GM1 Gangliosidosis Type Research Articles

GM1 gangliosidosis type II: Results of a 10-year prospective study

PurposeGM1 gangliosidosis (GM1) a lysosomal disorder caused by pathogenic variants in GLB1, is characterized by relentless neurodegeneration. There are no approved treatments. MethodsForty-one individuals with type II (late-infantile and juvenile) GM1 participated in a single-site prospective observational study. ResultsClassification of 37 distinct variants using American College of Medical Genetics and Genomics criteria resulted in the upgrade of 6 and the submission of 4 new variants. In contrast to type I infantile disease, children with type II had normal or near normal hearing and did not have cherry-red maculae or hepatosplenomegaly. Some older children with juvenile onset disease developed thickened aortic and/or mitral valves. Serial magnetic resonance images demonstrated progressive brain atrophy, more pronounced in late infantile patients. Magnetic resonance spectroscopy showed worsening elevation of myo-inositol and deficit of N-acetyl aspartate that were strongly correlated with scores on the Vineland Adaptive Behavior Scale, progressing more rapidly in late infantile compared with juvenile onset disease. ConclusionSerial phenotyping of type II GM1 patients expands the understanding of disease progression and clarifies common misconceptions about type II patients; these are pivotal steps toward more timely diagnosis and better supportive care. The data amassed through this 10-year effort will serve as a robust comparator for ongoing and future therapeutic trials.

A Case of GM 1 Gangliosidosis Type 2 Mimicking Zellweger Syndrome

Juvenile GM1-gangliosidosis, also known as type II or juvenile GM1-gangliosidosis, is an autosomal recessive lysosomal storage disorder that clinically differs from infantile GM1-gangliosidosis in the absence of the characteristic cherry-red patch and hepatosplenomegaly. The disease is characterized by mild skeletal abnormalities and slowly progressing neurodegeneration. Due to the late age of onset and unusual presentation, diagnostic confusion with other ataxic and purely neurological disorders is common. There are currently 3–4 recognized types of GM1-gangliosidosis, with type I being the most prevalent phenotype with an average onset age of 6 months. Several subtypes of GM1-gangliosidosis are caused by mutations in the GLB1 gene, but the location and type of deleterious mutations have a direct impact on the severity of the disease and the age at which it manifests. A fully immunized 8-month-old male presented to our hospital with complaints of mild feeding difficulty, periorbital edema, and fever. Facial dysmorphism, hypotonia, delayed development, and hepatomegaly were observed in the patient. As there is currently no effective treatment for GM1 gangliosidosis, the carrier of the disease receives only symptomatic and palliative care. Given that genetic counseling is now the only means of preventing the disease, early diagnosis is crucial.

Natural history of GM1 gangliosidosis-Retrospective cohort study of 61 French patients from 1998 to 2019.

GM1 gangliosidosis is a rare lysosomal storage disorder associated with β-galactosidase enzyme deficiency. There are three types of GM1 gangliosidosis based on age of symptom onset, which correlate with disease severity. In 2019, we performed a retrospective multicentric study including all patients diagnosed with GM1 gangliosidosis in France since 1998. We had access to data for 61 of the 88 patients diagnosed between 1998 and 2019. There were 41 patients with type 1 (symptom onset ≤6 months), 11 with type 2a (symptom onset from 7 months to 2 years), 5 with type 2b (symptom onset from 2 to 3 years), and 4 with type 3 (symptom onset >3 years). The estimated incidence in France was 1/210,000. In patients with type 1, the first symptoms were hypotonia (26/41, 63%), dyspnea (7/41, 17%), and nystagmus (6/41, 15%), whereas in patients with type 2a these were psychomotor regression (9/11, 82%) and seizures (3/11, 27%). In types 2b and 3, the initial symptoms were mild, such as speech difficulties, school difficulties, and progressive psychomotor regression. Hypotonia was observed in all patients, except type 3. The mean overall survival was 23 months (95% confidence interval [CI]: 7, 39) for type 1 and 9.1 years (95% CI: 4.5, 13.5) for type 2a. To the best of our knowledge, this is one of the largest historical cohorts reported, which provides important information on the evolution of all types of GM1 gangliosidosis. These data could be used as a historical cohort in studies assessing potential therapies for this rare genetic disease. This article is protected by copyright. All rights reserved.

Rapid Identification of New Biomarkers for the Classification of GM1 Type 2 Gangliosidosis Using an Unbiased 1H NMR-Linked Metabolomics Strategy.

Biomarkers currently available for the diagnosis, prognosis, and therapeutic monitoring of GM1 gangliosidosis type 2 (GM1T2) disease are mainly limited to those discovered in targeted proteomic-based studies. In order to identify and establish new, predominantly low-molecular-mass biomarkers for this disorder, we employed an untargeted, multi-analyte approach involving high-resolution 1H NMR analysis coupled to a range of multivariate analysis and computational intelligence technique (CIT) strategies to explore biomolecular distinctions between blood plasma samples collected from GM1T2 and healthy control (HC) participants (n = 10 and 28, respectively). The relationship of these differences to metabolic mechanisms underlying the pathogenesis of GM1T2 disorder was also investigated. 1H NMR-linked metabolomics analyses revealed significant GM1T2-mediated dysregulations in ≥13 blood plasma metabolites (corrected p < 0.04), and these included significant upregulations in 7 amino acids, and downregulations in lipoprotein-associated triacylglycerols and alanine. Indeed, results acquired demonstrated a profound distinctiveness between the GM1T2 and HC profiles. Additionally, employment of a genome-scale network model of human metabolism provided evidence that perturbations to propanoate, ethanol, amino-sugar, aspartate, seleno-amino acid, glutathione and alanine metabolism, fatty acid biosynthesis, and most especially branched-chain amino acid degradation (p = 10−12−10−5) were the most important topologically-highlighted dysregulated pathways contributing towards GM1T2 disease pathology. Quantitative metabolite set enrichment analysis revealed that pathological locations associated with these dysfunctions were in the order fibroblasts > Golgi apparatus > mitochondria > spleen ≈ skeletal muscle ≈ muscle in general. In conclusion, results acquired demonstrated marked metabolic imbalances and alterations to energy demand, which are consistent with GM1T2 disease pathogenesis mechanisms.

Clinical Features of Infantile GM1 Gangliosidosis: Report of an Iranian Patient

Background: GM1 gangliosidosis is an autosomal recessive lysosomal storage disease due to a lack of β-galactosidase activity, exactly because of mutations in the GLB1 gene. GM1 gangliosidosis is a rare disease that could occur either during infancy (infantile type 1), as a juvenile (type 2), or in adulthood (type 3) in both nervous and skeletal systems. Type 1 is characterized by premature psychomotor deterioration, visceromegaly, macular cherry-red spot, skeletal deformities, and death in the first 2 years of life. Case Presentation: We reported an Iranian infant who, on initial check-up, had coarse face, visceromegaly, dystonia, and hepatosplenomegaly that increased at 15 months of age. At the initial check-up, a genetic test was performed and GM1 gangliosidosis type 1 was diagnosed. Conclusion: infant form is characterized by early-onset before the age of 6 months and rapidly progressive psychomotor deterioration, facial abnormalities, and visceromegaly.

Comprehensive behavioral and biochemical outcomes of novel murine models of GM1-gangliosidosis and Morquio syndrome type B

Deficiencies in the lysosomal hydrolase β-galactosidase (β-gal) lead to two distinct diseases: the skeletal disease Morquio syndrome type B, and the neurodegenerative disease GM1-gangliosidosis. Utilizing CRISPR-Cas9 genome editing, the mouse β-gal encoding gene, Glb1, was targeted to generate both models of β-gal deficiency in a single experiment. For Morquio syndrome type B, the common human missense mutation W273L (position 274 in mice) was introduced into the Glb1 gene (Glb1W274L), while for GM1-gangliosidosis, a 20 bp mutation was generated to remove the catalytic nucleophile of β-gal (β-gal−/−). Glb1W274L mice showed a significant reduction in β-gal enzyme activity (8.4–13.3% of wildtype), but displayed no marked phenotype after one year. In contrast, β-gal−/− mice were devoid of β-gal enzyme activity (≤1% of wildtype), resulting in ganglioside accumulation and severe cellular vacuolation throughout the central nervous system (CNS). β-gal−/− mice also displayed severe neuromotor and neurocognitive dysfunction, and as the disease progressed, the mice became emaciated and succumbed to the disease by 10 months of age. Overall, in addition to generating a novel murine model that phenotypically resembles GM1-gangliosidosis, the first model of β-galactosidase deficiency with residual enzyme activity has been developed.

4-epi-Isofagomine derivatives as pharmacological chaperones for the treatment of lysosomal diseases linked to β-galactosidase mutations: Improved synthesis and biological investigations.

(5aR)-5a-C-pentyl-4-epi-isofagomine 1 is a powerful inhibitor of lysosomal β-galactosidase and a remarkable chaperone for mutations associated with GM1-gangliosidosis and Morquio disease type B. We report herein an improved synthesis of this compound and analogs (5a-C-methyl, pentyl, nonyl and phenylethyl derivatives), and a crystal structure of a synthetic intermediate that confirms its configuration resulting from the addition of a Grignard reagent. These compounds were evaluated as glycosidase inhibitors and their potential as chaperones for mutant lysosomal galactosidases determined. Based on these results and on docking studies, the 5-C-pentyl derivative 1 was selected as the optimal structure for further investigations: this compound induces the maturation of mutated β-galactosidase in fibroblasts of a GM1-gangliosidosis patient and promote the decrease of keratan sulfate and oligosaccharide load in patient cells. Compound 1 is clearly capable of restoring β-galactosidase activity and of promoting maturation of the protein, which should result in significant clinical benefit. These properties strongly support the development of compound 1 for the treatment of GM1-gangliosidosis and Morquio disease type B patients harboring β-galactosidase mutations sensitive to pharmacological chaperoning.

Protein modeling and clinical description of a novel in-frame GLB1 deletion causing GM1 gangliosidosis type II.

BackgroundBeta‐galactosidase‐1 ( GLB1) is a lysosomal hydrolase that is responsible for breaking down specific glycoconjugates, particularly GM1 (monosialotetrahexosylganglioside). Pathogenic variants in GLB1 cause two different lysosomal storage disorders: GM1 gangliosidosis and mucopolysaccharidosis type IVB. In GM1 gangliosidosis, decreased β‐galactosidase‐1 enzymatic activity leads to the accumulation of GM1 gangliosides, predominantly within the CNS. We present a 22‐month‐old proband with GM1 gangliosidosis type II (late‐infantile form) in whom a novel homozygous in‐frame deletion (c.1468_1470delAAC, p.Asn490del) in GLB1 was detected.MethodsWe used an experimental protein structure of β‐galactosidase‐1 to generate a model of the p.Asn490del mutant and performed molecular dynamic simulations to determine whether this mutation leads to altered ligand positioning compared to the wild‐type protein. In addition, residual mutant enzyme activity in patient leukocytes was evaluated using a fluorometric assay.ResultsMolecular dynamics simulations showed the deletion to alter the catalytic site leading to misalignment of the catalytic residues and loss of collective motion within the model. We predict this misalignment will lead to impaired catalysis of β‐galactosidase‐1 substrates. Enzyme assays confirmed diminished GLB1 enzymatic activity (~3% of normal activity) in the proband.ConclusionsWe have described a novel, pathogenic in‐frame deletion of GLB1 in a patient with GM1 gangliosidosis type II.

Case reports of juvenile GM1 gangliosidosisis type II caused by mutation in GLB1 gene

BackgroundType II or juvenile GM1-gangliosidosis is an autosomal recessive lysosomal storage disorder, which is clinically distinct from infantile form of the disease by the lack of characteristic cherry-red spot and hepatosplenomegaly. The disease is characterized by slowly progressive neurodegeneration and mild skeletal changes. Due to the later age of onset and uncharacteristic presentation, diagnosis is frequently puzzled with other ataxic and purely neurological disorders. Up to now, 3–4 types of GM1-gangliosidosis have been reported and among them type I is the most common phenotype with the age of onset around 6 months. Various forms of GM1-gangliosidosis are caused by GLB1 gene mutations but severity of the disease and age of onset are directly related to the position and the nature of deleterious mutations. However, due to its unique genetic cause and overlapping clinical features, some researchers believe that GM1 gangliosidosis represents an overlapped disease spectrum instead of four distinct types.Case presentationHere, we report a less frequent type of autosomal recessive GM1 gangliosidosis with perplexing clinical presentation in three families in the southwest part of Iran, who are unrelated but all from “Lurs” ethnic background. To identify disease-causing mutations, Whole Exome Sequencing (WES) utilizing next generation sequencing was performed. Four patients from three families were investigated with the age of onset around 3 years old. Clinical presentations were ataxia, gate disturbances and dystonia leading to wheelchair-dependent disability, regression of intellectual abilities, and general developmental regression. They all were born in consanguineous families with no previous documented similar disease in their parents. A homozygote missense mutation in GLB1 gene (c. 601 G > A, p.R201C) was found in all patients. Using Sanger sequencing this identified mutation was confirmed in the proband, their parents, grandparents, and extended family members, confirming its autosomal recessive pattern of inheritance.ConclusionsOur study identified a rare pathogenic missense mutation in GLB1 gene in patients with complex neurodevelopmental findings, which can extend the list of differential diagnoses for childhood ataxia in Iranian patients.

Urine oligosaccharide tests for the diagnosis of oligosaccharidoses

AbstractThis review discusses the development of capillary electrophoresis with laser-induced detection and mass spectrometry techniques for the analysis of urinary oligosaccharides to screen for human oligosaccharidoses and related disorders. Capillary electrophoresis is suitable for the analysis of urinary oligosaccharides. It has a high resolution efficiency, and when it is coupled to a laser-induced fluorescence detector system, it offers an optimal analytical sensitivity. Mass spectrometry techniques have evolved as powerful tools for glycan analyses, are important tools for the analysis of oligosaccharide structures, and offer precise results, analytical versatility, very high sensitivity, high precision and high speed. Mass spectrometry is tolerant of mixtures and is a natural choice for the analysis of this class of molecules. The urine oligosaccharide profiles from healthy controls and patients diagnosed with different lysosomal storage diseases (fucosidosis, α-mannosidosis, GM1 gangliosidosis, GM2 gangliosidosis type Sandhoff, glycogen storage disease type 2 and 3, aspartylglucosaminuria, Schindler disease and galactosialydosis) and related disorders (glycogen storage diseases) are presented. In summary, these procedures are powerful tools for the rapid identification and characterization of these disorders. In all cases, the oligosaccharide profiles are strongly informative, identified the abnormal compounds, and are good alternatives to traditional screening tests that use thin layer chromatography. These tests have great sensibility and resolution and are automatable, enabling extended screening of these diseases, both as a first step in diagnosis or for confirming the pathogenicity of mutations that may be detected with next generation sequencing techniques.

Clinical and molecular genetic analysis of six patients with GM1 gangliosidosis

Objective To analyze the clinical and molecular genetic features in 6 pedigrees with GM1 ganglio-sidosis. Methods Clinical data of 6 patients with GM1 gangliosidosis were collected from April 2014 to August 2015 in Department of Pediatrics, Peking University First Hospital.Lysosomal enzyme assays for examining its activity in white blood cell were used to analyze clinical characteristics.Lysosomal enzyme assays were used to examine the mutation of β-galactosidase-1(GLB1). Polymerase chain reaction (PCR) and Sanger sequencing were used to detect GLB1 mutations to analyze the genetic characteristics. Results (1) Clinical characteristics: all 6 patients showed their initial symptoms before 8 months old.Developmental retardation and regression were seen in all patients.Startle response, epilepsy, hypotonia were found in most patients, and hearing and visual loss, Mongolian spots, hepatomegaly and growth delay were found as well.Hypomyelination was found in all 6 patients′ cranial MRI.Four cases of T2WI hyperintensity in thalami and 4 cases of cerebral and/or cerebellar atrophy were seen as well.Activity of GLB in all 6 patients decreased.Three patients were diagnosed with GM1 gangliosidosis type Ⅰ while 3 patients were GM1 gangliosidosis type Ⅱ.(2) Genetic characteristics: 10 GLB1 mutations of c. 520T>C(p.Y174H), c.622C>T(p.R208C), c.550C>T(p.Q184X), c.446C>T(p.S149F), c.266 A>G(p.H89R), c.601C>T(p.R201C), c.148T>A(p.Y50N), c.618delC(p.R208AfsX21), c.1343A>T(p.D448V), c.410C>A(p.A137D) were detected in total, including 5 novel mutations: c.550C>T(p.Q184X), c.148T>A(p.Y50N), c.618delC(p.R208AfsX21), c.266T>C(p.H89R) and c. 410C>A(p.A137D); GLB1 mutations in 4 patients were compound heterozygous while the other 2 were homozygous, and all were inherited from their healthy parents. Conclusions Six patients were diagnosed with GM1 gangliosidosis clinically and genetically.Five novel GLB1 mutations were detected in this research, expanding the spectrum of GLB1 mutations.This research will provide correct genetic counseling and prenatal diagnosis for the patients′ families as well. Key words: GM1 gangliosidosis; Beta-galactosidase; Mutation

(5aR)-5a-C-Pentyl-4-epi-isofagomine: A powerful inhibitor of lysosomal β-galactosidase and a remarkable chaperone for mutations associated with GM1-gangliosidosis and Morquio disease type B

This report is about the identification, synthesis and initial biological characterization of derivatives of 4-epi-isofagomine as pharmacological chaperones (PC) for human lysosomal β-galactosidase. The two epimers of 4-epi-isofagomine carrying a pentyl group at C-5a, namely (5aR)- and (5aS)-5a-C-pentyl-4-epi-isofagomine, were prepared by an innovative procedure involving in the key step the addition of nitrohexane to a keto-pentopyranoside. Both epimers were evaluated as inhibitors of the human β-galactosidase: the (5aR)-stereoisomer (compound 1) was found to be a very potent inhibitor of the enzyme (IC50 = 8 nM, 30× more potent than 4-epi-isofagomine at pH 7.3) with a high selectivity for this glycosidase whereas the (5aS) epimer was a much weaker inhibitor. In addition, compound 1 showed a remarkable activity as a PC. It significantly enhanced the residual activity of mutant β-galactosidase in 15 patient cell lines out of 23, with enhancement factors greater than 3.5 in 10 cell lines and activity restoration up to 91% of normal. Altogether, these results indicated that (5aR)-5a-C-pentyl-4-epi-isofagomine constitutes a promising PC-based drug candidate for the treatment of GM1-gangliosidosis and Morquio disease type B.

Large Mongolian spots in GM1 gangliosidosis

A 9-month old male child with GM1 gangliosidosis type 1 presented with Mongolian spots. The cutaneous lesions were present since birth before the appearance of the other features of the disease. Our patient, whose clinical course and physical signs were in keeping with GM1 gangliosidosis, had extensive Mongolian blue spots and this adds to the evidence supporting such an association.

Clinical features of GM1 gangliosidosis type 3

Clinical features of GM1 gangliosidosis type 3

GM1 gangliosidosis associated with neonatal-onset of diffuse ecchymoses and mongolian spots

A 7-month old girl with GM1 gangliosidosis type 1 manifested with diffuse ecchymosis and Mongolian spots. The cutaneous lesions were present at birth before the appearance of the other features of the disease. We postulate that dermal pigmentation may be recognized as an early sign of GM1 gangliosidosis.

Facial grimacing as a clue for the diagnosis of GM1 type 3 gangliosidosis

GM1 Gangliosidosis is an autosomal recessive lysosomal storage disease caused by the deficiency of beta-galactosidase. Only few cases have been reported in the literature, owing to the rarity of the condition but also possibly due to its underrecognition in clinical practice1,2. Reports of GM1 gangliosidosis type 3 patients and recent literature review shows that oromandibular dystonia producing the aprearance of grimacing is a common feature of this disorder2. Herein we describe a patient in wich proeminent facial grimacing served as [...]

Substrate reduction therapy with miglustat in chronic GM2 gangliosidosis type Sandhoff: results of a 3‐year follow‐up

GM2 gangliosidosis type Sandhoff is caused by a defect of beta-hexosaminidase, an enzyme involved in the catabolism of gangliosides. It has been proposed that substrate reduction therapy using N-butyl-deoxynojirimycin (miglustat) may delay neurological progression, at least in late-onset forms of GM2 gangliosidosis. We report the results of a 3-year treatment with miglustat (100 mg t.i.d) in a patient with chronic Sandhoff disease manifesting with an atypical, spinal muscular atrophy phenotype. The follow-up included serial neurological examinations, blood tests, abdominal ultrasound, and neurophysiologic, cognitive, brain, and muscle MRI studies. We document some minor effects on neurological progression in chronic Sandhoff disease by miglustat treatment, confirming the necessity of phase II therapeutic trials including early-stage patients in order to assess its putative efficacy in chronic Sandhoff disease.

Chronic GM2 gangliosidosis type Sandhoff associated with a novel missense HEXB gene mutation causing a double pathogenic effect

We identified a novel c.1556A > G transition in exon 12 of the HEXB gene associated with chronic Sandhoff’s disease, changing a conserved aspartic acid to glycine at position 494 of the Hex β-subunit; moreover, RT-PCR showed aberrant exon 12 skipping, causing a frame-shift and premature stop codon, consequent to the disruption of an exonic splicing enhancer motif by the mutation. These data suggest that the c.1556 A > G transition would affect both HEXB mRNA processing and biochemical properties of the β-subunit.

Dermal melanocytosis associated with GM1-gangliosidosis type 1

This article does not have an abstract.

Extensive Mongolian Spots: A Clinical Sign Merits Special Attention

Although typical and limited Mongolian spots are benign skin markings at birth which fade and disappear as the child grows, extensive Mongolian spots deserve special attention as possible indications of associated inborn error of metabolism. A few cases of extensive Mongolian spots in association with inheritable storage diseases have been reported. Some hypotheses have been put forward, but further investigation is necessary to elucidate the causative factors. This report describes three infants with generalized Mongolian spots, two infants with GM1 gangliosidosis type 1, and one in association with Hurler syndrome. Findings of generalized Mongolian spots in newborns may lead to an early detection and early treatment before irreversible organ damage occurs.