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Molecular Genetics of Neurodegenerative Diseases and Neuromuscular Diseases
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Molecular Genetics of Neurodegenerative Diseases and Neuromuscular 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: closed (25 January 2025) | Viewed by 20137

Special Issue Editors

Dr. Emiliano Giardina

E-Mail Website
Guest Editor
1. Genomic Medicine Laboratory UILDM, Santa Lucia Foundation, 00142 Rome, Italy
2. Forensic Genetics Laboratory, Department of Biomedicine and Prevention, Tor Vergata University, 00133 Rome, Italy
Interests: forensic genetics; genetic counselling; human identification; neurogenetics; prenatal and postnatal genetic diagnosis
Special Issues, Collections and Topics in MDPI journals
Dr. Stefania Zampatti

E-Mail Website
Guest Editor
Genomic Medicine Laboratory UILDM, IRCCS Fondazione Santa Lucia, 00142 Rome, Italy
Interests: genetic counseling; neurogenetics; pharmacogenetics; rare disorders; genetic diagnosis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Technological advances in molecular genetics have allowed the development of new diagnostic protocols. In recent decades, the time needed for the diagnosis of neurodegenerative and neuromuscular diseases has been significantly reduced with the introduction in clinical practice of high-resolution neuroimaging and next-generation sequencing. To date, the availability of new technologies for molecular, clinical, and instrumental characterization of disorders makes it possible to perform phenotype stratification for research and diagnostic purposes. The discovery of new molecular causes of these disorders is crucial to improve diagnosis and genotype–phenotype correlation as well as provide indications for therapeutical interventions. In the present scenario, patients affected by neurodegenerative and neuromuscular disease can now benefit from new-generation technologies that should significantly reduce the diagnostic odyssey. Furthermore, the phenotype stratification of diseases supports the development of new treatments and therapies.

In this Special Issue, we welcome reviews and original articles covering many aspects of neurodegenerative and neuromuscular disorders. These include but are not limited to new diagnostic, therapeutic, and neuroimaging protocols, functional and molecular evaluation of genetic disorders, translation of research data into medical protocols, new therapeutical perspectives, epigenetic signatures of disease, and multiomic analysis of disease trajectory. This Special Issue of Genes will highlight recent advances in the field and new applications of omic data in the diagnosis and treatment of neurodegenerative and neuromuscular diseases.

Prof. Dr. Emiliano Giardina
Dr. Stefania Zampatti
Guest Editors

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Keywords

  • neurogenetics
  • neurodegenerative disease
  • neuromuscular disease
  • genomics
  • molecular genetics

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Published Papers (9 papers)

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Research

Jump to: Review

13 pages, 1346 KiB  
Article
The POLG Variant c.678G>C; p.(Gln226His) Is Associated with Mitochondrial Abnormalities in Fibroblasts Derived from a Patient Compared to a First-Degree Relative
by Imra Mantey, Felix Langerscheidt, Çağla Çakmak Durmaz, Naomi Baba, Katharina Burghardt, Mert Karakaya and Hans Zempel
Genes 2025, 16(2), 198; https://doi.org/10.3390/genes16020198 - 5 Feb 2025
Viewed by 912
Abstract
Background: The nuclear-encoded enzyme polymerase gamma (Pol-γ) is crucial in the replication of the mitochondrial genome (mtDNA), which in turn is vital for mitochondria and hence numerous metabolic processes and energy production in eukaryotic cells. Variants in the POLG gene, which encodes the [...] Read more.
Background: The nuclear-encoded enzyme polymerase gamma (Pol-γ) is crucial in the replication of the mitochondrial genome (mtDNA), which in turn is vital for mitochondria and hence numerous metabolic processes and energy production in eukaryotic cells. Variants in the POLG gene, which encodes the catalytic subunit of Pol-γ, can significantly impair Pol-γ enzyme function. Pol-γ-associated disorders are referred to as POLG-spectrum disorders (POLG-SDs) and are mainly autosomal-recessively inherited. Clinical manifestations include muscle weakness and fatigue, and severe forms of the disease can lead to premature death in infancy, childhood, and early adulthood, often associated with seizures, liver failure, or intractable epilepsy. Here, we analyzed fibroblasts from a compound heterozygous patient with the established pathogenic variant c.2419C>T; p.(Arg807Cys) and a previously undescribed variant c.678G>C; p.(Gln226His) with a clinical manifestation compatible with POLG-SDs, sensory ataxic neuropathy, and infantile muscular atrophy. We conducted a battery of functional studies for Pol-γ and mitochondrial dysfunction on the patient’s fibroblasts, to test whether the novel variant c.678G>C; p.(Gln226His) may be causative in human disease. Aims/Methods: We analyzed skin-derived fibroblasts in comparison to a first-degree relative (the mother of the patient), an asymptomatic carrier harboring only the established c.2419C>T; p.(Arg807Cys) mutation. Assessments of mitochondrial function included measurements of mtDNA content, mRNA levels of mitochondrial genes, mitochondrial mass, and mitochondrial morphology. Case Presentation and Results: A 13-year-old male presented with symptoms starting at three years of age, including muscle weakness and atrophy in the lower extremities and facial muscles, which later extended to the upper limbs, voice, and back muscles, without further progression. The patient also reported fatigue and muscle pain after physical activity, with no sensory deficits. Extensive diagnostic tests such as electromyography, nerve conduction studies, muscle biopsy, and MRI were unremarkable. Exome sequencing revealed that he carried the compound heterozygous variants in POLG c.678G>C; p.(Gln226His) and c.2419C>T; p.(Arg807Cys), but no other potential genetic pathogenic causes. In comparison to a first-degree relative (his mother) who only carried the c.2419C>T; p.(Arg807Cys) pathogenic mutation, in vitro analyses revealed a significant reduction in mtDNA content (~50%) and mRNA levels of mtDNA-encoded proteins. Mitochondrial mass was reduced by approximately 20%, and mitochondrial interconnectivity within cells was impaired, as determined by fluorescence microscopy and mitochondrial staining. Conclusions: Our findings suggest that the c.678G>C; p.(Gln226His) variant, in conjunction with the c.2419C>T; p.(Arg807Cys) mutation, may compromise mtDNA replication and mitochondrial function and could result in clinically significant mitochondriopathy. As this study is based on one patient compared to a first-degree relative (but with an identical mitochondrial genome), the pathogenicity of c.678G>C; p.(Gln226His) of POLG should be confirmed in future studies, in particular, in conjunction with other POLG-variants. Full article
(This article belongs to the Special Issue Molecular Genetics of Neurodegenerative Diseases and Neuromuscular Diseases)
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12 pages, 4045 KiB  
Article
Analysis of Short Tandem Repeat Expansions in a Cohort of 12,496 Exomes from Patients with Neurological Diseases Reveals Variable Genotyping Rate Dependent on Exome Capture Kits
by Clarissa Rocca, David Murphy, Chris Clarkson, Matteo Zanovello, Delia Gagliardi, Queen Square Genomics, Rauan Kaiyrzhanov, Javeria Alvi, Reza Maroofian, Stephanie Efthymiou, Tipu Sultan, Jana Vandrovcova, James Polke, Robyn Labrum, Henry Houlden and Arianna Tucci
Genes 2025, 16(2), 169; https://doi.org/10.3390/genes16020169 - 28 Jan 2025
Viewed by 1009
Abstract
Background/Objectives: Short tandem repeat expansions are the most common cause of inherited neurological diseases. These disorders are clinically and genetically heterogeneous, such as in myotonic dystrophy and spinocerebellar ataxia, and they are caused by different repeat motifs in different genomic locations. Major advances [...] Read more.
Background/Objectives: Short tandem repeat expansions are the most common cause of inherited neurological diseases. These disorders are clinically and genetically heterogeneous, such as in myotonic dystrophy and spinocerebellar ataxia, and they are caused by different repeat motifs in different genomic locations. Major advances in bioinformatic tools used to detect repeat expansions from short read sequencing data in the last few years have led to the implementation of these workflows into next generation sequencing pipelines in healthcare. Here, we aimed to evaluate the clinical utility of analysing repeat expansions through exome sequencing in a large cohort of genetically undiagnosed patients with neurological disorders. Methods: We here analyse 27 disease-causing DNA repeats found in the coding, intronic and untranslated regions in 12,496 exomes in patients with a range of neurogenetic conditions. Results: We identified—and validated by polymerase chain reaction—29 repeat expansions across a range of loci, 48% (n = 14) of which were diagnostic. We then analysed the genotyping performance across all repeat loci and found that, despite high coverage in most repeats in coding regions, some loci had low genotyping rates, such as those that cause spinocerebellar ataxia 2 (ATXN2, 0.1–8.4%) and Huntington disease (HTT, 0.2–58.2%), depending on the capture kit. Conversely, while most intronic repeats were not genotyped, we found a high genotyping rate in the intronic locus that causes spinocerebellar ataxia 36 (NOP56, 30.1–98.3%) and in the one that causes myotonic dystrophy type 1 (DMPK, myotonic dystrophy type 1). Conclusions: We show that the key factors that influence the genotyping rate of repeat expansion loci analysis are the sequencing read length and exome capture kit. These results provide important information about the performance of exome sequencing as a genetic test for repeat expansion disorders. Full article
(This article belongs to the Special Issue Molecular Genetics of Neurodegenerative Diseases and Neuromuscular Diseases)
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15 pages, 243 KiB  
Article
AI-Powered Neurogenetics: Supporting Patient’s Evaluation with Chatbot
by Stefania Zampatti, Juliette Farro, Cristina Peconi, Raffaella Cascella, Claudia Strafella, Giulia Calvino, Domenica Megalizzi, Giulia Trastulli, Carlo Caltagirone and Emiliano Giardina
Genes 2025, 16(1), 29; https://doi.org/10.3390/genes16010029 - 27 Dec 2024
Viewed by 948
Abstract
Background/Objectives: Artificial intelligence and large language models like ChatGPT and Google’s Gemini are promising tools with remarkable potential to assist healthcare professionals. This study explores ChatGPT and Gemini’s potential utility in assisting clinicians during the first evaluation of patients with suspected neurogenetic disorders. [...] Read more.
Background/Objectives: Artificial intelligence and large language models like ChatGPT and Google’s Gemini are promising tools with remarkable potential to assist healthcare professionals. This study explores ChatGPT and Gemini’s potential utility in assisting clinicians during the first evaluation of patients with suspected neurogenetic disorders. Methods: By analyzing the model’s performance in identifying relevant clinical features, suggesting differential diagnoses, and providing insights into possible genetic testing, this research seeks to determine whether these AI tools could serve as a valuable adjunct in neurogenetic assessments. Ninety questions were posed to ChatGPT (Versions 4o, 4, and 3.5) and Gemini: four questions about clinical diagnosis, seven about genetic inheritance, estimable recurrence risks, and available tests, and four questions about patient management, each for six different neurogenetic rare disorders (Hereditary Spastic Paraplegia type 4 and type 7, Huntington Disease, Fragile X-associated Tremor/Ataxia Syndrome, Becker Muscular Dystrophy, and FacioScapuloHumeral Muscular Dystrophy). Results: According to the results of this study, GPT chatbots demonstrated significantly better performance than Gemini. Nonetheless, all AI chatbots showed notable gaps in diagnostic accuracy and a concerning level of hallucinations. Conclusions: As expected, these tools can empower clinicians in assessing neurogenetic disorders, yet their effective use demands meticulous collaboration and oversight from both neurologists and geneticists. Full article
(This article belongs to the Special Issue Molecular Genetics of Neurodegenerative Diseases and Neuromuscular Diseases)
9 pages, 358 KiB  
Article
A Novel GBF1 Variant in a Charcot-Marie-Tooth Type 2: Insights from Familial Analysis
by Valentina Ciampana, Lucia Corrado, Luca Magistrelli, Elena Contaldi, Cristoforo Comi, Sandra D’Alfonso and Domizia Vecchio
Genes 2024, 15(12), 1556; https://doi.org/10.3390/genes15121556 - 29 Nov 2024
Viewed by 941
Abstract
Background/Objectives: Axonal Charcot–Marie–Tooth disease type 2 (CMT2) accounts for 24% of Hereditary Motor/Sensory Peripheral Neuropathies. CMT2 type GG, due to four distinct heterozygous mutations in the Golgi brefeldin A resistant guanine nucleotide exchange factor 1 (GBF1) gene (OMIM 606483), was described [...] Read more.
Background/Objectives: Axonal Charcot–Marie–Tooth disease type 2 (CMT2) accounts for 24% of Hereditary Motor/Sensory Peripheral Neuropathies. CMT2 type GG, due to four distinct heterozygous mutations in the Golgi brefeldin A resistant guanine nucleotide exchange factor 1 (GBF1) gene (OMIM 606483), was described in seven cases from four unrelated families with autosomal dominant inheritance. It is characterized by slowly progressive distal muscle weakness and atrophy, primarily affecting the lower limbs. Here, we present two siblings sharing a novel GBF1 variant. Methods: Patient II.1 (male, 61 years at onset) presented lower limb hypoesthesia and walking difficulty; the examination revealed a postural tremor, a positive Romberg test, and muscle atrophy in the lower limbs and hands. Patient II.2 (his sister, 59 years at onset) had lower limb dysesthesias, hand paresthesia, and lower-limb stiffness. They underwent clinical evaluations, blood tests, and electroneurography. Their father represents a potentially affected individual, although a genetic analysis was not conducted. Results: All tests for peripheral neuropathies were unremarkable, including metabolic and autoimmune screening. Both showed a mixed demyelinating–axonal sensory–motor neuropathy. Genetic analysis revealed a new heterozygous GBF1 variant of uncertain significance. Conclusions: Based on autosomal dominant inheritance, as well as clinical and physiological features, a possible novel CMT2GG was diagnosed. Further research, including functional assays and in vitro studies, is necessary to confirm this variant’s causal link. Full article
(This article belongs to the Special Issue Molecular Genetics of Neurodegenerative Diseases and Neuromuscular Diseases)
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13 pages, 233 KiB  
Article
Association of SCN1A Polymorphisms rs3812718 and rs2298771 with Epilepsy
by Martha-Spyridoula Katsarou, Anna Siatouni, Danae Tsikrika, Elena Kokkiou, Maria Stefanatou, Anastasia Verentzioti, Athanasia Alexoudi, Stylianos Gatzonis, Nikolaos Drakoulis and Maria Papasavva
Genes 2024, 15(9), 1224; https://doi.org/10.3390/genes15091224 - 19 Sep 2024
Cited by 1 | Viewed by 1505
Abstract
Background/Objectives: Epilepsy is a brain disease with both environmental and genetic inputs. Ion channel dysfunction seems to be of great significance for abnormal neuronal behavior during epileptic seizures. Within neurons, the voltage-gated sodium channels are crucial proteins contributing to the initiation and propagation [...] Read more.
Background/Objectives: Epilepsy is a brain disease with both environmental and genetic inputs. Ion channel dysfunction seems to be of great significance for abnormal neuronal behavior during epileptic seizures. Within neurons, the voltage-gated sodium channels are crucial proteins contributing to the initiation and propagation of action potentials. The voltage-gated sodium channel α subunit 1 (SCN1A) gene encodes for the α subunit of a voltage-gated ion channel. The aim of the study was to investigate the relation of two common SCN1A variants, i.e., rs3812718 and rs2298771, with distinct epileptic phenotypes in a South-Eastern European population. Methods: DNA was extracted from 214 unrelated participants with focal onset, focal to bilateral tonic–clonic, or generalized onset epileptic seizures and genotyped using real-time PCR (LightSNiP assays) followed by melting curve analysis. Statistical analysis of the results was performed using IBM SPSS Statistics software (version 29.0 for Windows). Results: Genotype frequency distribution analysis indicated an association for the A-allele-containing genotypes of both rs3812718 and rs2298771 polymorphisms of SCN1A with generalized onset seizures and focal to bilateral tonic–clonic seizures versus focal onset seizures. Conclusions: Consequently, the study provides evidence that supports a potential association of the investigated SCN1A polymorphisms with distinct seizure subtype susceptibility in South-Eastern Europeans. Full article
(This article belongs to the Special Issue Molecular Genetics of Neurodegenerative Diseases and Neuromuscular Diseases)
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18 pages, 1208 KiB  
Article
Application of OpenArray Technology to Assess Changes in the Expression of Functionally Significant Genes in the Substantia Nigra of Mice in a Model of Parkinson’s Disease
by Dmitry Troshev, Anna Kolacheva, Ekaterina Pavlova, Victor Blokhin and Michael Ugrumov
Genes 2023, 14(12), 2202; https://doi.org/10.3390/genes14122202 - 12 Dec 2023
Viewed by 2312
Abstract
Studying the molecular mechanisms of the pathogenesis of Parkinson’s disease (PD) is critical to improve PD treatment. We used OpenArray technology to assess gene expression in the substantia nigra (SN) cells of mice in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD and in controls. [...] Read more.
Studying the molecular mechanisms of the pathogenesis of Parkinson’s disease (PD) is critical to improve PD treatment. We used OpenArray technology to assess gene expression in the substantia nigra (SN) cells of mice in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD and in controls. Among the 11 housekeeping genes tested, Rps27a was taken as the reference gene due to its most stable expression in normal and experimental conditions. From 101 genes encoding functionally significant proteins of nigrostriatal dopaminergic neurons, 57 highly expressed genes were selected to assess their expressions in the PD model and in the controls. The expressions of Th, Ddc, Maoa, Comt, Slc6a3, Slc18a2, Drd2, and Nr4a2 decreased in the experiment compared to the control, indicating decreases in the synthesis, degradation, and transport of dopamine and the impaired autoregulation of dopaminergic neurons. The expressions of Tubb3, Map2, Syn1, Syt1, Rab7, Sod1, Cib1, Gpx1, Psmd4, Ubb, Usp47, and Ctsb genes were also decreased in the MPTP-treated mice, indicating impairments of axonal and vesicular transport and abnormal functioning of the antioxidant and ubiquitin-proteasome systems in the SN. The detected decreases in the expressions of Snca, Nsf, Dnm1l, and Keap1 may serve to reduce pathological protein aggregation, increase dopamine release in the striatum, prevent mitophagy, and restore the redox status of SN cells. Full article
(This article belongs to the Special Issue Molecular Genetics of Neurodegenerative Diseases and Neuromuscular Diseases)
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Review

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12 pages, 567 KiB  
Review
Preparing for Patient-Customized N-of-1 Antisense Oligonucleotide Therapy to Treat Rare Diseases
by Harry Wilton-Clark, Eric Yan and Toshifumi Yokota
Genes 2024, 15(7), 821; https://doi.org/10.3390/genes15070821 - 21 Jun 2024
Cited by 6 | Viewed by 4215
Abstract
The process of developing therapies to treat rare diseases is fraught with financial, regulatory, and logistical challenges that have limited our ability to build effective treatments. Recently, a novel type of therapy called antisense therapy has shown immense potential for the treatment of [...] Read more.
The process of developing therapies to treat rare diseases is fraught with financial, regulatory, and logistical challenges that have limited our ability to build effective treatments. Recently, a novel type of therapy called antisense therapy has shown immense potential for the treatment of rare diseases, particularly through single-patient N-of-1 trials. Several N-of-1 antisense therapies have been developed recently for rare diseases, including the landmark study of milasen. In response to the success of N-of-1 antisense therapy, the Food and Drug Administration (FDA) has developed unique guidelines specifically for the development of antisense therapy to treat N-of-1 rare diseases. This policy change establishes a strong foundation for future therapy development and addresses some of the major limitations that previously hindered the development of therapies for rare diseases. Full article
(This article belongs to the Special Issue Molecular Genetics of Neurodegenerative Diseases and Neuromuscular Diseases)
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15 pages, 897 KiB  
Review
Beyond CAG Repeats: The Multifaceted Role of Genetics in Huntington Disease
by Marta Pengo and Ferdinando Squitieri
Genes 2024, 15(6), 807; https://doi.org/10.3390/genes15060807 - 19 Jun 2024
Cited by 5 | Viewed by 4225
Abstract
Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG expansion on the huntingtin (HTT) gene and is characterized by progressive motor, cognitive, and neuropsychiatric decline. Recently, new genetic factors besides CAG repeats have been implicated in the [...] Read more.
Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG expansion on the huntingtin (HTT) gene and is characterized by progressive motor, cognitive, and neuropsychiatric decline. Recently, new genetic factors besides CAG repeats have been implicated in the disease pathogenesis. Most genetic modifiers are involved in DNA repair pathways and, as the cause of the loss of CAA interruption in the HTT gene, they exert their main influence through somatic expansion. However, this mechanism might not be the only driver of HD pathogenesis, and future studies are warranted in this field. The aim of the present review is to dissect the many faces of genetics in HD pathogenesis, from cis- and trans-acting genetic modifiers to RNA toxicity, mitochondrial DNA mutations, and epigenetics factors. Exploring genetic modifiers of HD onset and progression appears crucial to elucidate not only disease pathogenesis, but also to improve disease prediction and prevention, develop biomarkers of disease progression and response to therapies, and recognize new therapeutic opportunities. Since the same genetic mechanisms are also described in other repeat expansion diseases, their implications might encompass the whole spectrum of these disorders. Full article
(This article belongs to the Special Issue Molecular Genetics of Neurodegenerative Diseases and Neuromuscular Diseases)
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18 pages, 653 KiB  
Review
The Landscape of Monogenic Parkinson’s Disease in Populations of Non-European Ancestry: A Narrative Review
by Christos Koros, Anastasia Bougea, Athina Maria Simitsi, Nikolaos Papagiannakis, Efthalia Angelopoulou, Ioanna Pachi, Roubina Antonelou, Maria Bozi, Maria Stamelou and Leonidas Stefanis
Genes 2023, 14(11), 2097; https://doi.org/10.3390/genes14112097 - 17 Nov 2023
Cited by 5 | Viewed by 2793
Abstract
Introduction: There has been a bias in the existing literature on Parkinson’s disease (PD) genetics as most studies involved patients of European ancestry, mostly in Europe and North America. Our target was to review published research data on the genetic profile of PD [...] Read more.
Introduction: There has been a bias in the existing literature on Parkinson’s disease (PD) genetics as most studies involved patients of European ancestry, mostly in Europe and North America. Our target was to review published research data on the genetic profile of PD patients of non-European or mixed ancestry. Methods: We reviewed articles published during the 2000–2023 period, focusing on the genetic status of PD patients of non-European origin (Indian, East and Central Asian, Latin American, sub-Saharan African and Pacific islands). Results: There were substantial differences regarding monogenic PD forms between patients of European and non-European ancestry. The G2019S Leucine Rich Repeat Kinase 2 (LRRK2) mutation was rather scarce in non-European populations. In contrast, East Asian patients carried different mutations like p.I2020T, which is common in Japan. Parkin (PRKN) variants had a global distribution, being common in early-onset PD in Indians, in East Asians, and in early-onset Mexicans. Furthermore, they were occasionally present in Black African PD patients. PTEN-induced kinase 1 (PINK1) and PD protein 7 (DJ-1) variants were described in Indian, East Asian and Pacific Islands populations. Glucocerebrosidase gene variants (GBA1), which represent an important predisposing factor for PD, were found in East and Southeast Asian and Indian populations. Different GBA1 variants have been reported in Black African populations and Latin Americans. Conclusions: Existing data reveal a pronounced heterogeneity in the genetic background of PD. A number of common variants in populations of European ancestry appeared to be absent or scarce in patients of diverse ethnic backgrounds. Large-scale studies that include genetic screening in African, Asian or Latin American populations are underway. The outcomes of such efforts will facilitate further clinical studies and will possibly contribute to the identification of either new pathogenic mutations in already described genes or novel PD-related genes. Full article
(This article belongs to the Special Issue Molecular Genetics of Neurodegenerative Diseases and Neuromuscular Diseases)
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