Lysosomal storage disorders: from biology to the clinic with reference to India

Sheth, Jayesh; Nair, Aadhira; Jee, Babban

doi:10.1016/j.lansea.2022.100108

Cited by 5 publications

(4 citation statements)

References 75 publications

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“…The interfamilial variability in the severity of phenotypes might be due to homozygous substitution of Arginine at amino acid position 674 in the present patient and/or different ethnicities of the families reported by Zhao et al (1996) , Zhao et al (1998) . Furthermore, such variability in clinical presentations amongst patients harboring the same genetic variant have also been reported for other LSD subtypes, indicating the contribution of epigenetic modifications, environmental factors and/or genetic modifiers that is yet to be elucidated ( Davidson et al, 2018 ; Sheth et al, 2022 ).…”

Section: Discussionmentioning

confidence: 82%

Identification of genetic variants associated with a wide spectrum of phenotypes clinically diagnosed as Sanfilippo and Morquio syndromes using whole genome sequencing

Gul,

Firasat,

Schubert

et al. 2023

Front. Genet.

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Mucopolysaccharidoses (MPSs) are inherited lysosomal storage disorders (LSDs). MPSs are caused by excessive accumulation of mucopolysaccharides due to missing or deficiency of enzymes required for the degradation of specific macromolecules. MPS I-IV, MPS VI, MPS VII, and MPS IX are sub-types of mucopolysaccharidoses. Among these, MPS III (also known as Sanfilippo) and MPS IV (Morquio) syndromes are lethal and prevalent sub-types. This study aimed to identify causal genetic variants in cases of MPS III and MPS IV and characterize genotype-phenotype relations in Pakistan. We performed clinical, biochemical and genetic analysis using Whole Genome Sequencing (WGS) in 14 Pakistani families affected with MPS III or MPS IV. Patients were classified into MPS III by history of aggressive behaviors, dementia, clear cornea and into MPS IV by short trunk, short stature, reversed ratio of upper segment to lower segment with a short upper segment. Data analysis and variant selections were made based on segregation analysis, examination of known MPS III and MPS IV genes, gene function, gene expression, the pathogenicity of variants based on ACMG guidelines and in silico analysis. In total, 58 individuals from 14 families were included in the present study. Six families were clinically diagnosed with MPS III and eight families with MPS IV. WGS revealed variants in MPS-associated genes including NAGLU, SGSH, GALNS, GNPTG as well as the genes VWA3B, BTD, and GNPTG which have not previously associated with MPS. One family had causal variants in both GALNS and BTD. Accurate and early diagnosis of MPS in children represents a helpful step for designing therapeutic strategies to protect different organs from permanent damage. In addition, pre-natal screening and identification of genetic etiology will facilitate genetic counselling of the affected families. Identification of novel causal MPS genes might help identifying new targeted therapies to treat LSDs.

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Section: Discussionmentioning

confidence: 82%

Identification of genetic variants associated with a wide spectrum of phenotypes clinically diagnosed as Sanfilippo and Morquio syndromes using whole genome sequencing

Gul,

Firasat,

Schubert

et al. 2023

Front. Genet.

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“…Treatment options like enzyme replacement therapy, bone marrow transplantation, substrate reduction therapy are now available for common LSDs like Gaucher disease, Pompe disease, and Fabry disease 10 . In India too, therapy is being provided to around 300 LSD patients under various charitable programmes namely INCAP (India's charitable access programme), Shire's HGT charitable access programme and few under rare disease policy of the Government of India 33 . Approximately, 40 of these patients are likely to be an adult now.…”

Section: Discussionmentioning

confidence: 99%

“… 10 In India too, therapy is being provided to around 300 LSD patients under various charitable programmes namely INCAP (India's charitable access programme), Shire's HGT charitable access programme and few under rare disease policy of the Government of India. 33 Approximately, 40 of these patients are likely to be an adult now. Hence, exact number of adult LSD patients receiving therapy cannot be ascertained and to the best of our knowledge, none of the patients except one with GD and one with Fabry disease described in our study received enzyme replacement therapy.…”

Section: Discussionmentioning

confidence: 99%

Lysosomal storage disorders identified in adult population from India: Experience of a tertiary genetic centre and review of literature

Sheth,

Nair,

Bhavsar

et al. 2024

JIMD Reports

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Lysosomal storage disorders (LSDs) in adults have milder phenotype and variable age at presentation. Several studies have described the phenotype, genotype and treatment outcomes for adult‐onset LSDs like Gaucher, Fabry, Pompe disease and others. We describe the first systematic study on the occurrence of LSDs in an adult population from India. It describes, the key clinical signs seen in these patients and those from literature review that can aid in early detection. Of 2102 biochemically diagnosed LSDs cases, 32 adult patients were identified with LSDs. Based on the clinical suspicion, screening test and enzyme study was carried out. Twenty‐two patients were subjected to a genetic study to identify the causative variant in a respective gene. Of the 32 adult patients, we observed a maximum percentage of 37.5% (n = 12) cases with Gaucher disease, followed by 13% (n = 4) with Fabry disease. We found 10% of cases with MPS IVA and MPS I, and 9% cases with Pompe. Single case of adult mucolipidosis III and two cases each of Type 1 Sialidosis, Niemann‐Pick disease B and metachromatic leukodystrophy were identified. We observed two common variants p.Leu483Pro and p.Ala487Thr in the GBA1 gene in 23% of Indian patients with adult Gaucher disease. No common variants were observed in other aforementioned LSDs. Study identified 50% of Fabry patients and 4% of Gaucher patients diagnosed at our centre to be adults. The prevalence of adult Pompe patients was low (3.4%) as compared to 80% reported in the Caucasian population. Adult LSDs such as, MPS III, GM1/GM2 gangliosidosis and Krabbe disease were not identified in our cohort.

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“…LSDs encompass over 70 different genetic disorders. Each condition arises due to a deficiency in a specific lysosomal protein or activity ( Futerman and van Meer, 2004 ; Sheth et al, 2023 ). LSDs are typically progressive and can affect multiple organ systems, including the central nervous system ( Rajkumar and Dumpa, 2023 ).…”

Section: Lysosomes and Their Roles In Cellular Homeostasismentioning

confidence: 99%

Golgi defect as a major contributor to lysosomal dysfunction

Akaaboune,

Wang

2024

Front. Cell Dev. Biol.

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The Golgi apparatus plays a crucial role in lysosome biogenesis and the delivery of lysosomal enzymes, essential for maintaining cellular homeostasis and ensuring cell survival. Deficiencies in Golgi structure and function can profoundly impact lysosomal homeostasis, leading to various lysosomal storage diseases and neurodegenerative disorders. In this review, we highlight the role of the Golgi Reassembly Stacking Proteins (GRASPs) in the formation and function of the Golgi apparatus, emphasizing the current understanding of the association between the Golgi apparatus, lysosomes, and lysosomal storage diseases. Additionally, we discuss how Golgi dysfunction leads to the secretion of lysosomal enzymes. This review aims to serve as a concise resource, offering insights into Golgi structure, function, disease-related defects, and their consequential effects on lysosomal biogenesis and function. By highlighting Golgi defects as an underappreciated contributor to lysosomal dysfunction across various diseases, we aim to enhance comprehension of these intricate cellular processes.

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Lysosomal storage disorders: from biology to the clinic with reference to India

Cited by 5 publications

References 75 publications

Identification of genetic variants associated with a wide spectrum of phenotypes clinically diagnosed as Sanfilippo and Morquio syndromes using whole genome sequencing

Identification of genetic variants associated with a wide spectrum of phenotypes clinically diagnosed as Sanfilippo and Morquio syndromes using whole genome sequencing

Lysosomal storage disorders identified in adult population from India: Experience of a tertiary genetic centre and review of literature

Golgi defect as a major contributor to lysosomal dysfunction

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