scholarly journals Solving a case of allelic dropout in the GNPTAB gene: implications in the molecular diagnosis of mucolipidosis type III alpha/beta

2016 ◽  
Vol 29 (10) ◽  
Author(s):  
Maria Francisca Coutinho ◽  
Marisa Encarnação ◽  
Francisco Laranjeira ◽  
Lúcia Lacerda ◽  
Maria João Prata ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Molecular Diagnosis ◽  
Autosomal Recessive ◽  
Genetic Disorders ◽  
Causative Mutation ◽  
Lysosomal Storage ◽  
Allelic Dropout ◽  
Type Iii ◽  
Alpha Beta ◽  
Mucolipidosis Type

AbstractWhile being well known that the diagnosis of many genetic disorders relies on a combination of clinical suspicion and confirmatory genetic testing, not rarely, however, genetic testing needs much perseverance and cunning strategies to identify the causative mutation(s). Here we present a case of a thorny molecular diagnosis of mucolipidosis type III alpha/beta, which is an autosomal recessive lysosomal storage disorder, caused by a defect in the

The lysosomal storage disorders mucolipidosis type II, type III alpha/beta, and type III gamma: Update onGNPTABandGNPTGmutations

2019 ◽  
Author(s):  
Renata Voltolini Velho ◽  
Frederike L. Harms ◽  
Tatyana Danyukova ◽  
Nataniel F. Ludwig ◽  
Michael J. Friez ◽  
...  
Keyword(s):  
Lysosomal Storage Disorders ◽  
Type Ii ◽  
Lysosomal Storage ◽  
Type Iii ◽  
Alpha Beta ◽  
Mucolipidosis Type ◽  
Storage Disorders

β-Mannosidosis in German Shepherd Dogs

2019 ◽  
Vol 56 (5) ◽  
pp. 743-748 ◽  
Author(s):  
Robert D. Jolly ◽  
Keren E. Dittmer ◽  
Dorian J. Garrick ◽  
Anastasia Chernyavtseva ◽  
Kim M. Hemsley ◽  
...  
Keyword(s):  
Nervous Tissue ◽  
Autosomal Recessive ◽  
Storage Disease ◽  
Periodic Acid ◽  
Causative Mutation ◽  
Lysosomal Storage ◽  
German Shepherd ◽  
Periodic Acid Schiff ◽  
Genomic Studies ◽  
Renal Tubular

A neurological disease was investigated in 3 German Shepherd pups from the same litter that failed to grow normally, appeared stiff, were reluctant to move, and were deaf. They developed intermittent seizures and ataxia and had proprioceptive defects. Histopathology showed severe vacuolation of neurons, astrocytes in nervous tissue, renal tubular epithelial cells, and macrophages in nervous tissue, spleen, and liver. Vacuoles appeared empty with no storage material stained by periodic acid–Schiff (PAS) or Sudan black stains, leading to a diagnosis of a lysosomal storage disease and in particular an oligosaccharidosis. Biochemical and genomic studies showed that this was β-mannosidosis, not previously diagnosed in dogs. A c.560T>A transition in exon 4 of the MANBA gene was found, which segregated in these and other family members in a manner consistent with it being the causative mutation of an autosomal recessive disease. This mutation led to substitution of isoleucine to asparagine at position 187 of the 885 amino acid enzyme, a change expected to have functional significance.

Practice of Genetics in Clinical Medicine

2010 ◽  
Author(s):  
Bruce R Korf ◽  
Carlos Gallego
Keyword(s):  
Genetic Testing ◽  
Autosomal Recessive ◽  
Clinical Medicine ◽  
Maternal Inheritance ◽  
Genetic Disorders ◽  
Gene Mutations ◽  
Basic Principles ◽  
Direct To Consumer ◽  
Risk Assessment And Prevention ◽  
Traditional Area

This review provides a general overview of the genetic approach in medical practice, discusses the principles of genetic testing, including interpretation of genetic tests and direct-to-consumer genomic testing, and looks at genetic counseling and approaches to treatment. The internist should become familiar with genetic disorders such as those associated with mutations in single genes or changes in chromosome number or structure. This is the traditional area of focus for medical geneticists and is likely to remain so. The internist should be familiar with basic principles of care for individuals with the more common of these conditions and needs to recognize clues that suggest the presence of these disorders, especially in family history. The section on genetics of common disorders focuses on pharmacogenetics, risk assessment, and prevention. Figures illustrate commonly used standard pedigree symbols and examples of autosomal recessive, autosomal dominant, X-linked recessive, and maternal inheritance. Tables offer different forms of genetic testing and types of gene mutations at genome and DNA levels. This review contains 2 figures, 2 tables, and 83 references.

Mucolipidosis Type III α/β: The First Characterization of This Rare Disease by Autopsy

2011 ◽  
Vol 135 (4) ◽  
pp. 503-510
Author(s):  
Darcy A Kerr ◽  
Vincent A Memoli ◽  
Sara S Cathey ◽  
Brent T Harris
Keyword(s):  
Electron Microscopy ◽  
Heart Valves ◽  
Light And Electron Microscopy ◽  
Lysosomal Storage ◽  
Cytoplasmic Granules ◽  
Type Iii ◽  
Mucolipidosis Type ◽  
Electron Lucent ◽  
And Cartilage

Abstract We report findings from an autopsy of a 45-year-old woman with the rare lysosomal storage disease mucolipidosis type III α/β. Her disease manifested most notably as multiple bone and cartilage problems with tracheal and bronchial malacia. Principal autopsy findings included gross abnormalities in bone and cartilage with corresponding microscopic cytoplasmic lysosomal granules. These cytoplasmic granules were also seen in histologic preparations of the brain, myocardium, heart valves, and fibroblasts of the liver and skin by light and electron microscopy. By electron microscopy there were scattered, diffuse vesicular cytoplasmic granules in neurons and glia and an increase in lysosomal structures with fine electron lucent granularity in the above tissue types. Our findings help elaborate current understanding of this disease and differentiate it from the mucopolysaccharidoses and related disorders. To our knowledge, this is the first report to document pathologic findings in a patient with mucolipidosis type III α/β by autopsy.

Practice of Genetics in Clinical Medicine

2010 ◽  
Author(s):  
Bruce R Korf ◽  
Carlos Gallego
Keyword(s):  
Genetic Testing ◽  
Autosomal Recessive ◽  
Clinical Medicine ◽  
Maternal Inheritance ◽  
Genetic Disorders ◽  
Gene Mutations ◽  
Basic Principles ◽  
Direct To Consumer ◽  
Risk Assessment And Prevention ◽  
Traditional Area

This review provides a general overview of the genetic approach in medical practice, discusses the principles of genetic testing, including interpretation of genetic tests and direct-to-consumer genomic testing, and looks at genetic counseling and approaches to treatment. The internist should become familiar with genetic disorders such as those associated with mutations in single genes or changes in chromosome number or structure. This is the traditional area of focus for medical geneticists and is likely to remain so. The internist should be familiar with basic principles of care for individuals with the more common of these conditions and needs to recognize clues that suggest the presence of these disorders, especially in family history. The section on genetics of common disorders focuses on pharmacogenetics, risk assessment, and prevention. Figures illustrate commonly used standard pedigree symbols and examples of autosomal recessive, autosomal dominant, X-linked recessive, and maternal inheritance. Tables offer different forms of genetic testing and types of gene mutations at genome and DNA levels. This review contains 2 figures, 2 tables, and 83 references.

scholarly journals Imbalanced cellular metabolism compromises cartilage homeostasis and joint function in a mouse model of mucolipidosis type III gamma

2020 ◽  
Vol 13 (11) ◽  
pp. dmm046425 ◽  
Author(s):  
Lena Marie Westermann ◽  
Lutz Fleischhauer ◽  
Jonas Vogel ◽  
Zsuzsa Jenei-Lanzl ◽  
Nataniel Floriano Ludwig ◽  
...  
Keyword(s):  
Lysosomal Enzymes ◽  
Structural Changes ◽  
Joint Stiffness ◽  
Lysosomal Storage ◽  
Intracellular Location ◽  
Type Iii ◽  
Γ Subunit ◽  
Joint Pathology ◽  
Key Enzyme ◽  
Mucolipidosis Type

ABSTRACTMucolipidosis type III (MLIII) gamma is a rare inherited lysosomal storage disorder caused by mutations in GNPTG encoding the γ-subunit of GlcNAc-1-phosphotransferase, the key enzyme ensuring proper intracellular location of multiple lysosomal enzymes. Patients with MLIII gamma typically present with osteoarthritis and joint stiffness, suggesting cartilage involvement. Using Gnptg knockout (Gnptgko) mice as a model of the human disease, we showed that missorting of a number of lysosomal enzymes is associated with intracellular accumulation of chondroitin sulfate in Gnptgko chondrocytes and their impaired differentiation, as well as with altered microstructure of the cartilage extracellular matrix (ECM). We also demonstrated distinct functional and structural properties of the Achilles tendons isolated from Gnptgko and Gnptab knock-in (Gnptabki) mice, the latter displaying a more severe phenotype resembling mucolipidosis type II (MLII) in humans. Together with comparative analyses of joint mobility in MLII and MLIII patients, these findings provide a basis for better understanding of the molecular reasons leading to joint pathology in these patients. Our data suggest that lack of GlcNAc-1-phosphotransferase activity due to defects in the γ-subunit causes structural changes within the ECM of connective and mechanosensitive tissues, such as cartilage and tendon, and eventually results in functional joint abnormalities typically observed in MLIII gamma patients. This idea was supported by a deficit of the limb motor function in Gnptgko mice challenged on a rotarod under fatigue-associated conditions, suggesting that the impaired motor performance of Gnptgko mice was caused by fatigue and/or pain at the joint.This article has an associated First Person interview with the first author of the paper.

scholarly journals Early diagnosis of mucopolysaccharidosis type III (Sanfilippo syndrome) in the practice of a pediatrician

2021 ◽  
Vol 66 (5) ◽  
pp. 233-239
Author(s):  
S. Ya. Volgina ◽  
O. A. Spiridonova ◽  
E. A. Kurmaeva ◽  
R. G. Gamirova ◽  
S. I. Polyakova
Keyword(s):  
Autosomal Recessive ◽  
Multiple Organ ◽  
Speech Development ◽  
The Body ◽  
Lysosomal Storage ◽  
Sanfilippo Syndrome ◽  
Type Iii ◽  
Multiple Sulfatase Deficiency ◽  
Autosomal Recessive Manner

Mucopolysaccharidosis (MPS) type III (Sanfilippo syndrome) is a lysosomal storage disease inherited in an autosomal recessive manner, it is characterized by the accumulation of heparan sulfate in the cells of the body, which leads to the development of multiple organ failure. It occurs with a frequency of 1: 70 thousand newborns. There are 4 subtypes of the disease: A, B, C, D. Cognitive and neurological disorders are the earliest symptoms of the disease. Delay (loss) of speech development, regression of acquired skills, hyperreactivity, autistic character traits, mental retardation, sleep disturbance, epilepsy are noted; aggressive behavior is formed, the ability to move is impaired, hepatomegaly appears. There are observed the violations of other organs and systems – the organ of vision, bone, respiratory, cardiovascular systems, ENT organs, dental problems. Clinically, the subtypes of mucopolysaccharidosis III are practically indistinguishable. The average age at diagnosis is 2–6 years. Diagnostic search includes qualitative and quantitative determination of glycosaminoglycans in urine. It should be remembered that with mild variants of the disease, these indicators may be within the normal range. In the future, it is necessary to assess the activity of the corresponding enzymes in leukocytes, plasma or serum, in skin fibroblasts. Genetic testing is then performed to identify the mutation of the corresponding defective gene. Differential diagnosis should be carried out with other types of mucopolysaccharidosis, mucolipidosis, gangliosidosis, multiple sulfatase deficiency, some rheumatoid diseases.

Practice of Genetics in Clinical Medicine

2010 ◽  
Author(s):  
Bruce R Korf ◽  
Carlos Gallego
Keyword(s):  
Genetic Testing ◽  
Autosomal Recessive ◽  
Clinical Medicine ◽  
Maternal Inheritance ◽  
Genetic Disorders ◽  
Gene Mutations ◽  
Basic Principles ◽  
Direct To Consumer ◽  
Risk Assessment And Prevention ◽  
Traditional Area

This review provides a general overview of the genetic approach in medical practice, discusses the principles of genetic testing, including interpretation of genetic tests and direct-to-consumer genomic testing, and looks at genetic counseling and approaches to treatment. The internist should become familiar with genetic disorders such as those associated with mutations in single genes or changes in chromosome number or structure. This is the traditional area of focus for medical geneticists and is likely to remain so. The internist should be familiar with basic principles of care for individuals with the more common of these conditions and needs to recognize clues that suggest the presence of these disorders, especially in family history. The section on genetics of common disorders focuses on pharmacogenetics, risk assessment, and prevention. Figures illustrate commonly used standard pedigree symbols and examples of autosomal recessive, autosomal dominant, X-linked recessive, and maternal inheritance. Tables offer different forms of genetic testing and types of gene mutations at genome and DNA levels. This review contains 2 figures, 2 tables, and 83 references.

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