RESUMO
Amyotrophic lateral sclerosis (ALS) is characterized by the progressive, irreversible loss of upper and lower motor neurons (UMNs, LMNs). MN axonal dysfunctions are emerging as relevant pathogenic events since the early ALS stages. However, the exact molecular mechanisms leading to MN axon degeneration in ALS still need to be clarified. MicroRNA (miRNA) dysregulation plays a critical role in the pathogenesis of neuromuscular diseases. These molecules represent promising biomarkers for these conditions since their expression in body fluids consistently reflects distinct pathophysiological states. Mir-146a has been reported to modulate the expression of the NFL gene, encoding the light chain of the neurofilament (NFL) protein, a recognized biomarker for ALS. Here, we analyzed miR-146a and Nfl expression in the sciatic nerve of G93A-SOD1 ALS mice during disease progression. The miRNA was also analyzed in the serum of affected mice and human patients, the last stratified relying on the predominant UMN or LMN clinical signs. We revealed a significant miR-146a increase and Nfl expression decrease in G93A-SOD1 peripheral nerve. In the serum of both ALS mice and human patients, the miRNA levels were reduced, discriminating UMN-predominant patients from the LMN ones. Our findings suggest a miR-146a contribution to peripheral axon impairment and its potential role as a diagnostic and prognostic biomarker for ALS.
Assuntos
Esclerose Lateral Amiotrófica , MicroRNAs , Degeneração Neural , Animais , Humanos , Camundongos , Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Biomarcadores/sangue , Biomarcadores/metabolismo , Modelos Animais de Doenças , Camundongos Transgênicos , MicroRNAs/sangue , MicroRNAs/genética , MicroRNAs/metabolismo , Degeneração Neural/diagnóstico , Degeneração Neural/genética , Degeneração Neural/metabolismo , Nervos Periféricos/patologia , Superóxido Dismutase-1/genética , Axônios/patologia , Proteínas de Neurofilamentos , Diagnóstico Precoce , Progressão da DoençaRESUMO
Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and/or lower motor neurons and characterized by complex etiology. Familial cases show high genetic heterogeneity and sporadic cases (90%) are associated with several genetic and environmental risk factors. Among the genetic risk factors, the contribution of non-coding elements, such as microRNAs (miRNAs), to ALS disease susceptibility remains largely unexplored. Aim: This work aims to identify rare variants in miRNA genes in sporadic ALS (sALS) patients which may cause a defective miRNA maturation or altered target gene recognition by changing miRNA secondary structure or seed sequence, respectively. Methods: Rare variants located in miRNA loci with a minor allele frequency (MAF) < 0.01 were extracted from whole genome sequencing (WGS) data of 100 sALS patients. The secondary pre-miRNA structures were predicted using MiRVas to evaluate the impact of the variants on RNA folding process. Human TargetScan was used to retrieve all the potential target genes of miRNAs with variants in the seed region. Over Representation Analysis (ORA) was conducted to compare the lists of target genes for the reference and mutated miRNAs in the seed sequence. Results: Our analysis identified 86 rare variants in 77 distinct miRNAs and distributed in different parts of the miRNA precursors. The presence of these variants changed miRNA secondary structures in â¼70% of MiRVas predictions. By focusing on the 6 rare variants mapping within the seed sequence, the predicted target genes increased in number compared to the reference miRNA and included novel targets in a proportion ranging from 30 to 82%. Interestingly, ORA revealed significant changes in gene set enrichment only for mutated miR-509-1 and miR-941-3 for which the Gene Ontology term related to "nervous system development" was absent and present, respectively, compared to target lists of the reference miRNA. Conclusion: We here developed a workflow to study miRNA rare variants from WGS data and to predict their biological effects on miRNA folding, maturation and target gene recognition. Although this in silico approach certainly needs functional validation in vitro and in vivo, it may help define the role of miRNA variability in ALS and complex diseases.
RESUMO
Background and objectives: Multisystem involvement in spinal muscular atrophy (SMA) is gaining prominence since different therapeutic options are emerging, making the way for new SMA phenotypes and consequent challenges in clinical care. Defective immune organs have been found in preclinical models of SMA, suggesting an involvement of the immune system in the disease. However, the immune state in SMA patients has not been investigated so far. Here, we aimed to evaluate the innate and adaptive immunity pattern in SMA type 1 to type 3 patients, before and after nusinersen treatment. Methods: Twenty one pediatric SMA type 1, 2, and 3 patients and 12 adult SMA type 2 and 3 patients were included in this single-center retrospective study. A Bio-Plex Pro-Human Cytokine 13-plex Immunoassay was used to measure cytokines in serum and cerebrospinal fluid (CSF) of the study cohort before and after 6 months of therapy with nusinersen. Results: We detected a significant increase in IL-1ß, IL-4, IL-6, IL-10, IFN-γ, IL-17A, IL-22, IL-23, IL-31, and IL-33, in serum of pediatric and adult SMA patients at baseline, compared to pediatric reference ranges and to adult healthy controls. Pediatric patients showed also a significant increase in TNF-α and IL-17F levels at baseline. IL-4, IFN-γ, Il-22, IL-23, and IL-33 decreased in serum of pediatric SMA patients after 6 months of therapy when compared to baseline. A significant decrease in IL-4, IL-6, INF-γ, and IL-17A was detected in serum of adult SMA patients after treatment. CSF of both pediatric and adult SMA patients displayed detectable levels of all cytokines with no significant differences after 6 months of treatment with nusinersen. Notably, a higher baseline expression of IL-23 in serum correlated with a worse motor function outcome after treatment in pediatric patients. Moreover, after 6 months of treatment, patients presenting a higher IL-10 concentration in serum showed a better Hammersmith Functional Motor Scale Expanded (HFMSE) score. Discussion: Pediatric and adult SMA patients show an inflammatory signature in serum that is reduced upon SMN2 modulating treatment, and the presence of inflammatory mediators in CSF. Our findings enhance SMA knowledge with potential clinical and therapeutic implications.
RESUMO
BACKGROUND AND OBJECTIVES: SOD1 variants in patients with amyotrophic lateral sclerosis (ALS) have been associated to peculiar clinical features and disease progression but rarely to cognitive and behavioural impairment. This study aims at describing the features of frontotemporal syndromes in ALS patients carrying SOD1 variants. METHODS: Italian patients with ALS were consecutively enrolled between 2012 and 2020 at our Motor Neuron Disease center. All underwent clinical assessment, extensive neurophysiological test battery for the evaluation of cognitive functions and behavior, and targeted next generation sequencing of SOD1, FUS, TARDBP, VCP, PFN1, TUBA4A, OPTN, SQSTM1, UBQLN2 and C9orf72 genes. Neuropsychological profiles of SOD1+ patients (SOD1+) were compared to those with no gene variants (SOD1-). To this aim, the occurrence of cognitive and behavioral impairment defined according to current guidelines, the number of pathological test performances based on Italian normative values, and scores of the Frontal Behavioural Inventory were collected. RESULTS: Among 288 patients consecutively examined, we identified 8 known pathogenic SOD1 variants and one variant of uncertain significance (p.Ser26Asn) not previously described in 14 ALS patients belonging to 11 families. The clinical phenotypes were mainly characterized by predominant lower motor neuron involvement with onset at the lower limbs, and one patient had bulbar onset. SOD1+ patients (n=14) were compared to SOD1- patients (N = 274). SOD1+ patients were younger than SOD1-, and both groups had similar functional motor disabilities and disease duration. Based on the overall neuropsychological findings, the percentage of SOD1+ and SOD1- patients with altered profiles were about 60%. However, behavioral impairment defined by the Strong criteria, and most commonly featuring with irritability and mental rigidity, was more frequent in SOD1+ than SOD1- patients, and mainly associated with variants in exon 5. Conversely, cognitive impairment was mainly found in SOD1- patients. DISCUSSION: Our findings from a large cohort of deeply phenotyped ALS patients demonstrated that behavioral involvement is more common than previously thought among patients harboring SOD1 variants, and that it is independent from patients' age and disease stage. These findings could be relevant for the assessment of clinical trial outcomes and disease management.
RESUMO
BACKGROUND: ALS symptoms have been previously described only in the context of ATXN2 CAG expansions, whereas missense mutations of the gene have never been described in ALS patients. CASE PRESENTATION: We identified a novel missense mutation (c.2860C > T) of ATXN2, for which in silico analysis showed a possible pathogenic effect on protein expression, in a patient presenting an aggressive disease phenotype. DISCUSSION: Our findings raise the possibility for unknown genetic factors interacting with ATXN2 mutations, or for an autonomous pathogenic role for this specific point mutation in ATXN2 gene in driving the clinical phenotype toward ALS. We also found that stress granules in the fibroblasts from the patient entrapped higher amounts of defective ribosomal products compared to fibroblasts from three healthy subjects, suggesting that ATXN2 mutation-related toxicity may have implication in protein quality control.
Assuntos
Esclerose Lateral Amiotrófica , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Ataxina-2/genética , Humanos , Mutação , Mutação de Sentido Incorreto , Fenótipo , Proteínas/genética , Expansão das Repetições de TrinucleotídeosRESUMO
Mutations in FUS gene have been described classically in young ALS patients with aggressive disease course. Here we report a large family carrying a missense mutation c.1520 G>A in FUS gene with a tight association with an atypical FUS-ALS phenotype. A 60-year-old man with unilateral leg involvement at onset showed very slow disease progression with selective posterior legs atrophy, tracing his aunt's disease history. His father and uncle died for ALS after a long disease course. Another patient with a 14 years history of ALS with the same phenotype, was found to belong to the same family. In all cases, genetic analysis of FUS gene revealed a missense mutation c.1520 G>A (p.G507D) inherited with a heterozygous pattern. Co-segregation of p.G507D mutation and a specific disease phenotype within the family, characterised by predominant involvement at the lower limbs, slow progression, late bulbar and respiratory failure, demonstrates pathogenicity of this mutation, establishes a well-defined genotype-phenotype correlation and expands the clinical spectrum of heterogeneity in FUS-ALS.
Assuntos
Esclerose Lateral Amiotrófica , Esclerose Lateral Amiotrófica/genética , Progressão da Doença , Estudos de Associação Genética , Humanos , Mutação/genética , Proteína FUS de Ligação a RNA/genéticaRESUMO
Mutations in Matrin-3 (MATR3) gene have been described in ALS, suggesting a role for this gene in the disease pathogenesis. While most of MATR3 mutations are point mutations, here we report the first case of ALS associated with duplication in exons 15 and 16. The patient presented with limb-onset ALS and a complex past medical history because of Sjögren syndrome, antiphospholipid antibodies positivity, polyallergies, endometriosis, aldosterone-secreting adrenal cortical adenoma, congenital vesicoureteral reflux, and right breast hypoplasia. We discuss MATR3 effect in ALS and the role of this previously undescribed mutation in this peculiar ALS phenotype associated with systemic autoimmunity involvement.
Assuntos
Esclerose Lateral Amiotrófica , Esclerose Lateral Amiotrófica/genética , Éxons/genética , Feminino , Humanos , Mutação/genética , Proteínas Associadas à Matriz Nuclear , Fenótipo , Proteínas de Ligação a RNARESUMO
Motor neuron diseases (MNDs) are neurodegenerative disorders characterized by upper and/or lower MN loss. MNDs include amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and spinal and bulbar muscular atrophy (SBMA). Despite variability in onset, progression, and genetics, they share a common skeletal muscle involvement, suggesting that it could be a primary site for MND pathogenesis. Due to the key role of muscle-specific microRNAs (myomiRs) in skeletal muscle development, by real-time PCR we investigated the expression of miR-206, miR-133a, miR-133b, and miR-1, and their target genes, in G93A-SOD1 ALS, Δ7SMA, and KI-SBMA mouse muscle during disease progression. Further, we analyzed their expression in serum of SOD1-mutated ALS, SMA, and SBMA patients, to demonstrate myomiR role as noninvasive biomarkers. Our data showed a dysregulation of myomiRs and their targets, in ALS, SMA, and SBMA mice, revealing a common pathogenic feature associated with muscle impairment. A similar myomiR signature was observed in patients' sera. In particular, an up-regulation of miR-206 was identified in both mouse muscle and serum of human patients. Our overall findings highlight the role of myomiRs as promising biomarkers in ALS, SMA, and SBMA. Further investigations are needed to explore the potential of myomiRs as therapeutic targets for MND treatment.
Assuntos
Esclerose Lateral Amiotrófica , Atrofia Bulboespinal Ligada ao X , MicroRNAs , Mutação de Sentido Incorreto , Superóxido Dismutase-1 , Superóxido Dismutase , Substituição de Aminoácidos , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Animais , Atrofia Bulboespinal Ligada ao X/genética , Atrofia Bulboespinal Ligada ao X/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , MicroRNAs/genética , MicroRNAs/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismoRESUMO
INTRODUCTION: X-linked adrenoleukodystrophy (ALD) is a metabolic disorder in which very long chain fatty acids (VLCFAs) are accumulated in the nervous system and adrenal cortex, impairing their functions. Three main variants are described in males: adrenomyeloneuropathy (AMN), a cerebral form (cALD or cAMN) and Addison's disease only (AD), while for females no classification is used. To evaluate pain and the functional state of afferent fibers, a series of tests was carried out in male and female patients. METHODS: Chronic pain occurrence and sensory phenotype profile were assessed in 30 patients (20 male: 10 AMN, 1 cAMN, 1 cALD, 8 AD; and 10 female). A set of instruments assessed the intensity, quality and extent of pain, while a battery of quantitative sensory testing (QST) procedures examined the functional status of Aß and Aδ fibers. Principal component analysis and hierarchical clustering with sensory responses input were used to identify distinct clusters. RESULTS: Nearly half of the subjects reported pain, with a high prevalence in females and male AMN patients. No sex differences in pain dimensions were found. The sensory responses were heterogeneous, differing among the clinical variants and between genders. Male AMN/cAMN/cALD patients showed the worst impairment. Aß and Aδ fibers were affected in males and females, but Aß fibers appeared undamaged in females when tactile sensitivity was tested. Abnormal responses were localized in the lower body district, according to the dying-back pattern of the neuropathy. Cluster analysis showed discrete clusters for each function examined, with well-interpretable sensory and clinical phenotypes. CONCLUSION: The study of pain and of the sensory profile appears to indicate a difference in the mechanisms underlying the AMN/cAMN/cALD and AD clinical forms and in the treatment of the respective generated pain types.
RESUMO
BACKGROUND: Adrenoleukodystrophy (ALD) encompasses different neurological phenotypes, ranging from the most severe cerebral forms (C-ALD) to the less severe adrenomyeloneuropathy (AMN). As visual system can be varyingly involved, we aimed at exploring whether optical coherence tomography (OCT) may detect retinal abnormalities and their longitudinal changes in adult ALD patients. METHODS: In this cross-sectional and longitudinal study, we measured the thicknesses of peripapillary retinal nerve fiber layer (pRNFL), macular ganglion cell complex (mGCC), and segmented inner and outer macula at baseline and their changes over time in 11 symptomatic adult ALD males and 10 age- and sex-matched healthy controls. Statistical analyses were performed for the patients as complete group, and splitting them into two subgroups, one (C-ALD) with and the other (AMN) without cerebral parieto-occipital white matter (WM) lesions. RESULTS: In the complete ALD group and in the C-ALD subgroup, the average pRNFL, mGCC, and inner macula were significantly thinner than in controls (p ≤ 0.01), whereas in the AMN subgroup, they were constantly, though non-significantly, thinner. Significant outer macula thinning was also observed (p < 0.01). In the complete ALD group, follow-up assessment (mean 26.8 months, range 8-48) showed mildly progressive thinning of inferior pRNFL, average mGCC, and inner macula. CONCLUSIONS: In adult ALD patients, OCT can reveal retinal abnormalities which are prominent in the more compromised patients, namely those with parieto-occipital WM lesions. The inferior pRNFL, average mGCC and inner macula thicknesses might be sensitive-to-change OCT parameters, but their utility and consistency for short-term longitudinal studies deserve further investigations.
Assuntos
Adrenoleucodistrofia , Tomografia de Coerência Óptica , Adrenoleucodistrofia/diagnóstico por imagem , Adulto , Estudos Transversais , Humanos , Estudos Longitudinais , Masculino , Fibras Nervosas , Células Ganglionares da RetinaRESUMO
Amyotrophic lateral sclerosis (ALS) is an adult-onset progressive neurodegenerative disease due to motor neuron loss variably associated with frontotemporal dementia (FTD). Next generation sequencing technology revealed an increasing number of rare and novel genetic variants and interpretation of their pathogenicity represents a major challange in the diagnosis of ALS. We selected 213 consecutive patients with sporadic or familial (16%) ALS, tested negative for SOD1, FUS, TARDBP, and C9orf72 mutations. To reveal rare forms of genetic ALS, we performed a comprehensive multi-gene panel screening including 46 genes associated with ALS, hereditary motor neuronopathies, spastic paraplegia, and FTD. Our study allowed the identification of pathogenic or likely pathogenic variants in 4.2% of patients. The genes with the highest percentage of pathogenic variants were OPTN (1%), VCP (1%) SQSTM1(1%), SETX (0.4%), FIG4 (0.4%), and GARS1 (0.4%) genes. We also found 49 novel or rare gene variants of unknown significance in 30 patients (14%), 44 unlikely pathogenic variants (39%), and 48 variants in ALS susceptibility genes. The results of our study suggest the screening of OPTN, VCP, and SQSTM1 genes in routine diagnostic investigations for both sporadic and familial cases, and confirm the importance of diagnosis and couselling for patients and their relative family members.
RESUMO
Here, we described the first amyotrophic lateral sclerosis patient presenting the c.881 G > T p.G294V TARDBP mutation in homozygous status. The patient belongs to a large pedigree from Morocco. Except for one older affected brother his parents and remaining 8 sibs are referred to be healthy and do not show any neurological sign or symptom. The lack of evidence of TARDBP deletions of any sizes, together with the presence of several AOH segments, strongly suggests that the homozygosity status of p.G294V in the proband derived from parental consanguinity. A revision of the literature and our cohorts indicates that the p.G294V mutation has been detected in only 15 additional ALS patients in heterozygosity and, except for one additional Moroccan patient, all were of Italian origin. The analysis of microsatellite markers surrounding the TARDBP gene in 8 individuals carrying the p.G294V mutation showed that the haplotypic context of the Moroccan proband is shared with most patients of European origin indicating that they carry the p.G294V mutation inherited from a common ancestor. The analysis of the 15 ALS pedigrees (from literature data and present study), strongly suggests a reduced penetrance of the p.G294V mutation since for 13 of the 15 described p.G294V ALS cases the parents did not show any neurological symptoms. This result has potentially important implications in genetic counseling, since genetic testing of a reduced penetrance mutation on pre-symptomatic individuals proves very difficult to predict the outcome based on the genotype.
Assuntos
Alelos , Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/genética , Proteínas de Ligação a DNA/genética , Homozigoto , Mutação/genética , Adulto , Humanos , Masculino , LinhagemRESUMO
INTRODUCTION: X-linked adrenoleukodystrophy (X-ALD) encompasses several clinical and neuroimaging phenotypes, including cerebral X-ALD, the most common phenotype in children, and adrenomyeloneuropathy, the most common phenotype in adults. A spinocerebellar variant of X-ALD has been described in individuals from the Far East, but the criteria for its diagnosis are unclear. CASE REPORT: A 35-year-old man from Albania was assessed because of a familial, slowly progressive spastic-ataxic gait associated with neurogenic bladder, sexual dysfunctions, and manic-like behavior. There was no definite clinical feature that suggested cerebellar involvement (eg, cerebellar limb ataxia, nystagmus, and dysarthria). A few months earlier, he had received a diagnosis of Addison disease. Brain magnetic resonance imaging showed a leukoencephalopathy with predominant cerebellum and brainstem involvement, and FDG-PET revealed marked cerebellar hypometabolism. The diagnosis of X-ALD was made because we found an increase of very long chain fatty acids, and a new ABCD1 mutation (c.1627C>T, p.Pro543Ser). CONCLUSIONS: X-ALD should be included in the differential diagnosis of adult leukoencephalopathies with predominant involvement of infratentorial structures, that is, the cerebellum and brainstem. From a classification perspective, our patient (of white origin), like others (all of Asian origin), should be considered as suffering from a variant of adrenomyeloneuropathy rather than from spinocerebellar X-ALD. Actually, the term "spinocerebellar" or similar ones, such as "cerebello-brainstem dominant form," should be limited to those exceptional cases, in which both the clinical and neuroimaging findings point exclusively (or at least predominantly) to the involvement of infratentorial structures.
Assuntos
Membro 1 da Subfamília D de Transportadores de Cassetes de Ligação de ATP/genética , Adrenoleucodistrofia/diagnóstico , Adrenoleucodistrofia/genética , Cerebelo/patologia , Adrenoleucodistrofia/patologia , Adulto , Tronco Encefálico/patologia , Humanos , Masculino , Substância Branca/patologiaRESUMO
OBJECTIVE: The notion that cerebellar pathology may contribute to cognitive impairment in ALS, especially in patients with C9orf72 repeated expansion, has been inconsistently reported. This study aimed exploring the relationship between cerebellar involvement, cognitive impairment and C9orf72 repeated expansion of patients with ALS. METHODS: Quantitative in vivo assessment of cerebellar lobules has been investigated in 66 non-demented patients with ALS and 28 healthy controls (HCs). Pathologic C9orf72 repeated expansion was found in 13 patients. Mild cognitive and/or behavioral impairment was diagnosed in 22 C9orf72 negative ALS patients. Measures of cortical volume (CV) and cortical thickness (CT) of cerebellar lobules of all participants were used for Principal Component Analysis (PCA) to identify clusters of lobular measures highly correlated with each other. PCA outcomes were used for between group comparisons and correlation analyses with neuropsychological and clinical features. RESULTS: Disease severity measured with ALS functional rating scale and index of disease progression rate significantly correlated with CV reduction of the second PCA cluster loading CV measures of anterior lobules. In all patients, cognitive impairment, measured with verbal fluency, was related to CV reduction of the third cluster comprising posterior lobules. No specific cortical thinning or volume reduction of cerebellar clustering patterns could be detected in ALS subgroups. CONCLUSION: Our data show that specific patterns of subregional cerebellar involvement are associated with physical disability or cognitive impairment in ALS, in line with the topographic organization of the cerebellum. However, there was no specific correlation between cerebellar degeneration and cognitive syndromes or C9orf72 mutations.
RESUMO
Amyotrophic lateral sclerosis (ALS) can be associated with a spectrum of cognitive and behavioural symptoms, but the related patterns of focal cortical atrophy in non-demented ALS patients remain largely unknown. We enrolled 48 non-demented ALS patients and 26 healthy controls for a comprehensive neuropsychological assessment and a magnetic resonance exam. Behavioural and cognitive impairment was defined on the basis of a data-driven multi-domain approach in 21 ALS patients. Averaged cortical thickness of 74 bilateral brain regions was used as a measure of cortical atrophy. Cortical thinning in a fronto-parietal network, suggesting a disease-specific pattern of neurodegeneration, was present in all patients, independent of cognitive and behavioural status. Between-group and correlational analyses revealed that inferior frontal, temporal, cingular and insular thinning are markers for cognitive and behavioural deficits, with language impairment mainly related to left temporal pole and insular involvement. These specific correlates support the concept of a spectrum of deficits, with an overlap between the ALS cognitive phenotypes and the syndromes of frontotemporal dementia.
Assuntos
Esclerose Lateral Amiotrófica/diagnóstico por imagem , Córtex Cerebral/diagnóstico por imagem , Transtornos Cognitivos/diagnóstico por imagem , Idoso , Esclerose Lateral Amiotrófica/complicações , Esclerose Lateral Amiotrófica/patologia , Atrofia/diagnóstico por imagem , Atrofia/patologia , Córtex Cerebral/patologia , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes NeuropsicológicosRESUMO
The genetic basis combined with the sporadic occurrence of amyotrophic lateral sclerosis (ALS) suggests a role of de novo mutations in disease pathogenesis. Previous studies provided some evidence for this hypothesis; however, results were conflicting: no genes with recurrent occurring de novo mutations were identified and different pathways were postulated. In this study, we analyzed whole-exome data from 82 new patient-parents trios and combined it with the datasets of all previously published ALS trios (173 trios in total). The per patient de novo rate was not higher than expected based on the general population (P = 0.40). We showed that these mutations are not part of the previously postulated pathways, and gene-gene interaction analysis found no enrichment of interacting genes in this group (P = 0.57). Also, we were able to show that the de novo mutations in ALS patients are located in genes already prone for de novo mutations (P < 1 × 10-15 ). Although the individual effect of rare de novo mutations in specific genes could not be assessed, our results indicate that, in contrast to previous hypothesis, de novo mutations in general do not impose a major burden on ALS risk.
Assuntos
Esclerose Lateral Amiotrófica/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Mutação , Alelos , Substituição de Aminoácidos , Esclerose Lateral Amiotrófica/metabolismo , Proteína C9orf72/genética , Estudos de Casos e Controles , Bases de Dados Genéticas , Feminino , Humanos , Masculino , Taxa de Mutação , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas , Sequenciamento do Exoma , Sequenciamento Completo do GenomaRESUMO
ASAH1 gene encodes for acid ceramidase that is involved in the degradation of ceramide into sphingosine and free fatty acids within lysosomes. ASAH1 variants cause both the severe and early-onset Farber disease and rare cases of spinal muscular atrophy (SMA) with progressive myoclonic epilepsy (SMA-PME), phenotypically characterized by childhood onset of proximal muscle weakness and atrophy due to spinal motor neuron degeneration followed by occurrence of severe and intractable myoclonic seizures and death in the teenage years. We studied two subjects, a 30-year-old pregnant woman and her 17-year-old sister, affected with a very slowly progressive non-5q SMA since childhood. No history of seizures or myoclonus has been reported and EEG was unremarkable. The molecular study of ASAH1 gene showed the presence of the homozygote nucleotide variation c.124A>G (r.124a>g) that causes the amino acid substitution p.Thr42Ala. Biochemical evaluation of cultured fibroblasts showed both reduction in ceramidase activity and accumulation of ceramide compared with the normal control. This study describes for the first time the association between ASAH1 variants and an adult SMA phenotype with no myoclonic epilepsy nor death in early age, thus expanding the phenotypic spectrum of ASAH1-related SMA. ASAH1 molecular analysis should be considered in the diagnostic testing of non-5q adult SMA patients.