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The syndromes of neurodegeneration with brain iron accumulation (NBIA) encompass a group of invalidating and progressive rare diseases that share the abnormal accumulation of iron in the basal ganglia. The onset of NBIA disorders ranges from infancy to adulthood. Main clinical signs are related to extrapyramidal features (dystonia, parkinsonism and choreoathetosis), and neuropsychiatric abnormalities. Ten NBIA forms are widely accepted to be caused by mutations in the genes PANK2, PLA2G6, WDR45, C19ORF12, FA2H, ATP13A2, COASY, FTL1, CP, and DCAF17. Nonetheless, many patients remain without a conclusive genetic diagnosis, which highlights that there must be additional as yet undiscovered NBIA genes. In line with this, isolated cases of known monogenic disorders, and also, new genetic diseases, which present with abnormal brain iron phenotype compatible with NBIA, have been described. Several pathways are involved in NBIA syndromes: iron and lipid metabolism, mitochondrial dynamics, and autophagy. However, many neurodegenerative conditions share features such as mitochondrial dysfunction and oxidative stress, given the bioenergetics requirements of neurons. This review aims to describe the existing link between the classical ten NBIA forms by examining their connection with mitochondrial impairment as well as oxidative stress and neuroinflammation.

Background: Hereditary spastic paraparesis (HSP) encompasses a genetically and clinically heterogeneous group of neurodegenerative disorders, primarily characterized by progressive lower limb spasticity and weakness of the lower limbs. Although more than 80 genes have been associated with HSP, achieving definite genetic diagnosis remains challenging, limiting effective patient care, genetic counseling, and understanding of genotype-phenotype correlations. This study aimed to investigate the diagnostic yield of clinical exome sequencing (CES) in a cohort of Spanish individuals with suspected HSP and to explore genotype-phenotype correlations. Methods: A total of 139 non-related Spanish individuals with HSP underwent standardized clinical evaluation and CES. Genetic analyses were performed using a virtual panel containing 129 HSP-associated genes, complemented by phenotype-driven filtering through the Human Phenotype Ontology. Statistical analyses were performed on core clinical and paraclinical features. Results: After clinical review, 108 index cases were included. Male patients were slightly more represented and mean age at onset was 33 years. Pure HSP forms were more prevalent. The most frequent presenting symptoms were gait disturbance and recurrent falls. A genetic diagnosis was achieved in 57 patients (52,8%), with SPAST and SPG7 being the most frequently mutated genes. In total, pathogenic/likely pathogenic variants were identified across 21 genes, including 8 novel variants. HSP with autosomal recessive inheritance was more common than autosomal dominant (29 vs. 25 cases), while dominant/recessive X-linked disease forms were rare (3 cases). Conclusions: CES combined with HPO-based filtering is an effective strategy for achieving genetic diagnosis in patients with suspicion of HSP.

Background Wilson's disease (WD) is a rare condition resulting from autosomal recessive mutations in ATP7B, a copper transporter, manifesting with hepatic, neurological, and psychiatric symptoms. Timely diagnosis and appropriate treatment yield a positive prognosis, while delayed identification and/or insufficient therapy lead to a poor outcome. Our aim was to establish a prognostic method for WD by characterising biomarkers based on circulating microRNAs. Methods We conducted investigations across three cohorts: discovery, validation (comprising unrelated patients), and follow-up (revisiting the discovery cohort 3 years later). All groups were compared to age- and gender-matched controls. Plasma microRNAs were analysed via RNA sequencing in the discovery cohort and subsequently validated using quantitative PCR in all three cohorts. To assess disease progression, we examined the microRNA profile in Atp7b−/− mice, analysing serum samples from 6 to 44 weeks of age and liver samples at three time points: 20, 30, and 40 weeks of age. Results In patients, elevated levels of the signature microRNAs (miR-122-5p, miR-192-5p, and miR-885-5p) correlated with serum activities of aspartate transaminase, alanine aminotransferase and gamma-glutamyl transferase. In Atp7b−/− mice, levels of miR-122-5p and miR-192-5p (miR-885-5p lacking a murine orthologue) increased from 12 weeks of age in serum, while exhibiting fluctuations in the liver, possibly attributable to hepatocyte regenerative capacity post-injury and the release of hepatic microRNAs into the bloodstream. Conclusions The upregulation of the signature miR-122-5p, miR-192-5p, and miR-885-5p in patients and their correlation with liver disease progression in WD mice support their potential as biomarkers of WD.

Objective To describe a new phenotype associated with a novel variant in BAG3: autosomal dominant adult-onset distal hereditary motor neuronopathy. Methods This study enrolled eight affected individuals from a single family and included a comprehensive evaluation of the clinical phenotype, neurophysiologic testing, muscle MRI, muscle biopsy and western blot of BAG3 protein in skeletal muscle. Genetic workup included whole exome sequencing and segregation analysis of the detected variant in BAG3. Results Seven patients developed slowly progressive and symmetric distal weakness and atrophy of lower limb muscles, along with absent Achilles reflexes. The mean age of onset was 46 years. The neurophysiological examination was consistent with the diagnosis of distal motor neuronopathy. One 57-year-old female patient was minimally symptomatic. The pattern of inheritance was autosomal dominant, with one caveat: one female patient who was an obligate carrier of the variant died at the age of 73 years without exhibiting any muscle weakness. The muscle biopsies revealed neurogenic changes. A novell heterozygous truncating variant c.1513_1514insGGAC (p.Val505GlyfsTer6) in the gene BAG3 was identified in all affected family members. Conclusions We report an autosomal dominant adult-onset distal hereditary motor neuronopathy with incomplete penetrance in women as a new phenotype related to a truncating variant in the BAG3 gene. Our findings expand the phenotypic spectrum of BAG3-related disorders, which previously included dilated cardiomyopathy, myofibrillar myopathy and adultonset Charcot-Marie-Tooth type 2 neuropathy. Variants in BAG3 should be considered in the differential diagnosis of distal hereditary motor neuronopathies.

Cerebellar atrophy (CA) is a frequent neuroimaging finding in paediatric neurology, usually associated with cerebellar ataxia. The list of genes involved in hereditary forms of CA is continuously growing and reveals its genetic complexity. We investigated ten cases with early-onset cerebellar involvement with and without ataxia by exome sequencing or by a targeted panel with 363 genes involved in ataxia or spastic paraplegia. Novel variants were investigated by in silico or experimental approaches. Seven probands carry causative variants in well-known genes associated with CA or cerebellar hypoplasia: SETX, CACNA1G, CACNA1A, CLN6, CPLANE1, and TBCD. The remaining three cases deserve special attention; they harbour variants in MAST1, PI4KA and CLK2 genes. MAST1 is responsible for an ultrarare condition characterised by global developmental delay and cognitive decline; our index case adds ataxia to the list of concomitant associated symptoms. PIK4A is mainly related to hypomyelinating leukodystrophy; our proband presents with a pure spastic paraplegia and normal intellectual capacity. Finally, in a patient who suffers from a mild ataxia with oculomotor apraxia, de novo novel CLK2 c.1120T>C variant was found. The protein expression of the mutated protein resulted to be reduced, which may indicate instability that would affect its kinase activity.

Our clinical series comprises 124 patients with movement disorders (MDs) and/or ataxia with cerebellar atrophy (CA), many of them showing signs of neurodegeneration with brain iron accumulation (NBIA). Ten NBIA genes are accepted, although isolated cases compatible with abnormal brain iron deposits are known. The patients were evaluated using standardised clinical assessments of ataxia and MDs. First, NBIA genes were analysed by Sanger sequencing and 59 patients achieved a diagnosis, including the detection of the founder mutation PANK2 p.T528M in Romani people. Then, we used a custom panel MovDisord and/or exome sequencing; 29 cases were solved with a great genetic heterogeneity (34 different mutations in 23 genes). Three patients presented brain iron deposits with Fe-sensitive MRI sequences and mutations in FBXO7, GLB1, and KIF1A, suggesting a NBIA-like phenotype. Eleven patients showed very early-onset ataxia and CA with cortical hyperintensities caused by mutations in ITPR1, KIF1A, SPTBN2, PLA2G6, PMPCA, and PRDX3. The novel variants were investigated by structural modelling, luciferase analysis, transcript/minigenes studies, or immunofluorescence assays. Our findings expand the phenotypes and the genetics of MDs and ataxias with early-onset CA and cortical hyperintensities, and highlight that the abnormal brain iron accumulation or early cerebellar gliosis may resembling a NBIA phenotype.

Oxidative stress is an imbalance between production and accumulation of oxygen reactive species and/or reactive nitrogen species in cells and tissues, and the capacity of detoxifying these products, using enzymatic and non-enzymatic components, such as glutathione. Oxidative stress plays roles in several pathological processes in the nervous system, such as neurotoxicity, neuroinflammation, ischemic stroke, and neurodegeneration. The concepts of oxidative stress and rare diseases were formulated in the eighties, and since then, the link between them has not stopped growing. The present review aims to expand knowledge in the pathological processes associated with oxidative stress underlying some groups of rare diseases: Friedreich's ataxia, diseases with neurodegeneration with brain iron accumulation, Charcot-Marie-Tooth as an example of rare neuromuscular disorders, inherited retinal dystrophies, progressive myoclonus epilepsies, and pediatric drug-resistant epilepsies. Despite the discrimination between cause and effect may not be easy on many occasions, all these conditions are Mendelian rare diseases that share oxidative stress as a common factor, and this may represent a potential target for therapies

(1) Background: A non-progressive congenital ataxia (NPCA) phenotype caused by ß-III spectrin (SPTBN2) mutations has emerged mimicking SCAR14 (spinocerebellar ataxia - autosomal recessive type 14). The pattern of inheritance, however, resembles that of autosomal dominant classical SCA5 (spinocerebellar ataxia type 5). (2) Methods: In depth-phenotyping of two boys studied by a customized gene panel. Candidate variants were sought by structural modelling and protein expression. An extensive review of the literature was conducted in order to better characterise the SPTBN2-associated NPCA. (3) Results: Patients exhibited a NPCA with hypotonia, developmental delay, a cerebellar syndrome, and cognitive deficits. Both probands presented with progressive global cerebellar volume loss in consecutive cerebral magnetic resonance imaging studies, characterised by decreasing midsagittal vermis relative diameter measurements. Cortical hyperintensities were observed on FLAIR (fluid-attenuated inversion recovery) images, suggesting a neurodegenerative process. Each patient carried a novel de novo SPTBN2 substitution: c.193A>G (p.K65E) or c.764A>G (p.D255G). Modelling and protein expression revealed that both mutations may be deleterious. (4) Conclusions: The reported findings contribute to a better understanding of the SPTBN2-associated phenotype. The mutations may preclude proper structural organization of the actin-spectrin-based membrane skeleton, which in turn is responsible for the underlying disease mechanism.

BACKGROUND: Mutations in the metalloendopeptidase (MME) gene were initially identified as a cause of autosomal recessive Charcot-Marie-Tooth disease type 2 (CMT2). Subsequently, variants in MME were linked to other late-onset autosomal dominant polyneuropathies. Thus, our goal was to define the phenotype and mode of inheritance of patients carrying changes in MME. METHODS: We screened 197 index cases with a hereditary neuropathy of the CMT type or distal hereditary motor neuropathy (dHMN) and 10 probands with familial amyotrophic lateral sclerosis (fALS) using a custom panel of 119 genes. In addition to the index case subjects, we also studied other clinically and/or genetically affected and unaffected family members. RESULTS: We found 17 variants in MME in a total of 20 index cases, with biallelic MME mutations detected in 13 cases from nine families (three in homozygosis and six in compound heterozygosis) and heterozygous variants found in 11 families. All patients with biallelic variants had a similar phenotype, consistent with late-onset axonal neuropathy. Conversely, the phenotype of patients carrying heterozygous mutations was highly variable [CMT type 1 (CMT1), CMT2, dHMN and fALS] and mutations did not segregate with the disease. CONCLUSION: MME mutations that segregate in an autosomal recessive pattern are associated with a late-onset CMT2 phenotype, yet we could not demonstrate that MME variants in heterozygosis cause neuropathy. Our data highlight the importance of establishing an accurate genetic diagnosis in patients carrying MME mutations, especially with a view to genetic counselling.

Members of the Junctophilin (JPH) protein family have emerged as key actors in all excitable cells, with crucial implications for human pathophysiology. In mammals, this family consists of four members (JPH1-JPH4) that are differentially expressed throughout excitable cells. The analysis of knockout mice lacking JPH subtypes has demonstrated their essential contribution to physiological functions in skeletal and cardiac muscles and in neurons. Moreover, mutations in the human JPH2 gene are associated with hypertrophic and dilated cardiomyopathies; mutations in JPH3 are responsible for the neurodegenerative Huntington's disease-like-2 (HDL2), whereas JPH1 acts as a genetic modifier in Charcot-Marie-Tooth 2K peripheral neuropathy. Drosophila melanogaster has a single junctophilin (jp) gene, as is the case in all invertebrates, which might retain equivalent functions of the four homologous JPH genes present in mammalian genomes. Therefore, owing to the lack of putatively redundant genes, a jpDrosophila model could provide an excellent platform to model the Junctophilin-related diseases, to discover the ancestral functions of the JPH proteins and to reveal new pathways. By up- and downregulation of Jp in a tissue-specific manner in Drosophila, we show that altering its levels of expression produces a phenotypic spectrum characterized by muscular deficits, dilated cardiomyopathy and neuronal alterations. Importantly, our study has demonstrated that Jp modifies the neuronal degeneration in a Drosophila model of Huntington's disease, and it has allowed us to uncover an unsuspected functional relationship with the Notch pathway. Therefore, this Drosophila model has revealed new aspects of Junctophilin function that can be relevant for the disease mechanisms of their human counterparts