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Diagnostic and Therapeutic Developments in Lysosomal Storage Disorders
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Diagnostic and Therapeutic Developments in Lysosomal Storage Disorders

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Clinical Neurology".

Deadline for manuscript submissions: closed (25 November 2023) | Viewed by 3810

Special Issue Editors

Dr. Karolina M. Stepien

E-Mail Website
Guest Editor
Salford Royal NHS Foundation Trust, Adult Inherited Metabolic Diseases Department, Salford, UK
Interests: lysosomal storage diseases; mucopolysaccharidosis; cardiovascular risk; fucosidosis; mucolipidosis I, II, III, and IV; secondary mitochondrial dysfunction; transition process; GM1-gangliosidosis; hematopoietic stem cell transplantation; hormonal dysfunction
Special Issues, Collections and Topics in MDPI journals
Dr. Jessica Gold

E-Mail Website
Co-Guest Editor
Division of Genetics, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
Interests: adult metabolic medicine; healthcare transition; neurocognitive outcomes; reproductive healthcare; adult manifestations of inherited metabolic disorders
Dr. Teodoro Jerves Serrano

E-Mail Website
Co-Guest Editor
Genetics, Yale School of Medicine, New Haven, CT, USA
Interests: adult metabolic medicine; lysosomal storage diseases; healthcare transition; laboratory of biochemical genetics; cardiac manifestations of inherited metabolic disorders; cardiogenetics

Special Issue Information

Dear Colleagues,

Lysosomal storage diseases (LSDs) are a heterogenous group of more than 70 inherited metabolic conditions caused by defects in genes that encode proteins required for lysosomal homeostasis. Individually, these conditions are rare, but their combined prevalence is estimated to be ~1 in 5000 live births.

Clinical manifestations can be observed from the prenatal period to adulthood; multiple organs throughout the body are affected, such as the central nervous system, heart, kidney, liver, and bones. The spectrum of clinical symptoms usually does not have a clear phenotype–genotype correlation, and intrafamilial variability is frequently described. Due to the multisystemic nature, non-metabolic clinicians (e.g., ophthalmologists, dermatologists) may first suspect an LSD diagnosis.

Newborn screening and massive parallel sequencing have facilitated earlier diagnoses, as well as the identification of attenuated forms and pre-symptomatic individuals. Therapeutic advances such as enzyme replacement therapy have improved healthcare outcomes and life expectancy over the last few decades. However, new challenges arise in the management of LSDs: transition of pediatric to adult care, coordination of multidisciplinary teams, reproductive planning, and newly recognized long-term complications.

This Special Issue of the Journal of Clinical Medicine aims to attract original research articles, reviews, and short communications on understanding recent advances in the natural history, diagnosis, and management of LSDs.

Dr. Karolina M. Stepien
Dr. Jessica Gold
Dr. Teodoro Jerves Serrano
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. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly 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

  • genetics
  • carrier screening
  • newborn screening
  • biomarkers
  • molecular diagnosis
  • massive parallel sequencing
  • cardiac complications
  • neurological complications
  • neurocognitive outcomes
  • pregnancy
  • reproductive planning
  • coordination of care
  • healthcare transition
  • adult-oriented medical care
  • gene therapy
  • enzyme replacement therapy
  • molecular chaperones

Published Papers (3 papers)

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Research

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15 pages, 2167 KiB  
Article
CNS Manifestations in Mucolipidosis Type II—A Retrospective Analysis of Longitudinal Data on Neurocognitive Development and Neuroimaging in Eleven Patients
by Luise Sophie Ammer, Karolin Täuber, Anna Perez, Thorsten Dohrmann, Jonas Denecke, René Santer, Ulrike Blümlein, Ann-Kathrin Ozga, Sandra Pohl and Nicole Maria Muschol
J. Clin. Med. 2023, 12(12), 4114; https://doi.org/10.3390/jcm12124114 - 18 Jun 2023
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Abstract
Mucolipidosis type II (MLII), an ultra-rare lysosomal storage disorder, manifests as a fatal multi-systemic disease. Mental inhibition and progressive neurodegeneration are commonly reported disease manifestations. Nevertheless, longitudinal data on neurocognitive testing and neuroimaging lack in current literature. This study aimed to provide details [...] Read more.
Mucolipidosis type II (MLII), an ultra-rare lysosomal storage disorder, manifests as a fatal multi-systemic disease. Mental inhibition and progressive neurodegeneration are commonly reported disease manifestations. Nevertheless, longitudinal data on neurocognitive testing and neuroimaging lack in current literature. This study aimed to provide details on central nervous system manifestations in MLII. All MLII patients with at least one standardized developmental assessment performed between 2005 and 2022 were included by retrospective chart review. A multiple mixed linear regression model was applied. Eleven patients with a median age of 34.0 months (range 1.6–159.6) underwent 32 neurocognitive and 28 adaptive behaviour assessments as well as 14 brain magnetic resonance imagings. The scales used were mainly BSID-III (42%) and VABS-II (47%). Neurocognitive testing (per patient: mean 2.9, standard deviation (SD) 2.0) performed over 0–52.1 months (median 12.1) revealed profound impairment with a mean developmental quotient of 36.7% (SD 20.4) at last assessment. The patients showed sustained development; on average, they gained 0.28 age-equivalent score points per month (confidence interval 0.17–0.38). Apart from common (63%) cervical spinal stenosis, neuroimaging revealed unspecific, non-progressive abnormalities (i.e., mild brain atrophy, white matter lesions). In summary, MLII is associated with profound developmental impairment, but not with neurodegeneration and neurocognitive decline. Full article
(This article belongs to the Special Issue Diagnostic and Therapeutic Developments in Lysosomal Storage Disorders)
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Review

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12 pages, 1930 KiB  
Review
The Complexities of Diagnosis with Co-Existing Gaucher Disease and Hemato-Oncology—A Case Report and Review of the Literature
by Paulina Sudul, Beata Piatkowska-Jakubas, Lukasz Pawlinski, Krystyna Galazka, Tomasz Sacha and Beata Kiec-Wilk
J. Clin. Med. 2023, 12(17), 5518; https://doi.org/10.3390/jcm12175518 - 25 Aug 2023
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Abstract
Hematological abnormalities are the most common early symptoms of Gaucher disease (GD), with an increased risk of hematopoietic system malignancies reported in patients with GD. GD may be associated with monoclonal and polyclonal gammopathies; however, the mechanism of association of GD with multiple [...] Read more.
Hematological abnormalities are the most common early symptoms of Gaucher disease (GD), with an increased risk of hematopoietic system malignancies reported in patients with GD. GD may be associated with monoclonal and polyclonal gammopathies; however, the mechanism of association of GD with multiple myeloma (MM) remains uncertain. Enzyme replacement therapy (ERT) has been shown to improve patients’ cytopenia and it seems to facilitate anti-myeloma therapy in patients with co-occurring GD and MM. Although it is necessary to demonstrate the deficiency of enzymatic activity, as well as using genetic tests to finally diagnose GD, due to changes in the blood count image, bone marrow biopsy is still a frequent element of the GD diagnosis procedure. The diagnosis of GD is often delayed, mainly due to the heterogeneity of the histopathological picture of bone marrow biopsy or overlapping hematological abnormalities. Unrecognized and untreated GD worsens the response of a patient with an oncological disease to targeted treatment. We present a literature review, inspired by the case of a Caucasian patient initially diagnosed with MM and later confirmed with comorbid GD type 1 (GD1). We would like to point out the problem of underdiagnosis and delay in patients with GD. Full article
(This article belongs to the Special Issue Diagnostic and Therapeutic Developments in Lysosomal Storage Disorders)
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Other

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8 pages, 899 KiB  
Brief Report
Increased Soluble Interleukin 6 Receptors in Fabry Disease
by Livia Lenzini, Elisabetta Iori, Monica Vettore, Giorgia Gugelmo, Claudia Radu, Andrea Padoan, Gianni Carraro, Paolo Simioni, Lorenzo Calò, Angelo Avogaro, Gian Paolo Rossi and Nicola Vitturi
J. Clin. Med. 2024, 13(1), 218; https://doi.org/10.3390/jcm13010218 - 29 Dec 2023
Viewed by 804
Abstract
Fabry disease (FD) is an X-linked lysosome storage disease that results in the accumulation of globotriaosylceramide (Gb3) throughout the body leading to irreversible target organ damage. As the role of secondary mediators (inflammatory molecules) and their mechanisms has not been fully elucidated, we [...] Read more.
Fabry disease (FD) is an X-linked lysosome storage disease that results in the accumulation of globotriaosylceramide (Gb3) throughout the body leading to irreversible target organ damage. As the role of secondary mediators (inflammatory molecules) and their mechanisms has not been fully elucidated, we focused on the interleukin (IL)-6 system in adult FD patients and in matched healthy subjects. To obtain insights into the complex regulation of IL-6 actions, we used a novel approach that integrates information from plasma and exosomes of FD patients (n = 20) and of healthy controls (n = 15). Soluble IL-6 receptor (sIL-6R) levels were measured in plasma with the ELISA method, and membrane-bound IL-6R was quantified in plasma and urinary exosomes using flow cytometry. In FD patients, the levels of soluble IL-6R in plasma were higher than in control subjects (28.0 ± 5.4 ng/mL vs. 18.9 ± 5.4 ng/mL, p < 0.0001); they were also higher in FD subjects with the classical form as compared to those with the late-onset form of the disease (36.0 ± 11.4 ng/mL vs. 26.1 ± 4.5 ng/mL, p < 0.0001). The percentage of urinary exosomes positive for IL-6R was slightly lower in FD (97 ± 1 vs. 100 ± 0% of events positive for IL-6R, p < 0.05); plasma IL-6 levels were not increased. These results suggest a potential role of IL-6 in triggering the inflammatory response in FD. As in FD patients only the levels of sIL-6Rs are consistently higher than in healthy controls, the IL-6 pathogenic signal seems to prevail over the homeostatic one, suggesting a potential mechanism causing multi-systemic damage in FD. Full article
(This article belongs to the Special Issue Diagnostic and Therapeutic Developments in Lysosomal Storage Disorders)
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