female ; Growth Hormone ; Head ; Humans ; Male ; Malnutrition ; Mucopolysaccharidosis I ; Parents ; Pediatrics ; Thyroid Function Tests

A 21-year-old woman with gargoyloid face and short trunkal stature showed progressive quadriparesis. Cervical spine MRI showed circumferential compression of cervical spinal cord by thickened dura mater. Elevated urinary dermatan sulfate and decreased enzyme activity of -iduronidase revealed that she has mild form of mucopolysaccharidosis type I. Her weakness was improved with cervical laminectomy and duraplasty. In this case, progressing quadriparesis resulted from cervical spinal cord compression by thickened dura mater. Earlier surgical decompression could have been better for the patient.
Decompression, Surgical ; Dermatan Sulfate ; Dura Mater ; Female ; Humans ; Laminectomy ; Magnetic Resonance Imaging ; Mucopolysaccharidoses* ; Mucopolysaccharidosis I* ; Quadriplegia ; Spinal Cord Compression* ; Spinal Cord* ; Spine ; Young Adult

Mucopolysaccharidosis type I (MPS-I) is an inborn error of metabolism with progressive multisystem involvement. Hurler syndrome is the most severe form of MPS-I that causes progressive deterioration of the central nervous system with ensuing death. This study reported the therapeutic effect of allogeneic hematopoietic stem cell transplantation (allo-HSCT) on Hurler syndrome in one case. The patient was a 25-month-old boy. He underwent allo-HSCT. The donor was his elder sister whose HLA-B locus was not matching. The reduced-intensity of BuCy conditioning regimen in allo-HSCT for this patient was as follows: busulfan 3.7 mg/kg daily at 9 to 6 days before transplantation, cyclophosphamide 42.8 mg/kg daily at 5 to 2 days before transplantation, and rabbit antithymocyte globulin 3.5 mg/kg daily at 1, 3, 5, and 7 days before transplantation. Human granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cells (CD34+ cells 12.8 x10(6)/kg) were infused and cyclosporine (CSA), short-course methotrexate, daclizumab and mycophenolate mofetil (MMF) were administered to prevent graft-versus-host disease (GVHD). Complete donor-type engraftment was confirmed by Short Tandem Repeat-Polymerase Chain Reaction (STR-PCR) on day 14 after transplantation. Neutrophil and platelet engraftment occurred on days 11 and 19 after transplantation respectively. Only grade I regimen-related toxicity of live and gastrointestinal tract occurred. GVHD and graft failure were not observed. After transplantation, the clinical symptoms and the neurocognitive function were greatly improved in this patient. It was concluded that allo-HSCT was effective for the treatment of MPS-I. The reduced-intensity conditioning regimen was helpful to decrease the regimen-related toxicity. Sufficient immunosuppressive therapy and adequate hematopoietic stem cells infusion may be beneficial to the donor cell engraftment and reducing the incidence of graft failure and GVHD.
Child, Preschool ; Follow-Up Studies ; Graft vs Host Disease ; etiology ; Hematopoietic Stem Cell Transplantation ; Humans ; Male ; Mucopolysaccharidosis I ; therapy ; Transplantation, Homologous

OBJECTIVEMucopolysaccharidosis 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.

METHODThe 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.

RESULTThe 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).

CONCLUSIONOf 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.

Child, Preschool ; DNA Mutational Analysis ; Female ; Genotype ; Heterozygote ; Homozygote ; Humans ; Iduronidase ; genetics ; Male ; Mucopolysaccharidosis I ; diagnosis ; genetics ; Mutation ; Phenotype ; Pregnancy ; Prenatal Diagnosis

Mucolipidosis II (ML II) or inclusion cell disease (I-cell disease) is a rarely occurring autosomal recessive lysosomal enzyme-targeting disease. This disease is usually found to occur in individuals aged between 6 and 12 months, with a clinical phenotype resembling that of Hurler syndrome and radiological findings resembling those of dysostosis multiplex. However, we encountered a rare case of an infant with ML II who presented with prenatal skeletal dysplasia and typical clinical features of severe secondary hyperparathyroidism at birth. A female infant was born at 37(+1) weeks of gestation with a birth weight of 1,690 g (<3rd percentile). Prenatal ultrasonographic findings revealed intrauterine growth retardation and skeletal dysplasia. At birth, the patient had characteristic features of ML II, and skeletal radiographs revealed dysostosis multiplex, similar to rickets. In addition, the patient had high levels of alkaline phosphatase and parathyroid hormone, consistent with severe secondary neonatal hyperparathyroidism. The activities of beta-D-hexosaminidase and alpha-N-acetylglucosaminidase were moderately decreased in the leukocytes but were 5- to 10-fold higher in the plasma. Examination of a placental biopsy specimen showed foamy vacuolar changes in trophoblasts and syncytiotrophoblasts. The diagnosis of ML II was confirmed via GNPTAB genetic testing, which revealed compound heterozygosity of c.3091C>T (p.Arg1031X) and c.3456_3459dupCAAC (p.Ile1154GlnfsX3), the latter being a novel mutation. The infant was treated with vitamin D supplements but expired because of asphyxia at the age of 2 months.
Acetylglucosaminidase ; Aged ; Alkaline Phosphatase ; Asphyxia ; Biopsy ; Birth Weight ; Dysostoses ; Enzyme Assays ; Female ; Fetal Growth Retardation ; Genetic Testing ; Humans ; Hyperparathyroidism ; Hyperparathyroidism, Secondary ; Infant ; Infant, Newborn ; Leukocytes ; Mucolipidoses ; Mucopolysaccharidosis I ; Parathyroid Hormone ; Parturition ; Phenotype ; Plasma ; Pregnancy ; Rickets ; Trophoblasts ; Vitamin D