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Diagnosis, Management and Therapy of Rare Diseases
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Diagnosis, Management and Therapy of Rare Diseases

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: 15 October 2026 | Viewed by 2381

Special Issue Editor

Dr. Giorgia Girotto

E-Mail Website
Guest Editor
1. Institute for Maternal and Child Health—IRCCS, Burlo Garofolo, 34127 Trieste, Italy
2. Department of Medicine, Surgery and Health Sciences, University of Trieste, 34149 Trieste, Italy
Interests: clinical and molecular genetics; hereditary and multifactorial hearing loss; rare diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We would like to invite you to contribute to the following Genes Special Issue: “Diagnosis, Management and Therapy of Rare Diseases”.

More than 8500 rare diseases have been described to this date, and the advances in genomic analyses have substantially improved the chance of achieving a genetic diagnosis of these disorders. Of note, only approximately 5% of these conditions recognize an approved tailored treatment, limiting the possibilities to provide truly personalized management.

This Special Issue aims at focusing on the role of clinical and molecular genetics in clinically complex cases, solved by applying the most advanced sequencing technologies, for which molecular diagnosis deeply modified the treatment and care of patients.

In particular, this Special Issue includes, but it is not limited to, the following topics:

  • Molecular mechanisms behind rare and ultrarare genetic diseases;
  • Diagnosis, clinical features, and expansion of the phenotypic spectrum of rare and ultrarare genetic diseases;
  • The clinical and molecular characterization of family members;
  • Ethnic variability in rare and ultrarare genetic diseases;
  • Gene-tailored therapeutic options (including pharmacogenomics);
  • Clinical trials with which to develop new treatments.

We look forward to receiving your contributions.

Dr. Giorgia Girotto
Guest Editor

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 250 words) can be sent to the Editorial Office for assessment.

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. Genes 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

  • rare and ultrarare genetic diseases
  • genetic mechanisms
  • gene-tailored management
  • personalized therapeutic approaches

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Further information on MDPI's Special Issue policies can be found here.

Published Papers (3 papers)

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Research

16 pages, 2108 KB  
Article
Infantile-Onset Glutaric Acidemia Type I with Mild Hepatopathy: Clinical, Biochemical, and Molecular Characterization of an Iranian Pediatric Cohort
by Zahra Beyzaei, Bita Geramizadeh, Seyed Mohsen Dehghani, Sorour Inaloo and Ralf Weiskirchen
Genes 2026, 17(4), 481; https://doi.org/10.3390/genes17040481 - 18 Apr 2026
Viewed by 258
Abstract
Background: Glutaric acidemia type 1 (GA1) is an autosomal recessive neurometabolic disorder caused by pathogenic variants in glutaryl-CoA dehydrogenase (GCDH), with variable clinical severity despite early biochemical detectability. Population-specific mutational spectra and genotype–phenotype correlations remain insufficiently defined in infantile-onset disease. Therefore, this study [...] Read more.
Background: Glutaric acidemia type 1 (GA1) is an autosomal recessive neurometabolic disorder caused by pathogenic variants in glutaryl-CoA dehydrogenase (GCDH), with variable clinical severity despite early biochemical detectability. Population-specific mutational spectra and genotype–phenotype correlations remain insufficiently defined in infantile-onset disease. Therefore, this study aimed to define the GCDH variant spectrum in GA1 patients with mild hepatopathy and assess genotype–phenotype correlations. Methods: We performed integrated clinical, biochemical, and molecular characterization of 15 unrelated patients with infantile-onset GA1. Whole-exome sequencing (WES) was performed for all participants, and the resulting data were compared with the reference sequence of the GCDH gene. Results: All patients presented within the first 6 months of life with macrocephaly, seizures, dystonia, and feeding difficulties. Neurological impairment and mild hepatopathy were variably observed, and one patient developed an acute encephalopathic crisis. Six homozygous GCDH variants were identified, predominantly missense. A common variant, c.541G>C (p.Glu181Gln), accounted for 73.3% of cases and defined a consistent phenotype of early macrocephaly and movement disorder with frequent mild hepatic involvement, suggesting regional enrichment and raising the possibility of a founder effect that warrants confirmation in future haplotype studies. A truncating variant, c.382C>T (p.Arg128Ter), was associated with severe early encephalopathy. Exon 6 represented a mutational hotspot. Biochemically, all patients showed elevated urinary glutaric and 3-hydroxyglutaric acids, increased glutarylcarnitine, and low-to-normal free carnitine, with higher metabolite levels in clinically more severe cases. All variants were pathogenic or likely pathogenic and extremely rare in population databases. Conclusions: This cohort reveals a striking predominance of the GCDH c.541G>C variant and establishes a clear biochemical signature with genotype-associated clinical patterns in infantile-onset GA1. These findings support a population-specific mutational spectrum, refine genotype–phenotype correlations, and underscore the importance of early molecular diagnosis to guide targeted neurological and hepatic monitoring as well as regional screening strategies. Full article
(This article belongs to the Special Issue Diagnosis, Management and Therapy of Rare Diseases)
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12 pages, 1000 KB  
Article
SINEUP-Mediated Overexpression of Endogenous α-Amylase as a Therapeutic Approach in Lafora Disease
by Lorenzo Allegri, Federica Baldan, Catia Mio, Valentina Imperatore, Cinzia Costa, Paolo Prontera, Francesca Bisulli, Lorenzo Muccioli and Giuseppe Damante
Genes 2026, 17(3), 321; https://doi.org/10.3390/genes17030321 - 16 Mar 2026
Viewed by 453
Abstract
Background/Objectives: Lafora disease is a fatal and progressive neurodegenerative disorder characterized by the accumulation of insoluble polyglucosan inclusions, known as Lafora bodies, due to impaired glycogen metabolism. Therapeutic strategies aimed at reducing intracellular glycogen accumulation represent a promising approach to mitigating disease progression. [...] Read more.
Background/Objectives: Lafora disease is a fatal and progressive neurodegenerative disorder characterized by the accumulation of insoluble polyglucosan inclusions, known as Lafora bodies, due to impaired glycogen metabolism. Therapeutic strategies aimed at reducing intracellular glycogen accumulation represent a promising approach to mitigating disease progression. This study aimed to evaluate the feasibility of promoting Lafora body degradation by increasing the protein levels of human pancreatic amylase, a glycogen-degrading enzyme, through the SINEUP approach. Methods: Two SINEUP constructs specifically targeting human pancreatic amylase were designed and tested in continuous tumor-derived cell lines of central nervous system origin, as well as in primary fibroblasts obtained from a patient with Lafora disease. Human pancreatic amylase protein and mRNA levels were assessed to determine the specificity of SINEUP-mediated regulation. Enzymatic activity assays were performed to evaluate functional protein upregulation, and intracellular glycogen content was measured in patient-derived fibroblasts. Results: Both SINEUP constructs significantly increased human pancreatic amylase protein expression without affecting mRNA levels, confirming a post-transcriptional mechanism of action. The elevated protein levels were associated with a significant increase in enzymatic activity. In primary fibroblasts derived from a Lafora disease patient, enhanced amylase expression correlated with a marked reduction in intracellular glycogen content. Conclusions: These findings provide proof of concept that SINEUP-mediated upregulation of glycogen-degrading enzymes may represent a viable therapeutic strategy to counteract Lafora body accumulation. Further studies are warranted to assess the efficacy, safety, and translational potential of this approach, particularly in relevant animal models of Lafora disease. Full article
(This article belongs to the Special Issue Diagnosis, Management and Therapy of Rare Diseases)
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22 pages, 1432 KB  
Article
Fifteen Years of Myotonic Dystrophy Type 1 in Mexico: Clinical, Molecular, and Socioeconomic Insights from a National Reference Cohort
by César M. Cerecedo-Zapata, Araceli Guerra-Grajeda, Luz C. Márquez-Quiróz, Paola Arciga-Portela, Rosa E. Escobar-Cedillo, Guadalupe E. Jiménez-Gutiérrez, Óscar A. Pérez-Méndez, Jorge S. Velasco-Flores, Blanca A. Barredo-Prieto, Norberto Leyva-García, Bulmaro Cisneros, Nadia M. Murillo-Melo and Jonathan J. Magaña
Genes 2025, 16(12), 1515; https://doi.org/10.3390/genes16121515 - 17 Dec 2025
Viewed by 1022
Abstract
Background/Objectives: Myotonic dystrophy type 1 (DM1) is a rare, multisystemic disorder caused by an expanded (CTG)n repeat in the DMPK gene. Although DM1 has been studied in several populations, access to molecular diagnosis and comprehensive care remains limited in many low- and [...] Read more.
Background/Objectives: Myotonic dystrophy type 1 (DM1) is a rare, multisystemic disorder caused by an expanded (CTG)n repeat in the DMPK gene. Although DM1 has been studied in several populations, access to molecular diagnosis and comprehensive care remains limited in many low- and middle-income countries. This study provides an updated overview of DM1 in Mexico, from diagnostic implementation to patient management, describing key clinical and genetic findings. Methods: We conducted a nationwide, 15-year prospective study at Mexico’s National Reference Center for neuromuscular diseases. A total of 853 individuals at risk were subjected to clinical and molecular evaluation using PCR, TP-PCR, and SP-PCR, encompassing symptomatic, pre-symptomatic, prenatal, and preimplantation genetic diagnosis. Socioeconomic, clinical, and molecular variables were analyzed. Results: A total of 488 individuals were confirmed as DM1 carriers, with the most prevalent phenotypes being classic (36.5%) and juvenile (28.5%). Genomic analysis revealed a correlation between CTG tract sizes and phenotypes. Intriguingly, interrupted CTG repeat tracts were identified in 2.8% of DM1 carriers, who exhibited milder clinical phenotypes and a reduced degree of somatic and intergenerational instability. Survival analysis revealed a reduction in symptom-free survival in patients with larger expansions, while interrupted CTG tracts were associated with delayed onset. Conclusions: The centralization of diagnostic services in Mexico resulted in regional disparities, impacting early diagnosis and family planning. This study highlights the clinical and molecular diversity of DM1 in a Latin American population and underscores the urgent need for decentralized diagnostic services, integrated care models, and tailored prognostic tools in underserved settings. Full article
(This article belongs to the Special Issue Diagnosis, Management and Therapy of Rare Diseases)
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