Population analysis of the GLB1 gene in South Brazil

Baiotto, Cléia Rosani; Sperb, Fernanda; Matte, Úrsula da Silveira; Silva, Claudia Dornelles da; Sano, Renata; Coelho, Janice Carneiro; Giugliani, Roberto

doi:10.1590/s1415-47572011000100009

Cited by 20 publications

(20 citation statements)

References 25 publications

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“…10B). Interestingly, a patient (P12–2363) with the mutation R59H, a GLB1 mutation commonly found in Brazil [32,33], where all the affected urine samples were sourced, had the highest urinary A2G2’ levels. This patient also exhibited significant clinical symptoms at birth (Table 2) suggesting a possible correlation between severity and biomarker levels.…”

Section: Resultsmentioning

confidence: 99%

Characterization of glycan substrates accumulating in GM1 Gangliosidosis

Lawrence

Vleet

Mangini

et al. 2019

Molecular Genetics and Metabolism Reports

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IntroductionGM1 gangliosidosis is a rare autosomal recessive genetic disorder caused by the disruption of the GLB1 gene that encodes β-galactosidase, a lysosomal hydrolase that removes β-linked galactose from the non-reducing end of glycans. Deficiency of this catabolic enzyme leads to the lysosomal accumulation of GM1 and its asialo derivative GA1 in β-galactosidase deficient patients and animal models. In addition to GM1 and GA1, there are other glycoconjugates that contain β-linked galactose whose metabolites are substrates for β-galactosidase. For example, a number of N-linked glycan structures that have galactose at their non-reducing end have been shown to accumulate in GM1 gangliosidosis patient tissues and biological fluids.ObjectiveIn this study, we attempt to fully characterize the broad array of GLB1 substrates that require GLB1 for their lysosomal turnover.ResultsUsing tandem mass spectrometry and glycan reductive isotope labeling with data-dependent mass spectrometry, we have confirmed the accumulation of glycolipids (GM1 and GA1) and N-linked glycans with terminal beta-linked galactose. We have also discovered a novel set of core 1 and 2 O-linked glycan metabolites, many of which are part of structurally-related isobaric series that accumulate in disease. In the brain of GLB1 null mice, the levels of these glycan metabolites increased along with those of both GM1 and GA1 as a function of age. In addition to brain tissue, we found elevated levels of both N-linked and O-linked glycan metabolites in a number of peripheral tissues and in urine. Both brain and urine samples from human GM1 gangliosidosis patients exhibited large increases in steady state levels for the same glycan metabolites, demonstrating their correlation with this disease in humans as well.ConclusionsOur studies illustrate that GLB1 deficiency is not purely a ganglioside accumulation disorder, but instead a broad oligosaccharidosis that include representatives of many β-linked galactose containing glycans and glycoconjugates including glycolipids, N-linked glycans, and various O-linked glycans. Accounting for all β-galactosidase substrates that accumulate when this enzyme is deficient increases our understanding of this severe disorder by identifying metabolites that may drive certain aspects of the disease and may also serve as informative disease biomarkers to fully evaluate the efficacy of future therapies.

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Section: Resultsmentioning

confidence: 99%

Characterization of glycan substrates accumulating in GM1 Gangliosidosis

Lawrence

Vleet

Mangini

et al. 2019

Molecular Genetics and Metabolism Reports

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“…GM1 gangliosidosis is the most common LSD in Brazil, with an incidence of 1:13,317 live births, compared with a worldwide incidence of 1:100,000 live births . Our patient's R59H and c.1577dupG mutations are common mutations in Brazilian individuals with type I GM1 gangliosidosis .…”

Section: Discussionmentioning

confidence: 67%

Extensive and Progressing Congenital Dermal Melanocytosis Leading to Diagnosis of GM1 Gangliosidosis

Vedak

Sells

Souza

et al. 2015

Pediatric Dermatology

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Congenital dermal melanocytosis (CDM) is a birthmark composed of macular blue-grey hyperpigmentation commonly observed in the lumbosacral region of infants. Generally resolving by childhood, it is traditionally considered a benign condition, but it may be a sign of underlying lysosomal storage disease. We report a case of biopsy-confirmed CDM in a 2-month-old girl of Brazilian descent later diagnosed with infantile GM1 gangliosidosis.

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“…Regarding molecular analysis, out of the 10 patients included in the study, we only had access to genotype data for four. All of these mutations have been previously reported . The mutations identified in the GLB1 gene are shown in Table .…”

Section: Resultsmentioning

confidence: 96%

Clinical findings in Brazilian patients with adult GM1 gangliosidosis

Steiner

Kim

Lourenço³

et al. 2019

JIMD Reports

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GM1 gangliosidosis is a lysosomal storage disorder caused by β‐galactosidase deficiency. To date, prospective studies for GM1 gangliosidosis are not available, and only a few have focused on the adult form. This retrospective cross‐sectional study focused on clinical findings in Brazilian patients with the adult form of GM1 gangliosidosis collected over 2 years. Ten subjects were included in the study. Eight were males and two females, with median age at diagnosis of 11.5 years (IQR, 4‐34 years). Short stature and weight below normal were seen in five out of the six patients with data available. Radiological findings revealed that the most frequent skeletal abnormalities were beaked vertebrae, followed by hip dysplasia, and platyspondyly. Neurological examination revealed that dystonia and swallowing problems were the most frequently reported. None of the patients presented hyperkinesia, truncal hypertonia, Parkinsonism, or spinal cord compression. Clinical evaluation revealed impairment in activities of cognitive/intellectual development and behavioral/psychiatric disorders in all nine subjects with data available. Language/speech impairment (dysarthria) was found in 8/9 patients, fine motor and gross motor impairments were reported in 7/9 and 5/9 patients, respectively. Impairment of cognition and daily life activities were seen in 7/9 individuals. Our findings failed to clearly identify typical early or late alterations presented in GM1 gangliosidosis patients, which confirms that it is a very heterogeneous condition with wide phenotypic variability. This should be taken into account in the evaluation of future therapies for this challenging condition.

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Population analysis of the GLB1 gene in South Brazil

Cited by 20 publications

References 25 publications

Characterization of glycan substrates accumulating in GM1 Gangliosidosis

Characterization of glycan substrates accumulating in GM1 Gangliosidosis

Extensive and Progressing Congenital Dermal Melanocytosis Leading to Diagnosis of GM1 Gangliosidosis

Clinical findings in Brazilian patients with adult GM1 gangliosidosis

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