Lysosomal diseases: diagnostic update

Winchester, Bryan

doi:10.1007/s10545-014-9710-y

Cited by 19 publications

(12 citation statements)

References 71 publications

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“…Lysosomal Storage Disorders (LSDs) are sometimes challenging to diagnose due to the wide spectrum of phenotypes that the patients may present [1]. Indeed, the recognition of LSDs clinical features requires clinical expertise, as most of them are not specific and can be caused by defects in other metabolic pathways (mitochondrial and peroxisomal) [1][2][3][4]. Therefore, it is common to have a long period between the onset of the first symptoms and the definitive diagnosis.…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, it is the identification of mutations in the proband and its family that allows for accurate, rapid and reliable MGT for other family members, including prenatal diagnosis. Naturally, the pathological significance of a novel variant has to be investigated before its application to diagnosis and counseling [3].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, most specialist laboratories are still working with more traditional methods. Recently published statistics state that currently about 85-90% of LSDs cases are still diagnosed by demonstrating a deficiency of the activity of a lysosomal enzyme [3]. Finally, even for the laboratories where NGS technology is already available, it should always be considered whether a targeted panel will be the most obvious choice, as there are several preliminary screens that can point out, if not the individual disease, at least the subgroup to which it belongs.…”

Section: Introductionmentioning

confidence: 99%

“…RT-PCR amplification of RNA extracted from the proband's father (Pf), carrier of the novel c.1213+5G>T [IVS6+5G>T] mutation. Total ARSB cDNA was amplified in three different fragments(1)(2)(3). The amplification of a control sample (Ct) is also presented.…”

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confidence: 99%

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Molecular Characterization of a Novel Splicing Mutation Underlying Mucopolysaccharidosis (MPS) Type VI—Indirect Proof of Principle on Its Pathogenicity

et al. 2020

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Here, we present the molecular diagnosis of a patient with a general clinical suspicion of Mucopolysaccharidosis, highlighting the different tools used to perform its molecular characterization. In order to decrease the turnaround time for the final report and contribute to reduce the “diagnostic odyssey”, which frequently afflicts affected families, the proband’s sample was simultaneously screened for mutations in a number of lysosomal function-related genes with targeted next-generation sequencing (NGS) protocol. After variant calling, the most probable cause for disease was a novel ARSB intronic variant, c.1213+5G>T [IVS6+5G>T], detected in homozygosity. In general, homozygous or compound heterozygous mutations in the ARSB gene, underlie MPS type VI or Maroteaux-Lamy syndrome. Still, even though the novel c.1213+5G>T variant was easy to detect by both NGS and Sanger sequencing, only through indirect studies and functional analyses could we present proof of principle on its pathogenicity. Globally, this case reminds us that whenever a novel variant is detected, its pathogenicity must be carefully assessed before a definitive diagnosis is established, while highlighting alternative approaches that may be used to assess its effect in the absence RNA/cDNA sample(s) from the proband. This is particularly relevant for intronic variants such as the one here reported. Special attention will be given to the use of reporter minigene systems, which may be constructed/designed to dissect the effect of this sort of alterations, providing an insight into their consequences over the normal pre-mRNA splicing process of the affected gene.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Molecular Characterization of a Novel Splicing Mutation Underlying Mucopolysaccharidosis (MPS) Type VI—Indirect Proof of Principle on Its Pathogenicity

et al. 2020

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“…The use of dried blood spots, initially for newborn screening, has stimulated the introduction of automated, rapid and more sensitive methods for the assay of lysosomal enzymes, including the synthesis of novel substrates. 12 The prospects for treatment of LSDs fall into a number of categories: Enzyme Replacement Therapy (ERT) or gene therapies, to restore the function of the missing protein: substrate reduction therapies, aimed at reducing the amount of storage material produced; small molecules, to rescuemis-folded or unstable enzymes; cellular therapies to restore the injured cell; stimulating survival pathways or; inhibiting pathways that cause cell death. [13][14][15][16][17][18] With the fall of deaths of children from diarrhoea, respiratory tract infections and malnutrition due to availability of improved health services and diet, more children are now surviving and visiting hospital with genetic disorders.…”

Section: Introductionmentioning

confidence: 99%

Current status and challenges for LSDs in Bangladesh

Hussain

Mamun

Mahbub

et al. 2019

JPNC

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Background: With the fall of deaths of children from diarrhoea, respiratory tract infections and malnutrition due to availability of improved health services and diet, more children are now surviving and visiting hospital with genetic disorders. Lysosomal storage disorders represent a group of genetically distinct, biochemically related, inherited diseases. Individually, these disorders are considered rare, but collectively prevalence is 1 per 5,000-10,000. These disorders are devastating for individuals and their families and result in difficulties in diagnosis; however, the magnitude of the problem is not well defined. Objective: To determine the current status and challenges regarding lysosomal storage disorders in Bangladesh. Methodology: It was a retrospective study conducted in Dhaka Shishu (Children) Hospital from 2007 to 2016. Data of suspected neurometabolic disorders form hospital records and from child development and pediatric neuroscience department were included in the study. Patients profile and neurometabolic screening reports were collected. Challenges in diagnosis and managementwere noted. Data were analyzed by using SPSS. Results: Total 181 neurometabolic diseases were analyzed and different lysosomal storage disorders were found in 79(43.65%) individualswith male predominance (64%). Majority were presented between 1 year to 5 years of age. H/O Consanguinity in 31%, sibling death in 17%, affected sib in family in 5%, perinatal insult in 51%, developmental regression in 41%, early developmental delay in 51% and seizure in 75% cases were the common presenting feature. Most of them were diagnosed on the basis of clinical findings, X-ray findings, bone marrow study, liver biopsy, echocardiography and MRI findings. Lack of suspicion, lack of facility of specific enzyme assay and unavailability of treatment are the major challenges. Conclusions: There have been significant advances in the field of LSDs but proper diagnosis and effective therapies are still not available to the patients suffering from these diseasesin Bangladesh.

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