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Molecular Genetics and Metabolism Mar 2020Type 1 GM1 gangliosidosis is an ultra-rare, rapidly fatal lysosomal storage disorder, with life expectancy of <3 years of age. To date, only one prospective natural... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Type 1 GM1 gangliosidosis is an ultra-rare, rapidly fatal lysosomal storage disorder, with life expectancy of <3 years of age. To date, only one prospective natural history study of limited size has been reported. Thus, there is a need for additional research to provide a better understanding of the progression of this disease. We have leveraged the past two decades of medical literature to conduct the first comprehensive retrospective study characterizing the natural history of Type 1 GM1 gangliosidosis.
OBJECTIVES
The objectives of this study were to establish a large sample of patients from the literature in order to identify: 1) clinically distinguishing factors between Type 1 and Type 2 GM1 gangliosidosis, 2) age at first symptom onset, first hospital admission, diagnosis, and death, 3) time to onset of common clinical findings, and 4) timing of developmental milestone loss.
METHODS
PubMed was searched with the keyword "GM1 Gangliosidosis" and for articles from the year 2000 onwards. A preliminary review of these results was conducted to establish subtype classification criteria for inclusion of only Type 1 patients, resulting in 44 articles being selected to generate the literature dataset of 154 Type 1 GM1 gangliosidosis patients. Key clinical events of these patient cases were recorded from the articles.
RESULTS
Comprehensive subtyping criteria for Type 1 GM1 gangliosidosis were created, and clinical events, including onset, diagnosis, death, and symptomology, were mapped over time. In this dataset, average age of diagnosis was 8.7 months, and average age of death was 18.9 months.
DISCUSSION
This analysis demonstrates the predictable clinical course of this disease, as almost all patients experienced significant multi-organ system dysfunction and neurodevelopmental regression, particularly in the 6- to 18-month age range. Patients were diagnosed at a late age relative to disease progression, indicating the need for improved public awareness and screening.
CONCLUSION
This study highlights the significant burden of illness in this disease and provides critical natural history data to drive earlier diagnosis, inform clinical trial design, and facilitate family counseling.
Topics: Gangliosidosis, GM1; Humans; Infant; Lysosomal Storage Diseases; Neurodevelopmental Disorders; PubMed; Rare Diseases; Retrospective Studies; beta-Galactosidase
PubMed: 31937438
DOI: 10.1016/j.ymgme.2019.12.012 -
Balkan Medical Journal Sep 2022GM1 gangliosidosis is an autosomal recessive lysosomal storage disease caused by biallelic mutations in the gene. Neurodegeneration, hypotonia, visceromegaly, macular...
BACKGROUND
GM1 gangliosidosis is an autosomal recessive lysosomal storage disease caused by biallelic mutations in the gene. Neurodegeneration, hypotonia, visceromegaly, macular cherry-red spots, skeletal dysplasia, and coarse and dysmorphic face are the major clinical features.
AIMS
To evaluate the demographic and clinical data of patients with GM1 gangliosidosis in a single center.
STUDY DESIGN
A retrospective clinical study.
METHODS
This study included patients followed at Hacettepe University İhsan Doğramacı Children’s Hospital Pediatric Metabolism Unit with the diagnosis of GM1 gangliosidosis between 1988 and 2021. Hospital records of the patients were reviewed for demographic, clinical, and laboratory findings.
RESULTS
Fourteen patients were included in the study and 10 (71.4%) were male. The age at onset of clinical symptoms was between 0 and 5 months, and the median time to diagnosis after the first symptom was 4.3 (0-13) months. Motor delay (54%) was the most common initial symptom. The median follow-up period was 14.8 (0.4-92.2) months. Twelve patients (85.7%) died, and all deaths occurred before the age of 24 months. The median survival was 21.3 (95% confidence interval, 15.5-24.9) months. Higher leukocyte beta-galactosidase activity correlated with later age at onset ( = 0.575), later age at diagnosis ( = 0.618), and longer diagnostic delay ( = 0.702) ( < 0.05).
CONCLUSION
Median survival in patients with GM1 gangliosidosis is less than 24 months. Beta-galactosidase enzyme activity may be associated with clinical onset and time of diagnosis in these patients.
Topics: Delayed Diagnosis; Female; Gangliosidosis, GM1; Humans; Infant; Infant, Newborn; Male; Retrospective Studies; beta-Galactosidase
PubMed: 35965426
DOI: 10.4274/balkanmedj.galenos.2022.2022-3-75 -
International Journal of Molecular... Nov 2017Sphingolipids, long thought to be passive components of biological membranes with merely a structural role, have proved throughout the past decade to be major players in... (Review)
Review
Sphingolipids, long thought to be passive components of biological membranes with merely a structural role, have proved throughout the past decade to be major players in the pathogenesis of many human diseases. The study and characterization of several genetic disorders like Fabry's and Tay Sachs, where sphingolipid metabolism is disrupted, leading to a systemic array of clinical symptoms, have indeed helped elucidate and appreciate the importance of sphingolipids and their metabolites as active signaling molecules. In addition to being involved in dynamic cellular processes like apoptosis, senescence and differentiation, sphingolipids are implicated in critical physiological functions such as immune responses and pathophysiological conditions like inflammation and insulin resistance. Interestingly, the kidneys are among the most sensitive organ systems to sphingolipid alterations, rendering these molecules and the enzymes involved in their metabolism, promising therapeutic targets for numerous nephropathic complications that stand behind podocyte injury and renal failure.
Topics: Animals; Fabry Disease; Humans; Kidney Diseases; Podocytes; Sphingolipids; Tay-Sachs Disease; Translational Research, Biomedical
PubMed: 29186855
DOI: 10.3390/ijms18122528 -
Scientific Reports Nov 2019GM1 ganglioside, a monosialic glycosphingolipid and a crucial component of plasma membranes, accumulates in lysosomal storage disorders, primarily in GM1 gangliosidosis....
GM1 ganglioside, a monosialic glycosphingolipid and a crucial component of plasma membranes, accumulates in lysosomal storage disorders, primarily in GM1 gangliosidosis. The development of biomarkers for simplifying diagnosis, monitoring disease progression and evaluating drug therapies is an important objective in research into neurodegenerative lysosomal disorders. With this in mind, we established fluorescent imaging and flow-cytometric methods to track changes in GM1 ganglioside levels in patients with GM1 gangliosidosis and in control cells. We also evaluated GM1 ganglioside content in patients' cells treated with the commercially available Miglustat, a substrate inhibitor potentially suitable for the treatment of late-onset GM1 gangliosidosis. The flow-cytometric method proved to be sensitive, unbiased, and rapid in determining variations in GM1 ganglioside content in human lymphocytes derived from small amounts of fresh blood. We detected a strong correlation between GM1 ganglioside content and the clinical severity of GM1 gangliosidosis. We confirm the ability of Miglustat to act as a substrate reduction agent in the patients' treated cells. As well as being suitable for diagnosing and managing patients with GM1 gangliosidosis this method could be useful in the diagnosis and management of other lysosomal diseases, such as galactosialidosis, Type C Niemann-Pick, and any other disease with pathologic variations of GM1 ganglioside.
Topics: 1-Deoxynojirimycin; Biomarkers; Cells, Cultured; Disease Progression; Female; Fibroblasts; Flow Cytometry; G(M1) Ganglioside; Gangliosidosis, GM1; Glycoside Hydrolase Inhibitors; Humans; Lymphocytes; Male; Optical Imaging; Phenotype; Severity of Illness Index
PubMed: 31776384
DOI: 10.1038/s41598-019-53995-5 -
Molecular Genetics and Metabolism Aug 2021Our study aimed to quantify structural changes in relation to metabolic abnormalities in the cerebellum, thalamus, and parietal cortex of patients with late-onset...
OBJECTIVE
Our study aimed to quantify structural changes in relation to metabolic abnormalities in the cerebellum, thalamus, and parietal cortex of patients with late-onset GM2-gangliosidosis (LOGG), which encompasses late-onset Tay-Sachs disease (LOTS) and Sandhoff disease (LOSD).
METHODS
We enrolled 10 patients with LOGG (7 LOTS, 3 LOSD) who underwent a neurological assessment battery and 7 age-matched controls. Structural MRI and MRS were performed on a 3 T scanner. Structural volumes were obtained from FreeSurfer and normalized by total intracranial volume. Quantified metabolites included N-acetylaspartate (NAA), choline (Cho), myo-inositol (mI), creatine (Cr), and combined glutamate-glutamine (Glx). Metabolic concentrations were corrected for partial volume effects.
RESULTS
Structural analyses revealed significant cerebellar atrophy in the LOGG cohort, which was primarily driven by LOTS patients. NAA was lower and mI higher in LOGG, but this was also significantly driven by the LOTS patients. Clinical ataxia deficits (via the Scale for the Assessment and Rating of Ataxia) were associated with neuronal injury (via NAA), neuroinflammation (via mI), and volumetric atrophy in the cerebellum.
INTERPRETATION
The decrease of NAA in the cerebellum suggests that, in addition to cerebellar atrophy, there is ongoing impaired neuronal function and/or loss, while an increase in mI indicates possible neuroinflammation in LOGG (more so within the LOTS subvariant). Quantifying cerebellar atrophy in relation to neurometabolic differences in LOGG may lead to improvements in assessing disease severity, progression, and pharmacological efficacy. Lastly, additional neuroimaging studies in LOGG are required to contrast LOTS and LOSD more accurately.
Topics: Adult; Cerebellum; Cohort Studies; Female; Gangliosidoses, GM2; Humans; Late Onset Disorders; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Parietal Lobe; Sandhoff Disease; Spectrum Analysis; Tay-Sachs Disease; Thalamus; Young Adult
PubMed: 34226107
DOI: 10.1016/j.ymgme.2021.06.008 -
Medicine Jan 2022Monosialotetrahexosylganglioside (GM1) gangliosidosis is a rare lysosomal storage disorder caused by the deficiency of ß-galactosidase. Because clinical symptoms of GM1...
RATIONALE
Monosialotetrahexosylganglioside (GM1) gangliosidosis is a rare lysosomal storage disorder caused by the deficiency of ß-galactosidase. Because clinical symptoms of GM1 gangliosidosis overlap with other neurodevelopmental disorders, the diagnosis of this disease is not easy, specifically in late infantile GM1 gangliosidosis. This report described a case of late-infantile GM1 gangliosidosis mistaken for juvenile idiopathic arthritis.
PATIENT CONCERNS
A 16-year-old girl was referred to our hospital due to persistent multiple joint deformities and mental retardation, which could not be explained by juvenile idiopathic arthritis.
DIAGNOSIS
We made a diagnosis of late infantile GM1 gangliosidosis through enzyme assays and genetic testing after a skeletal survey.
INTERVENTIONS
The patient underwent cervical domeplasty and laminectomy for cord compression and received rehabilitation treatment.
OUTCOMES
The patient is receiving multidisciplinary care at a tertiary center for variable skeletal disease and conditions associated with GM1 gangliosidosis.
LESSONS
Late infantile GM1 gangliosidosis should be considered in the differential diagnosis of progressive neurologic decline and skeletal dysostosis.
Topics: Adolescent; Arthritis, Juvenile; Diagnosis, Differential; Female; Gangliosidosis, GM1; Humans; Lysosomal Storage Diseases; Magnetic Resonance Imaging; beta-Galactosidase
PubMed: 35029890
DOI: 10.1097/MD.0000000000028435 -
Cellular and Molecular Life Sciences :... Jun 2014The ubiquitous distribution of lysosomes and their heterogeneous protein composition reflects the versatility of these organelles in maintaining cell homeostasis and... (Review)
Review
The ubiquitous distribution of lysosomes and their heterogeneous protein composition reflects the versatility of these organelles in maintaining cell homeostasis and their importance in tissue differentiation and remodeling. In lysosomes, the degradation of complex, macromolecular substrates requires the synergistic action of multiple hydrolases that usually work in a stepwise fashion. This catalytic machinery explains the existence of lysosomal enzyme complexes that can be dynamically assembled and disassembled to efficiently and quickly adapt to the pool of substrates to be processed or degraded, adding extra tiers to the regulation of the individual protein components. An example of such a complex is the one composed of three hydrolases that are ubiquitously but differentially expressed: the serine carboxypeptidase, protective protein/cathepsin A (PPCA), the sialidase, neuraminidase-1 (NEU1), and the glycosidase β-galactosidase (β-GAL). Next to this 'core' complex, the existence of sub-complexes, which may contain additional components, and function at the cell surface or extracellularly, suggests as yet unexplored functions of these enzymes. Here we review how studies of basic biological processes in the mouse models of three lysosomal storage disorders, galactosialidosis, sialidosis, and GM1-gangliosidosis, revealed new and unexpected roles for the three respective affected enzymes, Ppca, Neu1, and β-Gal, that go beyond their canonical degradative activities. These findings have broadened our perspective on their functions and may pave the way for the development of new therapies for these lysosomal storage disorders.
Topics: Animals; Cathepsin A; Disease Models, Animal; Gangliosidosis, GM1; Gene Expression Regulation; Humans; Lysosomal Storage Diseases; Lysosomes; Mice; Mice, Knockout; Mucolipidoses; Multienzyme Complexes; Neuraminidase; Signal Transduction; beta-Galactosidase
PubMed: 24337808
DOI: 10.1007/s00018-013-1538-3 -
Neurology Feb 2020A cross-sectional study was performed to evaluate whether quantitative oculomotor measures correlate with disease severity in late-onset GM2 gangliosidosis (LOGG) and...
OBJECTIVE
A cross-sectional study was performed to evaluate whether quantitative oculomotor measures correlate with disease severity in late-onset GM2 gangliosidosis (LOGG) and assess cognition and sleep as potential early nonmotor features.
METHODS
Ten patients with LOGG underwent quantitative oculomotor recordings, including measurements of the angular vestibulo-ocular reflex (VOR), with results compared to age- and sex-matched controls. Disease severity was assessed by ataxia rating scales. Cognitive/neuropsychiatric features were assessed by the cerebellar cognitive affective syndrome (CCAS) scale, Cerebellar Neuropsychiatric Rating Scale, and sleep quality evaluated using subjective sleep scales.
RESULTS
Oculomotor abnormalities were found in all participants, including 3/10 with clinically normal eye movements. Abnormalities involved impaired saccadic accuracy (5/10), abnormal vertical (8/10) and horizontal (4/10) pursuit, reduced optokinetic nystagmus (OKN) responses (7/10), low VOR gain (10/10), and impaired VOR cancellation (2/10). Compared to controls, the LOGG group showed significant differences in saccade, VOR, OKN, and visually enhanced VOR gains. Severity of saccadic dysmetria, OKN, and VOR fixation-suppression impairments correlated with ataxia scales ( < 0.05). Nine out of ten patients with LOGG had evidence of the CCAS (5/10 definite, 2/10 probable, 2/10 possible). Excessive daytime sleepiness was present in 4/10 and 8/10 had poor subjective sleep quality.
CONCLUSIONS
Cerebellar oculomotor abnormalities were present in all patients with LOGG, including those with normal clinical oculomotor examinations. Saccade accuracy (dorsal cerebellar vermis localization), fixation suppression, and OKN gain (cerebellar flocculus/paraflocculus localization) correlated with disease severity, suggesting that quantitative oculomotor measurements could be used to track disease progression. We found evidence of the CCAS, suggesting that cerebellar dysfunction may explain the cognitive disorder in LOGG. Sleep impairments were prevalent and require further study.
Topics: Adult; Brain; Cognition; Cohort Studies; Cross-Sectional Studies; Eye Movements; Female; Gangliosidoses, GM2; Humans; Male; Middle Aged; Ocular Motility Disorders; Psychiatric Status Rating Scales; Severity of Illness Index; Sleep; Sleep Wake Disorders
PubMed: 31964693
DOI: 10.1212/WNL.0000000000008959 -
Pediatric Endocrinology Reviews : PER Jun 2016The gangliosidoses are lysosomal storage disorders caused by accumulation of GM1 or GM2 gangliosides. GM1 gangliosidosis has both central nervous system and systemic... (Review)
Review
The gangliosidoses are lysosomal storage disorders caused by accumulation of GM1 or GM2 gangliosides. GM1 gangliosidosis has both central nervous system and systemic findings; while, GM2 gangliosidosis is restricted primarily to the central nervous system. Both disorders have autosomal recessive modes of inheritance and a continuum of clinical presentations from a severe infantile form to a milder, chronic adult form. Both are devastating diseases without cure or specific treatment however, with the use of supportive aggressive medical management, the lifespan and quality of life has been extended for both diseases. Naturally occurring and engineered animal models that mimic the human diseases have enhanced our understanding of the pathogenesis of disease progression. Some models have shown significant improvement in symptoms and lifespan with enzyme replacement, substrate reduction, and anti-inflammatory treatments alone or in combination. More recently gene therapy has shown impressive results in large and small animal models. Treatment with FDA-approved glucose analogs to reduce the amount of ganglioside substrate is used as off-label treatments for some patients. Therapies also under clinical development include small molecule chaperones and gene therapy.
Topics: Anti-Inflammatory Agents; Disease Progression; Enzyme Replacement Therapy; Gangliosidoses, GM2; Gangliosidosis, GM1; Genetic Therapy; Glucose; Humans; Severity of Illness Index
PubMed: 27491214
DOI: No ID Found -
International Journal of Molecular... Sep 2020Glycosphingolipids (GSLs) are a specialized class of membrane lipids composed of a ceramide backbone and a carbohydrate-rich head group. GSLs populate lipid rafts of the... (Review)
Review
Glycosphingolipids (GSLs) are a specialized class of membrane lipids composed of a ceramide backbone and a carbohydrate-rich head group. GSLs populate lipid rafts of the cell membrane of eukaryotic cells, and serve important cellular functions including control of cell-cell signaling, signal transduction and cell recognition. Of the hundreds of unique GSL structures, anionic gangliosides are the most heavily implicated in the pathogenesis of lysosomal storage diseases (LSDs) such as Tay-Sachs and Sandhoff disease. Each LSD is characterized by the accumulation of GSLs in the lysosomes of neurons, which negatively interact with other intracellular molecules to culminate in cell death. In this review, we summarize the biosynthesis and degradation pathways of GSLs, discuss how aberrant GSL metabolism contributes to key features of LSD pathophysiology, draw parallels between LSDs and neurodegenerative proteinopathies such as Alzheimer's and Parkinson's disease and lastly, discuss possible therapies for patients.
Topics: Alzheimer Disease; Animals; Gangliosides; Glycosphingolipids; Humans; Lysosomes; Parkinson Disease; Sandhoff Disease; Tay-Sachs Disease
PubMed: 32961778
DOI: 10.3390/ijms21186881