A splicing mutation in the ?/? GlcNAc-1-phosphotransferase gene results in an adult onset form of mucolipidosis III associated with sensory neuropathy and cardiomyopathy

Washington University in St. Louis, San Luis, Missouri, United States
American Journal of Medical Genetics Part A (Impact Factor: 2.05). 02/2005; 132(4):369-75. DOI: 10.1002/ajmg.a.30498
Source: PubMed

ABSTRACT 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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    ABSTRACT: Mucolipidosis III gamma (ML III gamma) is a slowly progressive disorder characterized by childhood onset of radiographic evidence of mild to moderate dysostosis multiplex; joint stiffness and pain initially in the shoulders, hips, and fingers; and gradual mild coarsening of facial features. Cardiorespiratory complications (restrictive lung disease, thickening and insufficiency of the mitral and aortic valves, left ventricular hypertrophy) can be significant. A few affected individuals have mild cognitive impairment. Because ML III gamma has only recently been distinguished from the more common ML III alpha/beta, previously published descriptions of ML III may have inadvertently included both of these disorders. Thus, much is to yet be learned about the specific manifestations and natural history of ML III gamma. In ML III gamma the activity of nearly all lysosomal hydrolases is up to tenfold higher in plasma and other body fluids than in normal controls because of inadequate targeting to lysosomes. ML III gamma is caused by mutations in GNPTG, which encodes the gamma subunit of the enzyme UDP-N-acetylglucosamine: lysosomal hydrolase N-acetylglucosamine 1-phosphotransferase. (Of note, the alpha and beta subunits of this enzyme are encoded by GNPTAB, mutations in which cause ML III alpha/beta.) Clinically available molecular genetic testing of GNPTG detects two disease-causing mutations in more than 95% of individuals with ML III gamma. Treatment of manifestations: Low-impact physical therapy is usually well tolerated. Carpal tunnel signs may require tendon release. In late childhood or early adolescence relief of hip pain becomes important; in older adolescents and adults bilateral hip replacement has been successful. Later in the disease course management focuses on relief of general bone pain associated with osteoporosis. In severe cases, when significant valvular dysfunction disrupts ventricular function, valve replacement should be seriously considered. Prevention of secondary complications: Because of concerns about airway management, surgical intervention should be undertaken only in tertiary care settings with pediatric anesthesiologists and intensivists. Persons with valvular involvement should be given antibiotic prophylaxis before minor and major surgical procedures (including dental procedures) to prevent bacterial endocarditis. Surveillance: Yearly outpatient clinic visits unless cardiac and/or respiratory monitoring need more frequent attention; annual orthopedic assessment; annual ophthalmology evaluation to monitor for corneal opacities and the possibility of adult-onset retinal degeneration; ERG for those with suspected retinal abnormalities; annual monitoring by echocardiogram for progressive valvular insufficiency; DEXA scan every five years to monitor for metabolic bone disease. Agents/circumstances to avoid: Stretching exercises because they are ineffective, painful, and may damage the surrounding joint capsule and adjacent tendons. ML III gamma is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the disease-causing mutations in the family are known.
    GeneReviews™, Edited by Roberta A Pagon, Thomas D Bird, Cynthia R Dolan, Karen Stephens, Margaret P Adam, 01/2010; University of Washington, Seattle.
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    ABSTRACT: Mucolipidosis (ML) II and ML IIIα/β are allelic autosomal recessive metabolic disorders due to mutations in GNPTAB. The gene encodes the enzyme UDP-GlcNAc-1-phosphotransferase (GNPT), which is critical to proper trafficking of lysosomal acid hydrolases. The ML phenotypic spectrum is dichotomous. Criteria set for defining ML II and ML IIIα/β are inclusive for all but the few patients with phenotypes that span the archetypes. Clinical and biochemical findings of the 'intermediate' ML in eight patients with the c.10A>C missense mutation in GNPTAB are presented to define this intermediate ML and provide a broader insight into ML pathogenesis. Extensive clinical information, including radiographic examinations at various ages, was obtained from a detailed study of all patients. GNPTAB was sequenced in probands and parents. GNPT activity was measured and cathepsin D sorting assays were performed in fibroblasts. Intermediate ML patients who share the c.10A>C/p.K4Q mutation in GNPTAB demonstrate a distinct, consistent phenotype similar to ML II in physical and radiographic features and to ML IIIα/β in psychomotor development and life expectancy. GNPT activity is reduced to 7-12% but the majority of newly synthesized cathepsin D remains intracellular. The GNPTAB c.10A>C/p.K4Q missense allele results in an intermediate ML II/III with distinct clinical and biochemical characteristics. This delineation strengthens the utility of the discontinuous genotype-phenotype correlation in ML II and ML IIIα/β and prompts additional studies on the tissue-specific pathogenesis in GNPT-deficient ML.European Journal of Human Genetics advance online publication, 18 September 2013; doi:10.1038/ejhg.2013.207.
    European journal of human genetics: EJHG 09/2013; DOI:10.1038/ejhg.2013.207 · 3.56 Impact Factor
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    ABSTRACT: Multiple sulfatase deficiency (MSD), mucolipidosis (ML) II/III and Niemann–Pick type C1 (NPC1) disease are rare but fatal lysosomal storage disorders caused by the genetic defect of non-lysosomal proteins. The NPC1 protein mainly localizes to late endosomes and is essential for cholesterol redistribution from endocytosed LDL to cellular membranes. NPC1 deficiency leads to lysosomal accumulation of a broad range of lipids. The precise functional mechanism of this membrane protein, however, remains puzzling. ML II, also termed I cell disease, and the less severe ML III result from deficiencies of the Golgi enzyme N-acetylglucosamine 1-phosphotransferase leading to a global defect of lysosome biogenesis. In patient cells, newly synthesized lysosomal proteins are not equipped with the critical lysosomal trafficking marker mannose 6-phosphate, thus escaping from lysosomal sorting at the trans Golgi network. MSD affects the entire sulfatase family, at least seven members of which are lysosomal enzymes that are specifically involved in the degradation of sulfated glycosaminoglycans, sulfolipids or other sulfated molecules. The combined deficiencies of all sulfatases result from a defective post-translational modification by the ER-localized formylglycine-generating enzyme (FGE), which oxidizes a specific cysteine residue to formylglycine, the catalytic residue enabling a unique mechanism of sulfate ester hydrolysis. This review gives an update on the molecular bases of these enigmatic diseases, which have been challenging researchers since many decades and so far led to a number of surprising findings that give deeper insight into both the cell biology and the pathobiochemistry underlying these complex disorders. In case of MSD, considerable progress has been made in recent years towards an understanding of disease-causing FGE mutations. First approaches to link molecular parameters with clinical manifestation have been described and even therapeutical options have been addressed. Further, the discovery of FGE as an essential sulfatase activating enzyme has considerable impact on enzyme replacement or gene therapy of lysosomal storage disorders caused by single sulfatase deficiencies.
    Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 04/2009; DOI:10.1016/j.bbamcr.2008.11.015 · 5.30 Impact Factor


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