- GNPTAB c.2404C > T nonsense mutation in a patient with mucolipidosis III alpha/beta: a case report. [Case Reports]
- BMBMC Med Genet 2018 09 12; 19(1):162
- CONCLUSIONS: The recently reported nonsense variant c.2404C > T in the GNPTAB gene is further recognized and this contributes to the genotype-phenotype spectrum of mucolipidosis alpha/beta.
- Mucolipidosis Type III: A Rare Disease in Differential Diagnosis of Joint Stiffness in Pediatric Rheumatology. [Case Reports]
- ARArch Rheumatol 2018; 33(1):93-98
- Mucolipidoses are metabolic disorders with autosomal recessive inheritance caused by deficiency of N-acetylglucosamine- 1-phosphotransferase leading to accumulation of glycosaminoglycans and sphingol…
Mucolipidoses are metabolic disorders with autosomal recessive inheritance caused by deficiency of N-acetylglucosamine- 1-phosphotransferase leading to accumulation of glycosaminoglycans and sphingolipids intracellularly. The differential diagnosis of mucolipidosis II or III is based on the age of onset, clinical findings and degree of severity. In this article, we present four pediatric patients with mucolipidosis III or pseudo-Hurler polydystrophy who admitted to our hospital with joint stiffness. They were from consanguineous families with characteristic radiographic findings. The joints were painless and the rheumatologic evaluation and inflammation markers were negative. Mucolipidosis is a rare disease in pediatric patients to remember in differential diagnosis of joint stiffness.
- GeneReviews®: Mucolipidosis III Alpha/Beta [BOOK]
- BOOKUniversity of Washington, Seattle: Seattle (WA)
- Mucolipidosis alpha/beta (ML III alpha/beta; pseudo-Hurler polydystrophy), a slowly progressive disorder with clinical onset at approximately age three years, is characterized by slow growth rate and…
Mucolipidosis alpha/beta (ML III alpha/beta; pseudo-Hurler polydystrophy), a slowly progressive disorder with clinical onset at approximately age three years, is characterized by slow growth rate and subnormal stature; radiographic evidence of mild to moderate dysostosis multiplex; joint stiffness and pain initially in the shoulders, hips, and fingers; gradual mild coarsening of facial features; and normal to mildly impaired cognitive development. If present, organomegaly is mild. Pain from osteoporosis that is clinically and radiologically apparent in childhood becomes more severe from adolescence. Cardiorespiratory complications (restrictive lung disease, thickening and insufficiency of the mitral and aortic valves, left and/or right ventricular hypertrophy) are common causes of death, typically in early to middle adulthood.
- Enlarged follicles and temporomandibular joint abnormalities in mucolipidosis Type III. [Case Reports]
- DRDentomaxillofac Radiol 2013; 42(4):22822014
- Mucolipidosis Type III, or pseudo-Hurler polydystrophy, is a rare genetic abnormality, the result of a mutation to one of two genes that encode the hexameric protein N-acetylglucosaminyl-1-phosphotra…
Mucolipidosis Type III, or pseudo-Hurler polydystrophy, is a rare genetic abnormality, the result of a mutation to one of two genes that encode the hexameric protein N-acetylglucosaminyl-1-phosphotransferase (Glc-NAc-PT). The abnormality results in the accumulation of unprocessed macromolecules in cell and tissue compartments throughout the body. In this case report, we describe the clinical and radiographic findings of a 15-year-old male with this disorder. He presented with bilateral ectopically developing mandibular molar teeth with enlarged follicles and multiple joint involvement, including the temporomandibular joints. The patient underwent surgical removal of the molar teeth and curettage of the associated follicles. The subsequent histopathological examination of the tissues revealed hyperplastic follicles suggestive of dentigerous cysts. This report presents the plain film and cone beam CT examinations of the patient.
- Loss of N-acetylglucosamine-1-phosphotransferase gamma subunit due to intronic mutation in GNPTG causes mucolipidosis type III gamma: Implications for molecular and cellular diagnostics. [Journal Article]
- AJAm J Med Genet A 2010; 152A(1):124-32
- Mucolipidosis type III gamma (MLIII, pseudo-Hurler polydystrophy) is a rare autosomal recessive disorder where the activity of the multimeric GlcNAc-1-phosphotransferase is reduced and formation of t…
Mucolipidosis type III gamma (MLIII, pseudo-Hurler polydystrophy) is a rare autosomal recessive disorder where the activity of the multimeric GlcNAc-1-phosphotransferase is reduced and formation of the mannose 6-phosphate (M6P) recognition marker on lysosomal enzymes is impaired. In this disease, the targeting of lysosomal enzymes is affected resulting in their hypersecretion, and an intracellular deficiency of multiple hydrolases. We report the biochemical and molecular diagnosis of MLIII in three siblings, aged 17, 15, and 14 years, who presented with joint pain and progressive joint stiffness. In addition to missorting of newly synthesized lysosomal protease cathepsin D, there were low levels of M6P-containing proteins in cell extracts and media of cultured fibroblasts of the Patients. Direct sequencing identified a novel homozygous mutation in intron 7, IVS7-10G>A, of the GNPTG gene, which encodes the gamma-subunit of the GlcNAc-1-phosphotransferase. This mutation created a cryptic 3'-splice site resulting in a frameshift and premature translational termination (p.V176GfsX18). The GNPTG mRNA levels were markedly reduced in Patients' fibroblasts indicating that the intronic mutation mediates mRNA decay, which was confirmed by absence of the gamma-subunit protein. These data contribute to an efficient diagnostic strategy to identify Patients with MLIII gamma and characterize their biochemical defect in fibroblasts.
- Missense mutation in the N-acetylglucosamine-1-phosphotransferase gene (GNPTA) in a patient with mucolipidosis II induces changes in the size and cellular distribution of GNPTG. [Case Reports]
- HMHum Mutat 2006; 27(8):830-1
- Mucolipidosis type II (ML II; I-cell disease) and mucolipidosis III (ML III; pseudo Hurler polydystrophy) are autosomal recessively inherited disorders caused by a defective N-acetylglucosamine 1-pho…
Mucolipidosis type II (ML II; I-cell disease) and mucolipidosis III (ML III; pseudo Hurler polydystrophy) are autosomal recessively inherited disorders caused by a defective N-acetylglucosamine 1-phosphotransferase (phosphotransferase). The formation of mannose 6-phosphate markers in soluble lysosomal enzymes is impeded leading to their increased excretion into the serum, to cellular deficiency of multiple hydrolases, and lysosomal storage of non-digested material. Phosphotransferase deficiency is caused by mutations in GNPTA and GNPTG encoding phosphotransferase subunits. Here we report on an adolescent with progressive joint contractions and other signs of mucolipidosis II who survived to the age of 14 years. Impaired trafficking of lysosomal enzymes cathepsin D and -hexosaminidase in metabolically labeled fibroblasts was documented. Mutations in the GNPTG gene and alterations in the GNPTG mRNA level were not detected. A different electrophoretic mobility of the 97 kDa GNPTG dimer suggested posttranslational modification abrogating the compartmentalization of GNPTG in the Golgi apparatus. A nucleotide substitution in the GNPTA gene (c.3707A>T) was identified altering the predicted C-terminal transmembrane anchor of the phosphotransferase subunit. The data demonstrate that defective GNPTA not only impairs lysosomal enzyme targeting but also the availability of intact GNPTG required for phosphotransferase activity and assembly of subunits.
- Mucolipidosis II (I-cell disease) and mucolipidosis IIIA (classical pseudo-hurler polydystrophy) are caused by mutations in the GlcNAc-phosphotransferase alpha / beta -subunits precursor gene. [Journal Article]
- AJAm J Hum Genet 2006; 78(3):451-63
- Mucolipidosis II (MLII; I-cell disease) and mucolipidosis IIIA (MLIIIA; classical pseudo-Hurler polydystrophy) are diseases in which the activity of the uridine diphosphate (UDP)-N-acetylglucosamine:…
Mucolipidosis II (MLII; I-cell disease) and mucolipidosis IIIA (MLIIIA; classical pseudo-Hurler polydystrophy) are diseases in which the activity of the uridine diphosphate (UDP)-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase) is absent or reduced, respectively. In the absence of mannose phosphorylation, trafficking of lysosomal hydrolases to the lysosome is impaired. In these diseases, mistargeted lysosomal hydrolases are secreted into the blood, resulting in lysosomal deficiency of many hydrolases and a storage-disease phenotype. To determine whether these diseases are caused by mutations in the GlcNAc-phosphotransferase alpha / beta -subunits precursor gene (GNPTAB), we sequenced GNPTAB exons and flanking intronic sequences and measured GlcNAc-phosphotransferase activity in patient fibroblasts. We identified 15 different mutations in GNPTAB from 18 pedigrees with MLII or MLIIIA and demonstrated that these two diseases are allelic. Mutations in both alleles were identified in each case, which demonstrated that GNPTAB mutations are the cause of both diseases. Some pedigrees had identical mutations. One frameshift mutation (truncation at amino acid 1171) predominated and was found in both MLII and MLIIIA. This mutation was found in combination with severe mutations (i.e., mutations preventing the generation of active enzyme) in MLII and with mild mutations (i.e., mutations allowing the generation of active enzyme) in MLIIIA. Some cases of MLII and MLIIIA were the result of mutations that cause aberrant splicing. Substitutions were inside the invariant splice-site sequence in MLII and were outside it in MLIIIA. When the mutations were analyzed along with GlcNAc-phosphotransferase activity, it was possible to confidently distinguish these two clinically related but distinct diseases. We propose criteria for distinguishing these two disorders by a combination of mutation detection and GlcNAc-phosphotransferase activity determination.
- Missense mutations in N-acetylglucosamine-1-phosphotransferase alpha/beta subunit gene in a patient with mucolipidosis III and a mild clinical phenotype. [Case Reports]
- AJAm J Med Genet A 2005 Sep 01; 137A(3):235-40
- Mucolipidosis type III (ML III, pseudo-Hurler polydystrophy), an autosomal recessive inherited disorder of lysosomal enzyme targeting is due to a defective N-acetylglucosamine 1-phosphotransferase (p…
Mucolipidosis type III (ML III, pseudo-Hurler polydystrophy), an autosomal recessive inherited disorder of lysosomal enzyme targeting is due to a defective N-acetylglucosamine 1-phosphotransferase (phosphotransferase) activity and leads to the impaired formation of mannose 6-phosphate markers in soluble lysosomal enzymes followed by their increased excretion into the serum. Mutations in the phosphotransferase gamma subunit gene (GNPTAG) have been reported to be responsible for ML III. Here we report on a 14-year-old adolescent with a mild clinical phenotype of ML III. He presented with progressive joint stiffness and swelling. Urinary oligosaccharide and mucopolysaccharide excretion was normal. Lysosomal enzyme activities were significantly elevated in the serum and decreased in cultured fibroblasts. Impaired trafficking of the lysosomal protease cathepsin D (CtsD) was confirmed by metabolic labeling of the patient's fibroblasts. Neither mutations in the GNPTAG gene nor alterations in the GNPTAG mRNA level were detected whereas the steady state concentration of the 97 kDa GNPTAG dimer was reduced. Most importantly, the patient is homozygous for a pathogenic nucleotide substitution and a polymorphism in the phosphotransferase alpha/beta subunit gene (GNPTA). The data indicate that defects in genes other than GNPTAG can be linked to ML III contributing to the variability of the phenotype.
- A splicing mutation in the alpha/beta GlcNAc-1-phosphotransferase gene results in an adult onset form of mucolipidosis III associated with sensory neuropathy and cardiomyopathy. [Case Reports]
- AJAm J Med Genet A 2005 Feb 01; 132A(4):369-75
- A 47-year-old female who presented with a dilated cardiomyopathy and mild neuropathy was found to have pseudoHurler polydystrophy (mucolipidosis III). The serum lysosomal enzymes were strikingly elev…
A 47-year-old female who presented with a dilated cardiomyopathy and mild neuropathy was found to have pseudoHurler polydystrophy (mucolipidosis III). The serum lysosomal enzymes were strikingly elevated and GlcNAc-1-phosphotransferase activity in the patient's fibroblasts was 3% of normal. Sequence analysis of the patient's genomic DNA revealed a homozygous mutation of the last nucleotide of the 135-bp exon 7 of the phosphotransferase gene encoding the alpha/beta subunits, resulting in aberrant splicing and skipping of this exon. Remarkably, none of the skeletal and connective tissue anomalies characteristic of the disease were present. This case is the first example of mucolipidosis III presenting in an adult patient and further broadens the clinical spectrum of the disease.
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- A mucolipidosis III patient presenting characteristic sonographic and magnetic resonance imaging findings of claw hand deformity. [Case Reports]
- JFJ Formos Med Assoc 2004; 103(9):715-20
- Mucolipidosis III (ML-III), or pseudo-Hurler polydystrophy, is an autosomal recessive Hurler-like disorder without mucopolysacchariduria. The diagnosis is challenging for rheumatologists since the mu…
Mucolipidosis III (ML-III), or pseudo-Hurler polydystrophy, is an autosomal recessive Hurler-like disorder without mucopolysacchariduria. The diagnosis is challenging for rheumatologists since the musculoskeletal presentation is similar to some rheumatic diseases. We report a case of ML-III in a 16-year-old Taiwanese boy. The characteristic findings of sonography and magnetic resonance imaging (MRI) of claw hand deformity are described. A 16-year-old boy was referred to our rheumatologic clinic because of progressive claw hand deformity, multiple joint stiffness and tightness of the skin over the fingers at the age of 6 years. Sonography and MRI examination disclosed tendon sheath thickening over extensor tendons of both wrists and fingers without features of active inflammation over tendons or joints nor thickening of skin. Urinary glycosaminoglycans were normal. The diagnosis of ML-III was confirmed by the presence of elevated activities of beta-glucuronidase (2141.99 nmol/mg protein/hour), arylsulfatase A (1237.7 nmol/mg protein/hour) and alpha-fucosidase (52.95 nmol/mg protein/hour) in his plasma and decreased activity of these lysosomal enzymes in cultured skin fibroblasts. Sonography and MRI screening for claw hand deformity may offer important clues enabling early diagnosis of ML-III.