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BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder with a multifactorial pathogenesis. Several genetic variants increase the risk of PD and about 5-10% of cases are monogenic. This study aims to define the genetic bases and clinical features of PD in a cohort of patients from Northeastern Italy, a peculiar geographical area previously not included in genetic screenings. METHODS: Using an NGS multigenic panel, 218 PD patients were tested based on age at onset, family history and development of atypical features. RESULTS: A total of 133 genetic variants were found in 103 patients. Monogenic PD was diagnosed in 43 patients (20% of the cohort); 28 (12.8%) carried mutations in GBA1, 10 in LRRK2 (4.6%) and 5 in PRKN (2.3%). In 17% of patients the genetic defect remained of uncertain interpretation. The selection criterion "age of onset < 55 years" was a significant predictor of a positive genetic test (OR 3.8, p 0.0037). GBA1 patients showed more severe symptoms and a higher burden of motor and non-motor complications compared to negative patients (dyskinesias OR 3, sleep disturbances OR 2.8, cognitive deficits OR 3.6; p < 0.05), with greater autonomic dysfunction (COMPASS-31 score 34.1 vs 20.2, p 0.03). CONCLUSIONS: Applying simple clinical criteria for genetic testing allows to increase the probability to identify patients with monogenic PD and better allocate resources. This process is critical to widen the understanding of disease mechanisms and to increase the individuation of patients potentially benefitting from future disease-modifying therapies.
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We report a newborn patient with trichothiodystrophy-3 (TTD3) caused by a novel homozygous variant in the GTF2H5 gene. His severe phenotype included congenital ichthyosis, complex posterior cranial fossa anomaly, life-threatening infections, bilateral cryptorchidism, and, notably, a complex cardiac malformation, which is unprecedented in TTD3 patients.
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Síndromes de Tricotiodistrofia , Humanos , Recién Nacido , Masculino , Homocigoto , Fenotipo , Factores de Transcripción/genética , Síndromes de Tricotiodistrofia/genéticaRESUMEN
The extent of central nervous system involvement in Kennedy's disease (KD) relative to other motor neuron disease (MND) phenotypes still needs to be clarified. In this study, we investigated cortical and white matter (WM) MRI alterations in 25 patients with KD, compared with 24 healthy subjects, 25 patients with sporadic amyotrophic lateral sclerosis (ALS), and 35 cases with lower motor neuron-predominant disease (LMND). LMND patients were clinically differentiated into 24 fast and 11 slow progressors. Whole-brain cortical thickness, WM tract-based spatial statistics and corticospinal tract (CST) tractography analyses were performed. No significant difference in terms of cortical thickness was found between groups. ALS patients showed widespread decreased fractional anisotropy and increased mean (MD) and radial diffusivity (radD) in the CST, corpus callosum and fronto-temporal extra-motor tracts, compared with healthy controls and other patient groups. CST tractography showed significant alterations of DT MRI metrics in ALS and LMND-fast patients whereas KD and LMND-slow patients were comparable with healthy controls. Our study demonstrated the absence of WM abnormalities in patients with KD and LMND-slow, in contrast with diffuse WM damage in ALS and focal CST degeneration in LMND-fast, supporting the use of DT MRI measures as powerful tools to differentiate fast- and slow-progressing MND syndromes, including KD.
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Encéfalo/patología , Atrofia Bulboespinal Ligada al X/patología , Sustancia Blanca/patología , Adulto , Anciano , Esclerosis Amiotrófica Lateral/diagnóstico por imagen , Esclerosis Amiotrófica Lateral/patología , Encéfalo/diagnóstico por imagen , Atrofia Bulboespinal Ligada al X/diagnóstico por imagen , Imagen de Difusión Tensora/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de la Neurona Motora/diagnóstico por imagen , Enfermedad de la Neurona Motora/patología , Sustancia Blanca/diagnóstico por imagenRESUMEN
Mutations in FUS are causative for amyotrophic lateral sclerosis with a dominant mode of inheritance. In trying to model FUS-amyotrophic lateral sclerosis (ALS) in mouse it is clear that FUS is dosage-sensitive and effects arise from overexpression per se in transgenic strains. Novel models are required that maintain physiological levels of FUS expression and that recapitulate the human disease-with progressive loss of motor neurons in heterozygous animals. Here, we describe a new humanized FUS-ALS mouse with a frameshift mutation, which fulfils both criteria: the FUS Delta14 mouse. Heterozygous animals express mutant humanized FUS protein at physiological levels and have adult onset progressive motor neuron loss and denervation of neuromuscular junctions. Additionally, we generated a novel antibody to the unique human frameshift peptide epitope, allowing specific identification of mutant FUS only. Using our new FUSDelta14 ALS mouse-antibody system we show that neurodegeneration occurs in the absence of FUS protein aggregation. FUS mislocalization increases as disease progresses, and mutant FUS accumulates at the rough endoplasmic reticulum. Further, transcriptomic analyses show progressive changes in ribosomal protein levels and mitochondrial function as early disease stages are initiated. Thus, our new physiological mouse model has provided novel insight into the early pathogenesis of FUS-ALS.
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Esclerosis Amiotrófica Lateral/genética , Modelos Animales de Enfermedad , Mutación del Sistema de Lectura , Ratones , Agregación Patológica de Proteínas/genética , Proteína FUS de Unión a ARN/genética , Esclerosis Amiotrófica Lateral/metabolismo , Animales , Retículo Endoplásmico Rugoso/metabolismo , Dosificación de Gen , Perfilación de la Expresión Génica , Técnicas de Sustitución del Gen , Heterocigoto , Humanos , Mitocondrias/metabolismo , Neuronas Motoras/metabolismo , Unión Neuromuscular/metabolismo , Agregación Patológica de Proteínas/metabolismo , Proteína FUS de Unión a ARN/metabolismo , Proteínas Ribosómicas/genéticaRESUMEN
OBJECTIVE: To carry out a deep characterisation of the main androgen-responsive tissues involved in spinal and bulbar muscular atrophy (SBMA). METHODS: 73 consecutive Italian patients underwent a full clinical protocol including biochemical and hormonal analyses, genitourinary examination, bone metabolism and densitometry, cardiological evaluation and muscle pathology. RESULTS: Creatine kinase levels were slightly to markedly elevated in almost all cases (68 of the 73; 94%). 30 (41%) patients had fasting glucose above the reference limit, and many patients had total cholesterol (40; 54.7%), low-density lipoproteins cholesterol (29; 39.7%) and triglyceride (35; 48%) levels above the recommended values. Although testosterone, luteinising hormone and follicle-stimulating hormone values were generally normal, in one-third of cases we calculated an increased Androgen Sensitivity Index reflecting the presence of androgen resistance in these patients. According to the International Prostate Symptom Score (IPSS), 7/70 (10%) patients reported severe lower urinal tract symptoms (IPSS score >19), and 21/73 (30%) patients were moderately symptomatic (IPSS score from 8 to 19). In addition, 3 patients were carriers of an indwelling bladder catheter. Videourodynamic evaluation indicated that 4 of the 7 patients reporting severe urinary symptoms had an overt prostate-unrelated bladder outlet obstruction. Dual-energy X-ray absorptiometry scan data were consistent with low bone mass in 25/61 (41%) patients. Low bone mass was more frequent at the femoral than at the lumbar level. Skeletal muscle biopsy was carried out in 20 patients and myogenic changes in addition to the neurogenic atrophy were mostly observed. CONCLUSIONS: Our study provides evidence of a wide non-neural clinical phenotype in SBMA, suggesting the need for comprehensive multidisciplinary protocols for these patients.
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Atrofia Muscular Espinal/metabolismo , Atrofia Muscular Espinal/fisiopatología , Adulto , Anciano , Síndrome de Resistencia Androgénica/complicaciones , Glucemia/metabolismo , Densidad Ósea , Estudios de Casos y Controles , Creatina Quinasa/sangre , Humanos , Italia , Lípidos/sangre , Masculino , Persona de Mediana Edad , Músculo Esquelético/patología , Atrofia Muscular Espinal/complicaciones , Atrofia Muscular Espinal/patología , Fenotipo , Enfermedades Urológicas/complicacionesRESUMEN
The Spinal and Bulbar Muscular Atrophy Functional Rating Scale (SBMAFRS) is an established rating instrument used to assess the functional status of patients with Spinal and Bulbar Muscular Atrophy (SBMA). Our aim was to validate an Italian version of the scale. We administered the SBMAFRS to sixty SBMA patients during routine follow-up of clinical evaluations. To estimate the test stability, the scale was re-administered to a subset of 39 randomly selected patients after 8 weeks. The patients underwent clinical evaluation including 6-min walk. Psychometric analysis included reliability assessment and factorial analysis. To evaluate convergent validity, correlations between SBMAFRS items and muscular force assessed by manual testing, ALSFRS total score and subscales scores, and forced vital capacity, were performed. Internal consistency as measured by Cronbach's alpha (total scale 0.85) was high. Test-retest reliability assessed by Spearman's rho was also high. Principal component analysis with varimax rotation yielded a four-factor solution accounting for approximately 79 % of the variance. The scale total score and subscales score were strongly correlated with respective items and subscores of the ALSFRS, with respiratory function and with the 6-min walk test. In conclusion, we performed an Italian validation of the only existing disease-specific Functional Rating Scale for SBMA patients. This scale will be a useful tool not only in the clinical practice but also as an outcome measure in upcoming clinical trials.
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Prueba de Esfuerzo/normas , Trastornos Musculares Atróficos/diagnóstico , Psicometría/instrumentación , Índice de Severidad de la Enfermedad , Adulto , Anciano , Humanos , Italia , Persona de Mediana Edad , Reproducibilidad de los ResultadosRESUMEN
Background/Objectives: Primary Familial Brain Calcification is a rare neurodegenerative disorder of adulthood characterized by calcium deposition in the basal ganglia and other brain areas; the main clinical manifestations include movement disorders, mainly parkinsonism. Non-motor symptoms are not well defined in PFBC. This work aims at defining the burden of non-motor symptoms in PFBC. Methods: A clinical, genetic and neuropsychological evaluation of a cohort of PFBC patients, COMPASS-31 scale administration. Results: A total of 50 PFBC patients were recruited; in 25, the genetic test was negative; 10 carried mutations in SLC20A2 gene, 8 in MYORG, 3 in PDGFB, 1 in PDGFRB, 2 in JAM2 (single mutations), and one test is still ongoing. The main motor manifestation was parkinsonism. Headache was reported in 26% of subjects (especially in PDGFB mutation carriers), anxiety or depression in 62%, psychosis or hallucinations in 10-12%, sleep disturbances in 34%; 14% of patients reported hyposmia, 32% constipation, and 34% urinary disturbances. A neuropsychological assessment revealed cognitive involvement in 56% (sparing memory functions, to some extent). The COMPASS-31 mean score was 20.6, with higher sub-scores in orthostatic intolerance and gastrointestinal problems. MYORG patients and subjects with cognitive decline tended to have higher scores and bladder involvement compared to other groups. Conclusions: The presence of non-motor symptoms is frequent in PFBC and should be systematically assessed to better meet patients' needs.
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Serum creatinine has been indicated as a potential marker of motor function in SBMA and results form previous longitudinal studies pointed to its decline over time. This is a longitudinal retrospective study investigating creatinine changes over a 36-month-period in 73 patients with SBMA. Severity and progression of the disease was assessed according to serum creatine kinase (CK) values, manual muscle testing (MMT), SBMA functional rating scale (SBMAFRS) score, 6-min-walk test (6MWT) value, and spirometry (forced vital capacity, fVC%) obtained at the baseline and at each of the annual follow-up visits. Baseline serum creatinine concentrations positively correlated with 6MWT, the MMT megascore score of both the upper (ULM) and lower (LLM) limbs and SBMAFRS. No correlation was found with CK or fVC% values. Similar correlation results were achieved at all the subsequent time points. Longitudinal assessments conducted by the generalized estimating equations (GEE) method returned significant changes for SBMAFRS (- 1.41 points per year, p < 0.001), ULM and LLM (- 0.69, p = 0.01; and - 1.07, p < 0.001, respectively), 6MWT (- 47 m, p < 0.001) but not for creatinine (- 0.82, p > 0.05). We also observed that creatinine levels at baseline did not correlate with changes in the other measures from baseline at each annual visit. Our data do not support a role for serum creatinine as sensitive biomarker of disease progression, and possibily prognosis, in SBMA.
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Atrofia Bulboespinal Ligada al X , Atrofia Muscular Espinal , Humanos , Creatinina , Estudios Retrospectivos , Biomarcadores , Progresión de la EnfermedadRESUMEN
Missense variants in RNA-binding proteins (RBPs) underlie a spectrum of disease phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy. Here, we present ten independent families with a severe, progressive muscular dystrophy, reminiscent of oculopharyngeal muscular dystrophy (OPMD) but of much earlier onset, caused by heterozygous frameshift variants in the RBP hnRNPA2/B1. All disease-causing frameshift mutations abolish the native stop codon and extend the reading frame, creating novel transcripts that escape nonsense-mediated decay and are translated to produce hnRNPA2/B1 protein with the same neomorphic C-terminal sequence. In contrast to previously reported disease-causing missense variants in HNRNPA2B1, these frameshift variants do not increase the propensity of hnRNPA2 protein to fibrillize. Rather, the frameshift variants have reduced affinity for the nuclear import receptor karyopherin ß2, resulting in cytoplasmic accumulation of hnRNPA2 protein in cells and in animal models that recapitulate the human pathology. Thus, we expand the phenotypes associated with HNRNPA2B1 to include an early-onset form of OPMD caused by frameshift variants that alter its nucleocytoplasmic transport dynamics.
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Esclerosis Amiotrófica Lateral , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/genética , Distrofia Muscular Oculofaríngea , Esclerosis Amiotrófica Lateral/genética , Animales , Mutación del Sistema de Lectura , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/metabolismo , Heterocigoto , Humanos , Distrofia Muscular Oculofaríngea/genéticaRESUMEN
The present study aims at investigating the association between common and rare variants of mitochondrial DNA (mtDNA), and increased risk of schizophrenia (SZ) and bipolar disorder (BPD) in a cohort of patients originating from the same Italian population. The distribution of the major European mtDNA haplogroups was determined in 89 patients and their frequencies did not significantly differ from those observed in the Italian population. Moreover, 27 patients with high probability of having inherited the disease from the maternal side were selected for whole mitochondrial genome sequencing to investigate the possible presence of causative point mutations. Overall, 213 known variants and 2 novel changes were identified, but none of them was predicted to have functional effects. Hence, none of the sequence changes we found in our sample could explain the maternal component of SZ and BPD predisposition.
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Trastorno Bipolar/genética , ADN Mitocondrial , Genoma Mitocondrial , Esquizofrenia/genética , Estudios de Cohortes , Predisposición Genética a la Enfermedad , Humanos , Filogenia , Mutación PuntualRESUMEN
Epidermolytic Ichthyosis is a rare genodermatosis related to point mutations affecting the genes encoding for keratin 1 or keratin 10. We report a case of Epidermolytic Ichthyosis in a newborn with a novel mutation (c.1433A>G) of KRT1 gene.
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Multiple acyl-CoA dehydrogenase deficiency, or glutaric aciduria type II, is an autosomal recessive disorder of fatty acid oxidation due to defects in electron transfer flavoprotein (ETF) encoded by ETFA and ETFB, or in electron transfer flavoprotein dehydrogenase (ETFDH) encoded by the ETFDH gene. The disease may present as a severe neonatal onset form and a mild late-onset form which is heterogeneous for the age at onset and clinical presentation. We describe two patients in their seventies, referred for a nonspecific myopathy, which resulted to manifest carriers of ETFDH gene mutation. Treatment with riboflavin and L-carnitine improved the clinical picture and the biochemical profile. This condition should be included in the differential diagnosis of myopathies even at an old age.
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Envejecimiento , Deficiencia Múltiple de Acil Coenzima A Deshidrogenasa/diagnóstico , Anciano , Diagnóstico Diferencial , Femenino , Heterocigoto , Humanos , Masculino , Enfermedades Musculares/diagnósticoRESUMEN
OBJECTIVE: To test efficacy and tolerability of edaravone in patients with amyotrophic lateral sclerosis (ALS) originating from North-Eastern Italy. METHODS: We compared 3-month and 6-month changes of ALSFRS-R score, FVC value, and MRC score of 31 consecutive patients with ALS who were treated with edaravone to those of 50 historical ALS patients who were not treated with edaravone. RESULTS: No significant difference for any functional measures was found between the two groups at each time point as compared to baseline. In treated patients, we also observed creatinine values to significantly decrease at 3 and 6â¯months (pâ¯=â¯0.0078 and 0.030, respectively) and ALSAQ5 score to significantly increase (i.e. worse quality of life) at 3 and 6â¯months (pâ¯=â¯0.0005 and 0.0078, respectively). Yet, we observed an overall safety of the medication over the 6-month period of observation. CONCLUSIONS: Our retrospective study suggests no benefit of edaravone on ALS in populations of Caucasian ancestry.
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Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Edaravona/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Edaravona/efectos adversos , Femenino , Humanos , Italia , Masculino , Persona de Mediana Edad , Fármacos Neuroprotectores/efectos adversos , Calidad de Vida , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: To determine whether blood biomarkers of neuronal damage (neurofilament light chain [NfL]), muscle damage (creatine kinase [CK]), and muscle mass (creatinine) are altered in spinal and bulbar muscular atrophy (SBMA) and can be used as biomarkers for disease severity. METHODS: In this multicenter longitudinal prospective study, plasma and serum were collected from 2 cohorts of patients with SBMA in London, United Kingdom (n = 50), and Padova, Italy (n = 43), along with disease (amyotrophic lateral sclerosis [ALS]) and healthy controls, and levels of plasma and serum NfL, CK, and creatinine were measured. Disease severity was assessed by the SBMA Functional Rating Scale and the Adult Myopathy Assessment Tool at baseline and 12 and 24 months. RESULTS: Blood NfL concentrations were increased in ALS samples, but were unchanged in both SBMA cohorts, were stable after 12 and 24 months, and were not correlated with clinical severity. Normal NfL levels were also found in a well-established mouse model of SBMA. Conversely, CK concentrations were significantly raised in SBMA compared with ALS samples, and were not correlated to the clinical measures. Creatinine concentrations were significantly reduced in SBMA, and strongly and significantly correlated with disease severity. CONCLUSIONS: While muscle damage and muscle mass biomarkers are abnormal in SBMA, axonal damage markers are unchanged, highlighting the relevant primary role of skeletal muscle in disease pathogenesis. Creatinine, but not CK, correlated with disease severity, confirming its role as a valuable biomarker in SBMA.
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Atrofia Bulboespinal Ligada al X/sangre , Creatina Quinasa/sangre , Creatinina/sangre , Proteínas de Neurofilamentos/sangre , Anciano , Esclerosis Amiotrófica Lateral/sangre , Animales , Biomarcadores/sangre , Atrofia Bulboespinal Ligada al X/fisiopatología , Modelos Animales de Enfermedad , Femenino , Humanos , Estudios Longitudinales , Masculino , Ratones , Persona de Mediana Edad , Estudios Prospectivos , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: To identify and characterize patients with calsequestrin 1 (CASQ1)-related myopathy. METHODS: Patients selected according to histopathologic features underwent CASQ1 genetic screening. CASQ1-mutated patients were clinically evaluated and underwent muscle MRI. Vacuole morphology and vacuolated fiber type were characterized. RESULTS: Twenty-two CASQ1-mutated patients (12 families) were identified, 21 sharing the previously described founder mutation (p.Asp244Gly) and 1 with the p.Gly103Asp mutation. Patients usually presented in the sixth decade with exercise intolerance and myalgias and later developed mild to moderate, slowly progressive proximal weakness with quadriceps atrophy and scapular winging. Muscle MRI (n = 11) showed a recurrent fibrofatty substitution pattern. Three patients presented subclinical cardiac abnormalities. Muscle histopathology in patients with p.Asp244Gly showed vacuoles in type II fibers appearing empty in hematoxylin-eosin, Gomori, and nicotinamide adenine dinucleotide (NADH) tetrazolium reductase stains but strongly positive for sarcoplasmic reticulum proteins. The muscle histopathology of p.Gly103Asp mutation was different, showing also NADH-positive accumulation consistent with tubular aggregates. CONCLUSIONS: We report the clinical and molecular details of the largest cohort of CASQ1-mutated patients. A possible heart involvement is presented, further expanding the phenotype of the disease. One mutation is common due to a founder effect, but other mutations are possible. Because of a paucity of symptoms, it is likely that CASQ1 mutations may remain undiagnosed if a muscle biopsy is not performed.
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Proteínas de Unión al Calcio/genética , Enfermedades por Almacenamiento Lisosomal/genética , Proteínas Mitocondriales/genética , Enfermedades Musculares/genética , Mutación/genética , Adolescente , Adulto , Anciano , Calcio/metabolismo , Calsecuestrina , Salud de la Familia , Femenino , Pruebas Genéticas , Humanos , Enfermedades por Almacenamiento Lisosomal/diagnóstico por imagen , Enfermedades por Almacenamiento Lisosomal/fisiopatología , Imagen por Resonancia Magnética , Masculino , Microscopía Electrónica de Transmisión , Persona de Mediana Edad , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/metabolismo , Músculo Esquelético/ultraestructura , Enfermedades Musculares/diagnóstico por imagen , Enfermedades Musculares/fisiopatología , NAD/metabolismo , Adulto JovenRESUMEN
OBJECTIVE: To determine the clinical spectrum of limb-girdle muscular dystrophy 2E (LGMD2E) and to investigate whether genetic or biochemical features can predict the phenotype of the disease. METHODS: All LGMD2E patients followed in participating centers were included. A specific clinical protocol was created, including quantitative evaluation of motor, respiratory, and cardiac function. Phenotype was defined as severe or mild if the age at loss of ambulation occurred before or after 18 years. Molecular analysis of SGCB gene and biochemical features of muscle biopsies were reviewed. RESULTS: Thirty-two patients were included (16 male, 16 female; age 7-67 years; 15 severe, 12 mild, and 5 unknown). Neurologic examination showed proximal muscle weakness in all patients, but distal involvement was also observed in patients with severe disease early in the disease course. Cardiac involvement was observed in 20 patients (63%) even before overt muscle involvement. Six patients had restrictive respiratory insufficiency requiring assisted ventilation (19%). Seventeen different mutations were identified, and 3 were recurrent. The c.377_384dup (13 alleles) was associated with the severe form, the c.-22_10dup (10) with the milder form, and the c.341C>T (9) with both. The entire sarcoglycan complex was undetectable by muscle immunohistochemistry or Western blot in 9/10 severe cases and reduced in 7/7 mild cases. The residual amount of sarcoglycan in muscle resulted a predictor of age at loss of ambulation. CONCLUSIONS: This study expands the spectrum of phenotype in ß-sarcoglycanopathy and provides strong evidence that severity of clinical involvement may be predicted by SGCB gene mutation and sarcoglycan protein expression.
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Fenotipo , Sarcoglicanopatías/fisiopatología , Sarcoglicanos/metabolismo , Adolescente , Adulto , Factores de Edad , Anciano , Niño , Consanguinidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Pronóstico , Sarcoglicanopatías/genética , Sarcoglicanopatías/metabolismo , Sarcoglicanos/genética , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
Amyotrophic lateral sclerosis (ALS) is as an adult-onset neurodegenerative disorder involving both upper and lower motor neurons. About 5% of all cases exhibit signs of frontotemporal degeneration (FTD). We established the mutation frequency of C9ORF72, SOD1, TARDBP, and FUS genes in 307 patients with sporadic ALS, 46 patients with familial ALS (FALS), and 73 patients affected with FTD, all originating from the northeastern part of Italy. C9ORF72 pathogenic expansion was found on 22% of familial ALS, 5% of sporadic ALS, and 14% of FTD patients, resulting the most frequently genetic determinant in our cohort. Sequence analysis of ALS cohort identified 2 novel variants on SOD1 (p.Glu41Gly) and FUS (p.Gly496Glyfs*31). Interestingly, the single base deletion on FUS was observed in an homozygous state, suggesting a recessive pattern of inheritance. No point mutations were identified on FTD cohort. Although useful to direct genetic testing, this study results expand the current knowledge of ALS genetics.
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Esclerosis Amiotrófica Lateral/genética , Tasa de Mutación , Mutación , Proteína FUS de Unión a ARN/genética , Superóxido Dismutasa/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Proteína C9orf72 , Estudios de Cohortes , Proteínas de Unión al ADN/genética , Femenino , Degeneración Lobar Frontotemporal/genética , Eliminación de Gen , Homocigoto , Humanos , Italia , Masculino , Persona de Mediana Edad , Proteínas/genética , Superóxido Dismutasa-1 , Adulto JovenRESUMEN
Mutations in the prion-like domain (PrLD) of hnRNPA1 and A2/B1 genes were recently identified in 2 families with inclusion body myopathy associated with Paget disease of bone, frontotemporal dementia (FTD), and amyotrophic lateral sclerosis, and in ALS patients. These mutations were shown to increase the propensity of hnRNPA1 and A2/B1 proteins, which are TDP-43-binding partners, to self-aggregate. hnRNPA3 protein contains a similar PrLD and was recently described in the p62-positive/TDP-43-negative inclusions in affected tissues of C9orf72-mutated ALS/FTD patients. We screened hnRNPA1, A2/B1, and A3 genes in a cohort of 113 familial ALS (FALS) individuals without mutations in other known ALS-causative genes. We extended our analysis to 108 FALS with mutations in other ALS-associated genes and to 622 sporadic cases by screening specifically the PrLDs of hnRNPA1, A2/B1, and A3. We failed to find variants in each cohort. Our results suggest that mutations in hnRNPA1, A2/B1, and A3 genes are a rare finding in ALS.
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Esclerosis Amiotrófica Lateral/genética , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/genética , Estudios de Cohortes , Análisis Mutacional de ADN , Proteínas de Unión al ADN , Salud de la Familia , Femenino , Ribonucleoproteína Nuclear Heterogénea A1 , Humanos , MasculinoRESUMEN
Mutations in the profilin 1 (PFN1) gene, encoding a protein regulating filamentous actin growth through its binding to monomeric G-actin, have been recently identified in familial amyotrophic lateral sclerosis (ALS). Functional studies performed on ALS-associated PFN1 mutants demonstrated aggregation propensity, alterations in growth cone, and cytoskeletal dynamics. Previous screening of PFN1 gene in sporadic ALS (SALS) cases led to the identification of the p.E117G mutation, which is likely to represent a less pathogenic variant according to both frequency data in control subjects and cases, and functional experiments. To determine the effective contribution of PFN1 mutations in SALS, we analyzed a large cohort of 1168 Italian SALS patients and also included 203 frontotemporal dementia (FTD) cases because of the great overlap between these 2 neurodegenerative diseases. We detected the p.E117G variant in 1 SALS patient and the novel synonymous change p.G15G in another patient, but none in a panel of 1512 control subjects. Our results suggest that PFN1 mutations in sporadic ALS and in FTD are rare, at least in the Italian population.