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Life
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New Insights into Lysosomal Storage Disorders and Other Rare Genetic...
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New Insights into Lysosomal Storage Disorders and Other Rare Genetic Diseases

A special issue of Life (ISSN 2075-1729). This special issue belongs to the section "Genetics and Genomics".

Deadline for manuscript submissions: closed (18 March 2022) | Viewed by 17762

Special Issue Editors

Dr. Olga Amaral

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Guest Editor
Department of Human Genetics, Unit of Research & Development, National Institute of Health Dr. Ricardo Jorge, R.Alexandre Herculano 321, Porto, Portugal
Interests: lysosomal storage disorders; human genetics; molecular genetics; human iPSCs; gene editing; cell models; epigenetics; neurometabolic diseases; neurodegenerative disorders
Special Issues, Collections and Topics in MDPI journals
Dr. Barbara Marques

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Guest Editor
Department of Human Genetics, Unit of Cytogenetics, National Institute of Health Dr. Ricardo Jorge, Av. Padre Cruz, 1600-560 Lisboa, Portugal
Interests: cytogenomics; next-generation cytogenetics; genomic disorders; complex chromosomal or genomic rearrangements; new genetic markers in solid tumours and rare diseases
Dr. José Braganca

E-Mail Website
Guest Editor
Faculdade de Medicina e Ciências Biomédicas, Universidade do Algarve, 8005-139 Faro, Portugal
Interests: stem cells; regenerative medicine; cardiovascular diseases; developmental biology; oncobiology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The lysosome is at the centre of a group of rare inherited diseases commonly referred to as Lysosomal Storage Disorders (LSDs). As a multifunctional organelle, where primary disposal and recycling take place, the lysosome is known to be involved in other functions and, subsequently, in diseases other than LSDs. Examples of lysosomal changes involved in other diseases include altered lysosomal trafficking and signalling in invasive tumors and immune diseases. Despite decades of work dissecting the pivotal role of the lysosome, its involvement in disease mechanisms remains elusive. Nevertheless, important lessons can be learned with the use of new research tools that allow for access to a vast array of insightful information. With these new technologies come different aspects to explore, such as functional studies; research with hard-to-source tissues; innovative therapeutic approaches; precise methods for identification of rare diseases; faster ways to diagnose rare variants; and new strategies for pathogenesis modelling and drug testing.

By widening the scope of this Special Issue, with a particular focus on lysosomal storage disorders, we hope to provide a platform for scientists to contribute with new insights and to help connect the clues in the puzzling field of rare genetic diseases.

In this Special Issue of Life, we invite researchers from all over the world to share their advances in our understanding of genetic, cellular, and molecular mechanisms of Lysosomal Storage Disorders, lysosome-related diseases, and other rare diseases. We welcome original research papers and review articles that provide new insights into Lysosomal Storage Disorders and other rare genetic diseases; therapeutic strategies; group studies; gene and protein regulation or modifications; Covid-19’s impact on rare diseases; and disease models or present recent discoveries in genetic human diseases resulting from the application of innovative techniques.

Dr. Olga Amaral
Dr. Barbara Marques
Prof. Dr. José Braganca
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Life is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • lysosomal disorders
  • rare genetic diseases
  • therapeutic approaches
  • pathophysiology of disease
  • innovation in research and diagnosis

Published Papers (6 papers)

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Research

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11 pages, 566 KiB  
Communication
Fabry’s Disease: The Utility of a Multidisciplinary Screening Approach
by Marco Angelo Monte, Massimiliano Veroux, Margherita Stefania Rodolico, Valentina Losi, Luigi Di Pino, Rita Bella, Giuseppe Lanza and Ines Paola Monte
Life 2022, 12(5), 623; https://doi.org/10.3390/life12050623 - 22 Apr 2022
Cited by 3 | Viewed by 1796
Abstract
(1) Background: As a lysosomal storage disorder, Fabry’s disease (FD) shows variable clinical manifestations. We applied our multidisciplinary approach to identify any organ damage in a sample of adult patients with different pathogenic variants. (2) Methods: 49 participants (mean age 44.3 ± 14.2 [...] Read more.
(1) Background: As a lysosomal storage disorder, Fabry’s disease (FD) shows variable clinical manifestations. We applied our multidisciplinary approach to identify any organ damage in a sample of adult patients with different pathogenic variants. (2) Methods: 49 participants (mean age 44.3 ± 14.2 years; 37 females), underwent a multidimensional clinical and instrumental assessment. (3) Results: At diagnosis, mean enzymatic activity was 5.2 ± 4.6 nM/mL/h in females and 1.4 ± 0.5 nM/mL/h in males (normal values > 3.0), whereas globotriaosylsphingosine was 2.3 ± 2.1 nM/L in females and 28.7 ± 3.5 nM/L in males (normal values < 2.0). Overall, cardiovascular, neurological, and audiological systems were the most involved, regardless of the variant detected. Patients with classic variants (10) showed typical multiorgan involvement and, in some cases, prevalent organ damage (cardiovascular, neurological, renal, and ocular). Those with late-onset variants (39) exhibited lower occurrence of multiorgan impairment, although some of them affected the cardiovascular and neurological systems more. In patients with lower enzymatic activity, the most frequent involvement was neurological, followed by peripheral vascular disease. (4) Conclusions: FD patients exhibited wide phenotypic variability, even at single-organ level, likely due to the individual genetic mutation, although other factors may contribute. Compared to the conventional management, a multidisciplinary approach, as that prompted at our Center, allows one to achieve early clinical detection and management. Full article
(This article belongs to the Special Issue New Insights into Lysosomal Storage Disorders and Other Rare Genetic Diseases)
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9 pages, 3929 KiB  
Article
Molecular Analysis of Vietnamese Patients with Mucopolysaccharidosis Type I
by Ngoc Thi Bich Can, Dien Minh Tran, Thao Phuong Bui, Khanh Ngoc Nguyen, Hoang Huy Nguyen, Tung Van Nguyen, Wuh-Liang Hwu, Shunji Tomatsu and Dung Chi Vu
Life 2021, 11(11), 1162; https://doi.org/10.3390/life11111162 - 30 Oct 2021
Viewed by 1757
Abstract
Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder caused by deleterious mutations in the α-L-iduronidase (IDUA) gene. Until now, MPS I in Vietnamese has been poorly addressed. Five MPS I patients were studied with direct DNA sequencing using [...] Read more.
Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder caused by deleterious mutations in the α-L-iduronidase (IDUA) gene. Until now, MPS I in Vietnamese has been poorly addressed. Five MPS I patients were studied with direct DNA sequencing using Illumina technology confirming pathogenic variants in the IDUA gene. Clinical characteristics, additional laboratory results, and family history were collected. All patients have presented with the classical characteristic of MPS I, and α-L-iduronidase activity was low with the accumulation of glycosaminoglycans. Three variants in the IDUA gene (c.1190-10C>A (Intronic), c.1046A>G (p.Asp349Gly), c.1862G>C (p.Arg621Pro) were identified. The c.1190-10C>A variant represents six of the ten disease alleles, indicating a founder effect for MPS I in the Vietnamese population. Using biochemical and genetic analyses, the precise incidence of MPS I in this population should accelerate early diagnosis, newborn screening, prognosis, and optimal treatment. Full article
(This article belongs to the Special Issue New Insights into Lysosomal Storage Disorders and Other Rare Genetic Diseases)
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10 pages, 1983 KiB  
Communication
Modeling Mucopolysaccharidosis Type II in the Fruit Fly by Using the RNA Interference Approach
by Laura Rigon, Nicole Kucharowski, Franka Eckardt and Reinhard Bauer
Life 2020, 10(11), 263; https://doi.org/10.3390/life10110263 - 30 Oct 2020
Cited by 6 | Viewed by 4021
Abstract
Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder that occurs due to the deficit of the lysosomal enzyme iduronate 2-sulfatase (IDS) that leads to the storage of the glycosaminoglycan heparan- and dermatan-sulfate in all organs and tissues. It is characterized by [...] Read more.
Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder that occurs due to the deficit of the lysosomal enzyme iduronate 2-sulfatase (IDS) that leads to the storage of the glycosaminoglycan heparan- and dermatan-sulfate in all organs and tissues. It is characterized by important clinical features and the severe form presents with a heavy neurological involvement. However, almost nothing is known about the neuropathogenesis of MPS II. To address this issue, we developed a ubiquitous, neuronal, and glial-specific knockdown model in Drosophila melanogaster by using the RNA interference (RNAi) approach. Knockdown of the Ids/CG12014 gene resulted in a significant reduction of the Ids gene expression and enzymatic activity. However, glycosaminoglycan storage, survival, molecular markers (Atg8a, Lamp1, Rab11), and locomotion behavior were not affected. Even strongly reduced, IDS-activity was enough to prevent a pathological phenotype in a MPS II RNAi fruit fly. Thus, a Drosophila MPS II model requires complete abolishment of the enzymatic activity. Full article
(This article belongs to the Special Issue New Insights into Lysosomal Storage Disorders and Other Rare Genetic Diseases)
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Review

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26 pages, 3102 KiB  
Review
Splicing Modulation as a Promising Therapeutic Strategy for Lysosomal Storage Disorders: The Mucopolysaccharidoses Example
by Juliana Inês Santos, Mariana Gonçalves, Liliana Matos, Luciana Moreira, Sofia Carvalho, Maria João Prata, Maria Francisca Coutinho and Sandra Alves
Life 2022, 12(5), 608; https://doi.org/10.3390/life12050608 - 19 Apr 2022
Cited by 1 | Viewed by 3589
Abstract
Over recent decades, the many functions of RNA have become more evident. This molecule has been recognized not only as a carrier of genetic information, but also as a specific and essential regulator of gene expression. Different RNA species have been identified and [...] Read more.
Over recent decades, the many functions of RNA have become more evident. This molecule has been recognized not only as a carrier of genetic information, but also as a specific and essential regulator of gene expression. Different RNA species have been identified and novel and exciting roles have been unveiled. Quite remarkably, this explosion of novel RNA classes has increased the possibility for new therapeutic strategies that tap into RNA biology. Most of these drugs use nucleic acid analogues and take advantage of complementary base pairing to either mimic or antagonize the function of RNAs. Among the most successful RNA-based drugs are those that act at the pre-mRNA level to modulate or correct aberrant splicing patterns, which are caused by specific pathogenic variants. This approach is particularly tempting for monogenic disorders with associated splicing defects, especially when they are highly frequent among affected patients worldwide or within a specific population. With more than 600 mutations that cause disease affecting the pre-mRNA splicing process, we consider lysosomal storage diseases (LSDs) to be perfect candidates for this type of approach. Here, we introduce the overall rationale and general mechanisms of splicing modulation approaches and highlight the currently marketed formulations, which have been developed for non-lysosomal genetic disorders. We also extensively reviewed the existing preclinical studies on the potential of this sort of therapeutic strategy to recover aberrant splicing and increase enzyme activity in our diseases of interest: the LSDs. Special attention was paid to a particular subgroup of LSDs: the mucopolysaccharidoses (MPSs). By doing this, we hoped to unveil the unique therapeutic potential of the use of this sort of approach for LSDs as a whole. Full article
(This article belongs to the Special Issue New Insights into Lysosomal Storage Disorders and Other Rare Genetic Diseases)
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Other

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15 pages, 4337 KiB  
Case Report
Tripeptidyl Peptidase 1 (TPP1) Deficiency in a 36-Year-Old Patient with Cerebellar-Extrapyramidal Syndrome and Dilated Cardiomyopathy
by Agnieszka Ługowska, Joanna K. Purzycka-Olewiecka, Rafał Płoski, Grażyna Truszkowska, Maciej Pronicki, Paulina Felczak, Mateusz Śpiewak, Aleksandra Podlecka-Piętowska, Martyna Sitek, Zofia T. Bilińska, Przemysław Leszek and Małgorzata Bednarska-Makaruk
Life 2022, 12(1), 3; https://doi.org/10.3390/life12010003 - 21 Dec 2021
Cited by 3 | Viewed by 2512
Abstract
We report on a 36-year-old man with cerebellar-extrapyramidal syndrome and severe heart failure because of dilated cardiomyopathy of unknown origin. Dysarthria and cardiac arrhythmia began at early childhood (4 years of age). Brain MRI (28 years of age) demonstrated severe cerebellar atrophy. At [...] Read more.
We report on a 36-year-old man with cerebellar-extrapyramidal syndrome and severe heart failure because of dilated cardiomyopathy of unknown origin. Dysarthria and cardiac arrhythmia began at early childhood (4 years of age). Brain MRI (28 years of age) demonstrated severe cerebellar atrophy. At the age 32, he presented with dysarthria, ataxia, dystonia, and tremor of the right hand, bilateral slowed neural conduction in the visual pathways, and decreased mental acuity. At the age of 33 years, the patient underwent cardiac transplantation because of severe dilated cardiomyopathy. In the TPP1 gene, biallelic variants were identified: previously reported p.(Leu13Pro) and novel p.(Tyr508Cys) variant. Additionally, hemizygous novel missense variant in the ABCD1 gene was inherited from the mother p.(Arg17His). Normal very-long-chain fatty acids (VLCFA) levels both in patient and his mother excluded ABCD1 mutation as the pathogenic one. Tripeptidyl peptidase 1 (TPP1) activity was reduced (8,8 U/mg protein/h; reference range: 47.4 ± 10.7). In light microscopy the biopsy specimens obtained from explanted heart showed severe myocyte hypertrophy with perinuclear vacuolization with inclusions. Electron microscopy revealed absence of lipofuscin accumulation, no ultrastructural curvilinear profiles, fingerprint bodies, or granular osmiophilic deposits (GRODs) in lysosomes. As described here, the patient presents clinical symptoms observed in benign forms of ceroid lipofuscinosis type 2 (CLN2) and simultaneously some features of autosomal recessive spinocerebellar ataxia type 7 (SCAR7), which is also caused by mutations in the TPP1 gene. Full article
(This article belongs to the Special Issue New Insights into Lysosomal Storage Disorders and Other Rare Genetic Diseases)
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16 pages, 1572 KiB  
Case Report
Serum Cytokine Profile, Beta-Hexosaminidase A Enzymatic Activity and GM2 Ganglioside Levels in the Plasma of a Tay-Sachs Disease Patient after Cord Blood Cell Transplantation and Curcumin Administration: A Case Report
by Alisa A. Shaimardanova, Daria S. Chulpanova, Valeriya V. Solovyeva, Ekaterina E. Garanina, Ilnur I. Salafutdinov, Alexander Vladimirovich Laikov, Vadim V. Kursenko, Lisa Chakrabarti, Ekaterina Yu. Zakharova, Tatiana M. Bukina, Galina V. Baydakova and Albert Anatolyevich Rizvanov
Life 2021, 11(10), 1007; https://doi.org/10.3390/life11101007 - 24 Sep 2021
Cited by 6 | Viewed by 2749
Abstract
Tay-Sachs disease (TSD) is a progressive neurodegenerative disorder that occurs due to a deficiency of a β hexosaminidase A (HexA) enzyme, resulting in the accumulation of GM2 gangliosides. In this work, we analyzed the effect of umbilical cord blood cell transplantation (UCBCT) [...] Read more.
Tay-Sachs disease (TSD) is a progressive neurodegenerative disorder that occurs due to a deficiency of a β hexosaminidase A (HexA) enzyme, resulting in the accumulation of GM2 gangliosides. In this work, we analyzed the effect of umbilical cord blood cell transplantation (UCBCT) and curcumin administration on the course of the disease in a patient with adult TSD. The patient’s serum cytokine profile was determined using multiplex analysis. The level of GM2 gangliosides in plasma was determined using mass spectrometry. The enzymatic activity of HexA in the plasma of the patient was assessed using a fluorescent substrate assay. The HexA α-subunit (HexA) concentration was determined using ELISA. It was shown that both UCBCT and curcumin administration led to a change in the patient’s cytokine profile. The UCBCT resulted in an increase in the concentration of HexA in the patient’s serum and in an improvement in the patient’s neurological status. However, neither UCBCT nor curcumin were able to alter HexA activity and the level of GM2 in patient’s plasma. The data obtained indicate that UCBCT and curcumin administration can alter the immunity of a patient with TSD, reduce the level of inflammatory cytokines and thereby improve the patient’s condition. Full article
(This article belongs to the Special Issue New Insights into Lysosomal Storage Disorders and Other Rare Genetic Diseases)
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