Browsing by Author "Cathey, Sara S."
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- Does the clinical phenotype of mucolipidosis-IIIγ differ from its αβ counterpart?: supporting facts in a Cohort of 18 patientsPublication . Nampoothiri, Sheela; Elcioglu, Nursel H.; Koca, Suleyman S.; Yesodharan, Dhanya; Kk, Chandrababu; Krishnan, Vinod; Bhat, Meenakshi; Nair K, Mohandas; Radhakrishnan, Natasha; Kappanayil, Mahesh; Sheth, Jayesh J.; Alves, Sandra; Coutinho, Francisca; Friez, Michael J.; Pauli, Richard M.; Unger, Sheila; Superti-Furga, Andrea; Leroy, Jules G.; Cathey, Sara S.Mucolipidosis-IIIγ (ML-IIIγ) is a recessively inherited slowly progressive skeletal dysplasia caused by mutations in GNPTG. We report the genetic and clinical findings in the largest cohort with ML-IIIγ so far: 18 affected individuals from 12 families including 12 patients from India, five from Turkey, and one from the USA. With consanguinity confirmed in eight of 12 families, molecular characterization showed that all affected patients had homozygous pathogenic GNPTG genotypes, underscoring the rarity of the disorder. Unlike ML-IIIαβ, which present with a broader spectrum of severity, the ML-III γ phenotype is milder, with onset in early school age, but nonetheless thus far considered phenotypically not differentiable from ML-IIIαβ. Evaluation of this cohort has yielded phenotypic findings including hypertrophy of the forearms and restricted supination as clues for ML-IIIγ, facilitating an earlier correct choice of genotype screening. Early identification of this disorder may help in offering a timely intervention for the relief of carpal tunnel syndrome, monitoring and surgery for cardiac valve involvement, and evaluation of the need for joint replacement. As this condition may be confused with rheumatoid arthritis, confirmation of diagnosis will prevent inappropriate use of immunosuppressants and disease-modifying agents.
- The lysosomal storage disorders mucolipidosis type II, type III alpha/beta, and type III gamma: update on GNPTAB and GNPTG mutationsPublication . Velho, Renata Voltolini; Harms, Frederike L.; Danyukova, Tatyana; Ludwig, Nataniel F.; Friez, Michael J.; Cathey, Sara S.; Filocamo, Mirella; Tappino, Barbara; Güneş, Nilay; Tüysüz, Beyhan; Tylee, Karen L.; Brammeier, Kathryn L.; Heptinstall, Lesley; Oussoren, Esmee; Ploeg, Ans T.; Petersen, Christine; Alves, Sandra; Saavedra, Gloria Durán; Schwartz, Ida V.; Muschol, Nicole; Kutsche, Kerstin; Pohl, SandraMutations in the GNPTAB and GNPTG genes cause mucolipidosis (ML) type II, type III alpha/beta, and type III gamma, which are autosomal recessively inherited lysosomal storage disorders. GNPTAB and GNPTG encode the α/β-precursor and the γ-subunit of N-acetylglucosamine (GlcNAc)-1-phosphotransferase, respectively, the key enzyme for the generation of mannose 6-phosphate targeting signals on lysosomal enzymes. Defective GlcNAc-1-phosphotransferase results in missorting of lysosomal enzymes and accumulation of non-degradable macromolecules in lysosomes, strongly impairing cellular function. MLII-affected patients have coarse facial features, cessation of statural growth and neuromotor development, severe skeletal abnormalities, organomegaly, and cardiorespiratory insufficiency leading to death in early childhood. MLIII alpha/beta and MLIII gamma are attenuated forms of the disease. Since the identification of the GNPTAB and GNPTG genes, 564 individuals affected by MLII or MLIII have been described in the literature. In this report, we provide an overview on 258 and 50 mutations in GNPTAB and GNPTG, respectively, including 58 novel GNPTAB and seven novel GNPTG variants. Comprehensive functional studies of GNPTAB missense mutations did not only gain insights into the composition and function of the GlcNAc-1-phosphotransferase, but also helped to define genotype-phenotype correlations to predict the clinical outcome in patients.
- The lysosomal storage disorders mucolipidosis type II, type III alpha/beta, and type III gamma: Update on GNPTAB and GNPTG mutationsPublication . Velho, Renata Voltolini; Harms, Frederike L.; Danyukova, Tatyana; Ludwig, Nataniel F.; Friez, Michael J.; Cathey, Sara S.; Filocamo, Mirella; Tappino, Barbara; Güneş, Nilay; Tüysüz, Beyhan; Tylee, Karen L.; Brammeier, Kathryn L.; Heptinstall, Lesley; Oussoren, Esmee; van der Ploeg, Ans T.; Petersen, Christine; Alves, Sandra; Saavedra, Gloria Durán; Schwartz, Ida V.; Muschol, Nicole; Kutsche, Kerstin; Pohl, SandraMutations in the GNPTAB and GNPTG genes cause mucolipidosis (ML) type II, type III alpha/beta, and type III gamma, which are autosomal recessively inherited lysosomal storage disorders. GNPTAB and GNPTG encode the α/β-precursor and the γ-subunit of N-acetylglucosamine (GlcNAc)-1-phosphotransferase, respectively, the key enzyme for the generation of mannose 6-phosphate targeting signals on lysosomal enzymes. Defective GlcNAc-1-phosphotransferase results in missorting of lysosomal enzymes and accumulation of non-degradable macromolecules in lysosomes, strongly impairing cellular function. MLII-affected patients have coarse facial features, cessation of statural growth and neuromotor development, severe skeletal abnormalities, organomegaly, and cardiorespiratory insufficiency leading to death in early childhood. MLIII alpha/beta and MLIII gamma are attenuated forms of the disease. Since the identification of the GNPTAB and GNPTG genes, 564 individuals affected by MLII or MLIII have been described in the literature. In this report, we provide an overview on 258 and 50 mutations in GNPTAB and GNPTG, respectively, including 58 novel GNPTAB and seven novel GNPTG variants. Comprehensive functional studies of GNPTAB missense mutations did not only gain insights into the composition and function of the GlcNAc-1-phosphotransferase, but also helped to define genotype-phenotype correlations to predict the clinical outcome in patients.