RESUMEN
OBJECTIVE: The aim of this study was to provide an overview of the clinical phenotypes associated with 4 SMN2 copies. METHODS: Clinical phenotypes were analyzed in all the patients with 4 SMN2 copies as part of a nationwide effort including all the Italian pediatric and adult reference centers for spinal muscular atrophy (SMA). RESULTS: The cohort includes 169 patients (102 men and 67 women) with confirmed 4 SMN2 copies (mean age at last follow-up = 36.9 ± 19 years). Six of the 169 patients were presymptomatic, 8 were classified as type II, 145 as type III (38 type IIIA and 107 type IIIB), and 8 as type IV. The remaining 2 patients were asymptomatic adults identified because of a familial case. The cross-sectional functional data showed a reduction of scores with increasing age. Over 35% of the type III and 25% of the type IV lost ambulation (mean age = 26.8 years ± 16.3 SD). The risk of loss of ambulation was significantly associated with SMA type (p < 0.0001), with patients with IIIB and IV less likely to lose ambulation compared to type IIIA. There was an overall gender effect with a smaller number of women and a lower risk for women to lose ambulation. This was significant in the adult (p = 0.009) but not in the pediatric cohort (p = 0.43). INTERPRETATION: Our results expand the existing literature on natural history of 4 SMN2 copies confirming the variability of phenotypes in untreated patients, ranging from type II to type IV and an overall reduction of functional scores with increasing age. ANN NEUROL 2023;94:1126-1135.
Asunto(s)
Atrofia Muscular Espinal , Masculino , Adulto , Niño , Humanos , Femenino , Adolescente , Adulto Joven , Persona de Mediana Edad , Estudios Transversales , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/genética , Fenotipo , Caminata , Proteína 1 para la Supervivencia de la Neurona Motora/genética , Proteína 2 para la Supervivencia de la Neurona Motora/genéticaRESUMEN
Neonatal screening for SMA has allowed the identification of infants who may present with early clinical signs. Our aim was to establish whether the presence and the severity of early clinical signs have an effect on the development of motor milestones. Infants identified through newborn screening were prospectively assessed using a structured neonatal neurological examination and an additional module developed for the assessment of floppy infants. As part of the follow-up, all infants were assessed using the HINE-2 to establish developmental milestones. Only infants with at least 24 months of follow-up were included. Normal early neurological examination (n = 11) was associated with independent walking before the age of 18 months while infants with early clinical signs of SMA (n = 4) did not achieve ambulation (duration follow-up 33.2 months). Paucisymptomatic patients (n = 3) achieved ambulation, one before the age of 18 months and the other 2 between 22 and 24 months. Conclusion: Our findings suggest that early clinical signs may contribute to predict motor milestones development. What is Known: ⢠There is increasing evidence of heterogeneity among the SMA newborns identified via NBS. ⢠The proposed nosology describes a clinically silent disease, an intermediate category ('paucisymptomatic') and 'symptomatic SMA'. What is New: ⢠The presence of minimal clinical signs at birth does not prevent the possibility to achieve independent walking but this may occur with some delay. ⢠The combination of genotype at SMN locus and clinical evaluation may better predict the possibility to achieve milestones.
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Tamizaje Neonatal , Examen Neurológico , Humanos , Tamizaje Neonatal/métodos , Recién Nacido , Femenino , Masculino , Examen Neurológico/métodos , Lactante , Estudios Prospectivos , Estudios de Seguimiento , Preescolar , Desarrollo Infantil/fisiologíaRESUMEN
BACKGROUND: Spinal muscular atrophy (SMA) is due to the homozygous absence of SMN1 in around 97% of patients, independent of the severity (classically ranked into types I-III). The high genetic homogeneity, coupled with the excellent results of presymptomatic treatments of patients with each of the three disease-modifying therapies available, makes SMA one of the golden candidates to genetic newborn screening (NBS) (SMA-NBS). The implementation of SMA in NBS national programmes occurring in some countries is an arising new issue that the scientific community has to address. We report here the results of the first Italian SMA-NBS project and provide some proposals for updating the current molecular diagnostic scenario. METHODS: The screening test was performed by an in-house-developed qPCR assay, amplifying SMN1 and SMN2. Molecular prognosis was assessed on fresh blood samples. RESULTS: We found 15 patients/90885 newborns (incidence 1:6059) having the following SMN2 genotypes: 1 (one patient), 2 (eight patients), 2+c.859G>C variant (one patient), 3 (three patients), 4 (one patient) or 6 copies (one patient). Six patients (40%) showed signs suggestive of SMA at birth. We also discuss some unusual cases we found. CONCLUSION: The molecular diagnosis of SMA needs to adapt to the new era of the disease with specific guidelines and standard operating procedures. In detail, SMA diagnosis should be felt as a true medical urgency due to therapeutic implications; SMN2 copy assessment needs to be standardised; commercially available tests need to be improved for higher SMN2 copies determination; and the SMN2 splicing-modifier variants should be routinely tested in SMA-NBS.
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Atrofia Muscular Espinal , Tamizaje Neonatal , Humanos , Recién Nacido , Proyectos Piloto , Tamizaje Neonatal/métodos , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/genética , Genotipo , ItaliaRESUMEN
BACKGROUND: We report the 4-year follow-up in type I patients treated with nusinersen and the changes in motor, respiratory and bulbar function in relation to subtype, age and SMN2 copy number. METHODS: The study included SMA 1 patients with at least one assessment after 12, 24 and 48 months from the first dose of nusinersen. The assessments used were Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and the Hammersmith Infant Neurological Examination (HINE-II). RESULTS: Forty-eight patients, with ages ranging from 7 days to 12 years (mean 3.3 years, SD 3.6 years) were included in the study. The CHOP INTEND and HINE-II scores significantly increased between baseline and 48 months (p < 0.001). When age at starting treatment subgroups (<210 days, <2 years, 2-4 years, 5-11 years, ≥12 years) were considered, the CHOP INTEND increased significantly in patients younger than 4 years at treatment, while the HINE-2 increased significantly in patients younger than 2 years at treatment. In a mixed-model analysis, age, nutritional and respiratory status were predictive of changes on both scales while SMN2 copy number and decimal classification were not. CONCLUSIONS: Our results confirm the safety profile previously reported and support the durability of the efficacy of nusinersen at 4 years with an overall stability or mild improvement and no evidence of deterioration over a long period of time.
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Atrofia Muscular Espinal , Atrofias Musculares Espinales de la Infancia , Niño , Lactante , Humanos , Recién Nacido , Atrofias Musculares Espinales de la Infancia/tratamiento farmacológico , Estudios de Seguimiento , Oligonucleótidos/uso terapéutico , Examen Neurológico , Atrofia Muscular Espinal/tratamiento farmacológicoRESUMEN
BACKGROUND: Natural history of spinal muscular atrophy (SMA) in adult age has not been fully elucidated yet, including factors predicting disease progression and response to treatments. Aim of this retrospective, cross-sectional study, is to investigate motor function across different ages, disease patterns and gender in adult SMA untreated patients. METHODS: Inclusion criteria were as follows: (1) clinical and molecular diagnosis of SMA2, SMA3 or SMA4 and (2) clinical assessments performed in adult age (>18 years). RESULTS: We included 64 (38.8%) females and 101 (61.2%) males (p=0.0025), among which 21 (12.7%) SMA2, 141 (85.5%) SMA3 and 3 (1.8%) SMA4. Ratio of sitters/walkers within the SMA3 subgroup was significantly (p=0.016) higher in males (46/38) than in females (19/38). Median age at onset was significantly (p=0.0071) earlier in females (3 years; range 0-16) than in males (4 years; range 0.3-28), especially in patients carrying 4 SMN2 copies. Median Hammersmith Functional Rating Scale Expanded scores were significantly (p=0.0040) lower in males (16, range 0-64) than in females (40, range 0-62); median revised upper limb module scores were not significantly (p=0.059) different between males (24, 0-38) and females (33, range 0-38), although a trend towards worse performance in males was observed. In SMA3 patients carrying three or four SMN2 copies, an effect of female sex in prolonging ambulation was statistically significant (p=0.034). CONCLUSIONS: Our data showed a relevant gender effect on SMA motor function with higher disease severity in males especially in the young adult age and in SMA3 patients.
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Atrofia Muscular Espinal , Atrofias Musculares Espinales de la Infancia , Adulto Joven , Masculino , Humanos , Femenino , Preescolar , Adolescente , Atrofias Musculares Espinales de la Infancia/epidemiología , Atrofias Musculares Espinales de la Infancia/genética , Atrofias Musculares Espinales de la Infancia/tratamiento farmacológico , Estudios Transversales , Estudios Retrospectivos , Atrofia Muscular Espinal/epidemiología , Atrofia Muscular Espinal/genética , Progresión de la EnfermedadRESUMEN
The possibility to identify patients with spinal muscular atrophy through neonatal screenings has highlighted the need for clinical assessments that may systematically evaluate the possible presence of early neurological signs. The aim of this study was to use the Hammersmith Neonatal Neurological Examination (HNNE) and a module specifically designed for floppy infants to assess the possible variability of neurological findings in infants identified through neonatal screening. The infants included in this study were identified as part of a pilot study exploring neonatal screening in two Italian regions. A neurological examination was performed using the HNNE and an additional module developed for the assessment of floppy infants. Seventeen infants were identified through the screening. One patient had 1 SMN2 copy, 9 had 2 copies, 3 had 3, and 4 had more than 3 copies. Nine of the 17 infants (53%) had completely normal results on both scales, 3 had minimal signs, and the other 5 had more obvious clinical signs. The number of SMN2 copies was related to the presence of abnormal neurological signs (p = 0.036) but two SMN2 copies were associated with variable clinical signs as they were found in some infants with respectively normal examination or obvious severe early signs. CONCLUSIONS: Our results suggest that the combination of both scales increases the possibility to detect neonatal neurological signs and to define different early patterns of involvement also identifying paucisymptomatic patients. WHAT IS KNOWN: ⢠The use of new therapeutic options in presymptomatic SMA patients leads to a dramatic reduction of the onset and severity of the diesease. ⢠The already existing tools commonly used in Type I SMA (HINE and CHOP-intend) may not be suitable to identify minor neurological signs in the neonatal period. WHAT IS NEW: ⢠Combining the HNNE and the floppy infant module, we were able to identify early neurological signs in SMA infants identified through newborn screening and may help to predict the individual therapeutic outcome of these patients. ⢠Iinfants with 2 SMN2 copies identified through the screening had a more variable neonatal examination compared to those with three or more copies, in agreement with similar findings in older infants.
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Atrofia Muscular Espinal , Tamizaje Neonatal , Anciano , Humanos , Lactante , Recién Nacido , Atrofia Muscular Espinal/diagnóstico , Tamizaje Neonatal/métodos , Examen Neurológico , Proyectos PilotoRESUMEN
OBJECTIVE: The aim of the study was to report 12-month changes after treatment with nusinersen in a cohort of 85 type I spinal muscular atrophy patients of ages ranging from 2 months to 15 years and 11 months. METHODS: All patients were assessed using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and the Hammersmith Infant Neurological Examination-Section 2 (HINE-2). RESULTS: Two of the 85 patients had 1 SMN2 copy, 61 had 2 copies, and 18 had 3 copies. In 4 patients the SMN2 copy number was not available. At baseline, the mean CHOP INTEND scores ranged between 0 and 52 (mean = 15.66, standard deviation [SD] = ±13.48), and the mean HINE-2 score was between 0 and 5 (mean = 0.69, SD = ±1.23). There was a difference between baseline and the 12-month scores on both the CHOP INTEND and the HINE-2 for the whole group (p < 0.001), the subgroups with 2 SMN2 copies (p < 0.001), and those with 3 SMN2 copies (p < 0.001). The difference was found not only in patients younger than 210 days at baseline (p < 0.001) but also in those younger than 5 years on the CHOP INTEND and younger than 2 years on the HINE-2. INTERPRETATION: Our results, expanding the age range and the severity of type I patients treated with nusinersen over 1 year, provide additional data on the range of efficacy of the drug that will be helpful in making an informed decision on whether to start treatment in patients of different ages and severity. ANN NEUROL 2019;86:443-451.
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Oligonucleótidos/uso terapéutico , Atrofias Musculares Espinales de la Infancia/tratamiento farmacológico , Adolescente , Niño , Preescolar , Variaciones en el Número de Copia de ADN/genética , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Índice de Severidad de la Enfermedad , Atrofias Musculares Espinales de la Infancia/genética , Proteína 2 para la Supervivencia de la Neurona Motora/genética , Resultado del TratamientoRESUMEN
BACKGROUND: Danon disease (OMIM 300257) is an X-linked lysosomal storage disorder, characterized by hypertrophic cardiomyopathy (HCM), skeletal myopathy, variable intellectual disability, and other minor clinical features. This condition accounts for ~ 4% of HCM patients, with a more severe and early onset phenotype in males, causing sudden cardiac death (SCD) in the first three decades of life. Genetic alterations in the LAMP2 gene are the main cause of this inherited fatal condition. Up to date, more than 100 different pathogenic variants have been reported in the literature. However, the majority of cases are misdiagnosed as HCM or have a delay in the diagnosis. CASE PRESENTATION: Here, we describe a young boy with an early diagnosis of HCM. After 2 episodes of ventricular fibrillation within 2 years, genetic testing identified a novel LAMP2 pathogenic variant. Subsequently, further clinical evaluations showing muscle weakness and mild intellectual disability confirmed the diagnosis of Danon disease. CONCLUSIONS: This report highlights the role of genetic testing in the rapid diagnosis of Danon disease, underscoring the need to routinely consider the inclusion of LAMP2 gene in the genetic screening for HCM, since an early diagnosis of Danon disease in patients with a phenotype mimicking HCM is essential to plan appropriate treatment, ie cardiac transplantation.
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Cardiomiopatía Hipertrófica/diagnóstico , Análisis Mutacional de ADN , Pruebas Genéticas , Enfermedad por Depósito de Glucógeno de Tipo IIb/diagnóstico , Proteína 2 de la Membrana Asociada a los Lisosomas/genética , Mutación , Adolescente , Errores Diagnósticos , Diagnóstico Precoz , Predisposición Genética a la Enfermedad , Enfermedad por Depósito de Glucógeno de Tipo IIb/diagnóstico por imagen , Enfermedad por Depósito de Glucógeno de Tipo IIb/genética , Humanos , Masculino , Fenotipo , Valor Predictivo de las PruebasRESUMEN
BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder, due to the loss of function of the survival motor neuron (SMN1) gene. The first treatment for the condition, recently approved, is based on the reduction of exon 7 skipping in mRNAs produced by a highly homologous gene (SMN2). The primary objective of the present study was to evaluate the applicability of the dosage of SMN gene produts in blood, as biomarker for SMA, and the safety of oral salbutamol, a beta2-adrenergic agonist modulating SMN2 levels. METHODS: We have performed a 1-year multicentre, double-blind, placebo-controlled study with salbutamol in 45 adult patients with SMA. Patients assumed 4 mg of salbutamol or placebo/three times a day. Molecular tests were SMN2 copy number, SMN transcript and protein levels. We have also explored the clinical effect, by the outcome measures available at the time of study design. RESULTS: Thirty-six patients completed the study. Salbutamol was safe and well tolerated. We observed a significant and progressive increase in SMN2 full-length levels in peripheral blood of the salbutamol-treated patients (p<0.00001). The exploratory analysis of motor function showed an improvement in most patients. CONCLUSIONS: Our data demonstrate safety and molecular efficacy of salbutamol. We provide the first longitudinal evaluation of SMN levels (both transcripts and protein) in placebo and in response to a compound modulating the gene expression: SMN transcript dosage in peripheral blood is reliable and may be used as pharmacodynamic marker in clinical trials with systemic compounds modifying SMN2levels. TRIAL REGISTRATION NUMBER: EudraCT no. 2007-001088-32.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2/uso terapéutico , Albuterol/uso terapéutico , Biomarcadores , Atrofia Muscular Espinal/tratamiento farmacológico , Atrofia Muscular Espinal/genética , Proteína 1 para la Supervivencia de la Neurona Motora/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/metabolismo , Proteína 1 para la Supervivencia de la Neurona Motora/metabolismo , Proteína 2 para la Supervivencia de la Neurona Motora/genética , Proteína 2 para la Supervivencia de la Neurona Motora/metabolismo , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: Mild cognitive impairment (MCI) is a condition intermediate between physiological brain aging and dementia. Amnesic-MCI (aMCI) subjects progress to dementia (typically to Alzheimer-Dementia = AD) at an annual rate which is 20 times higher than that of cognitively intact elderly. The present study aims to investigate whether EEG network Small World properties (SW) combined with Apo-E genotyping, could reliably discriminate aMCI subjects who will convert to AD after approximately a year. METHODS: 145 aMCI subjects were divided into two sub-groups and, according to the clinical follow-up, were classified as Converted to AD (C-MCI, 71) or Stable (S-MCI, 74). RESULTS: Results showed significant differences in SW in delta, alpha1, alpha2, beta2, gamma bands, with C-MCI in the baseline similar to AD. Receiver Operating Characteristic(ROC) curve, based on a first-order polynomial regression of SW, showed 57% sensitivity, 66% specificity and 61% accuracy(area under the curve: AUC=0.64). In 97 out of 145 MCI, Apo-E allele testing was also available. Combining this genetic risk factor with Small Word EEG, results showed: 96.7% sensitivity, 86% specificity and 91.7% accuracy(AUC=0.97). Moreover, using only the Small World values in these 97 subjects, the ROC showed an AUC of 0.63; the resulting classifier presented 50% sensitivity, 69% specificity and 59.6% accuracy. When different types of EEG analysis (power density spectrum) were tested, the accuracy levels were lower (68.86%). INTERPRETATION: Concluding, this innovative EEG analysis, in combination with a genetic test (both low-cost and widely available), could evaluate on an individual basis with great precision the risk of MCI progression. This evaluation could then be used to screen large populations and quickly identify aMCI in a prodromal stage of dementia. Ann Neurol 2018 Ann Neurol 2018;84:302-314.
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Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/fisiopatología , Apolipoproteínas E/genética , Encéfalo/fisiopatología , Disfunción Cognitiva/genética , Disfunción Cognitiva/fisiopatología , Electroencefalografía/métodos , Anciano , Enfermedad de Alzheimer/diagnóstico , Disfunción Cognitiva/diagnóstico , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Marcadores Genéticos/genética , Humanos , Masculino , Red Nerviosa/fisiopatología , Valor Predictivo de las PruebasRESUMEN
Alternating hemiplegia of childhood is an early onset neurodevelopmental disorder characterized by paroxystic episodes of alternating hemiplegia, variable degrees of intellectual disability, and dystonic movements. The main causative gene, ATP1A3, is also responsible for other neurodevelopmental disorders. While the neurological profile of this condition is well defined, the question whether a recognizable pattern of physical anomalies does exist in this condition is still open. We performed a morphological evaluation of 30 patients at different ages. All patients were evaluated independently by each author and evaluation sheets were compared, discussed, and agreed afterwards. This study started before the identification of ATP1A3 as the causative gene, and the patients were selected upon their neurological picture. Four of these 30 patients tested negative for ATP1A3 mutations and were excluded from the present work. On physical ground, almost all patients shared a similar physical phenotype consisting of hypotonia, long face, thin eyebrows, strabismus, hypertelorism, long palpebral fissures, downturned mouth, and slender habitus. Such phenotype is sufficiently typical to generate a recognizable gestalt. We also evaluated patients photographs taken from the parents in early childhood (6-20 months) to delineate a clinical profile possibly recognizable before the neurological signs suggest the diagnosis. Our data suggest that the typical early gestalt is sufficient to advise the molecular analysis of ATP1A3, even in absence of the pathognomonic neurological signs. Finally, since a number of patients is now adult, some information can be drawn on the phenotypic evolution of the facial appearance of patients with alternating hemiplegia of childhood. © 2016 Wiley Periodicals, Inc.
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Facies , Hemiplejía/diagnóstico , Fenotipo , Sustitución de Aminoácidos , Preescolar , Codón , Femenino , Hemiplejía/genética , Humanos , Lactante , Recién Nacido , Masculino , Mutación , Diagnóstico Prenatal , ATPasa Intercambiadora de Sodio-Potasio/genéticaRESUMEN
Spinal muscular atrophy (SMA) is a clinically and genetically heterogeneous disease characterized by the degeneration of lower motor neurons. The most frequent form is linked to mutations in SMN1. Childhood SMA associated with progressive myoclonic epilepsy (SMA-PME) has been reported as a rare autosomal-recessive condition unlinked to mutations in SMN1. Through linkage analysis, homozygosity mapping, and exome sequencing in three unrelated SMA-PME-affected families, we identified a homozygous missense mutation (c.125C>T [p.Thr42Met]) in exon 2 of ASAH1 in the affected children of two families and the same mutation associated with a deletion of the whole gene in the third family. Expression studies of the c.125C>T mutant cDNA in Farber fibroblasts showed that acid-ceramidase activity was only 32% of that generated by normal cDNA. This reduced activity was able to normalize the ceramide level in Farber cells, raising the question of the pathogenic mechanism underlying the CNS involvement in deficient cells. Morpholino knockdown of the ASAH1 ortholog in zebrafish led to a marked loss of motor-neuron axonal branching, a loss that is associated with increased apoptosis in the spinal cord. Our results reveal a wide phenotypic spectrum associated with ASAH1 mutations. An acid-ceramidase activity below 10% results in Farber disease, an early-onset disease starting with subcutaneous lipogranulomata, joint pain, and hoarseness of the voice, whereas a higher residual activity might be responsible for SMA-PME, a later-onset phenotype restricted to the CNS and starting with lower-motor-neuron disease.
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Ceramidasa Ácida/genética , Mutación , Atrofias Musculares Espinales de la Infancia/genética , Adolescente , Animales , Niño , Preescolar , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Epilepsias Mioclónicas Progresivas/genética , Linaje , Pez CebraRESUMEN
OBJECTIVE: To present the clinical features and the results of laboratory investigations in three patients with spinal muscular atrophy associated with progressive myoclonic epilepsy (SMA-PME), a rare condition caused by mutations in the N-acylsphingosine amidohydrosilase 1 (ASAH1) gene. METHODS: The patients were submitted to clinical evaluation, neurophysiologic investigations (that included wakefulness and sleep electroencephalography [EEG], video-polygraphic recording with jerk-locked back-averaging, multimodal evoked potentials, and electromyography), brain magnetic resonance imaging (MRI), biochemical screening, muscle and skin biopsies, and molecular genetic analysis. RESULTS: The main clinical features were onset in childhood with proximal muscular weakness, generalized epilepsy with absences and myoclonic seizures, cognitive impairment of variable degree; the course was progressive with muscle wasting and uncontrolled epileptic seizures. In one patient, earlier onset before the age of 2 years was associated with a more complex clinical picture, with abnormal eye movements, progressive cognitive impairment, and a more rapid and severe course. EEG/polygraphic data were consistent with PME, demonstrating generalized spike-and-wave discharges, evidence of positive and negative myoclonia, and prominent photosensitivity. In one patient, transcranial magnetic stimulation showed a hyperexcitable motor cortex, whereas somatosensory evoked potentials were unaffected. Possible involvement of the central acoustic and visual pathways was suggested by abnormal auditory and visual evoked potentials. Muscle biopsies showed typical signs of neurogenic damage. Molecular genetic analysis showed mutations of the ASAH1 gene. SIGNIFICANCE: Our data indicate that SMA-PME associated with ASAH1 mutations is a genetically distinct condition with specific clinical and neurophysiologic features. Further studies are warranted to explore the role of the ASAH1 gene in muscle and brain function.
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Ceramidasa Ácida/genética , Atrofia Muscular Espinal/complicaciones , Atrofia Muscular Espinal/genética , Mutación/genética , Epilepsias Mioclónicas Progresivas/complicaciones , Epilepsias Mioclónicas Progresivas/genética , Adolescente , Niño , Preescolar , Análisis Mutacional de ADN , Electroencefalografía , Potenciales Evocados/genética , Femenino , Humanos , Neuroimagen , Estimulación Transcraneal de Corriente DirectaRESUMEN
OBJECTIVE: In the last years, there has been increasing evidence of cardiac involvement in spinal muscular atrophy (SMA). Autonomic dysfunction has been reported in animal models and in several patients with types I and III SMA, these findings raising the question whether heart rate should be routinely investigated in all SMA patients. The aim of our study was to detect possible signs of autonomic dysfunction and, more generally, of cardiac involvement in types II and III SMA. PATIENTS AND METHODS: We retrospectively reviewed 24-hour electrocardiography (ECG) in 157 types II and III SMA patients (age range, 2-74 years). Of them, 82 also had echocardiography. RESULTS: None of the patients had signs of bradycardia, atrial fibrillation, or the other previously reported rhythm disturbances regardless of the age at examination or the type of SMA. Echocardiography was also normal. There were no signs of congenital cardiac defects with the exception of one patient with a history of ventricular septal defects. CONCLUSIONS: Our results suggest that cardiac abnormalities are not common in type II and type III SMA. These findings provide no evidence to support a more accurate cardiac surveillance or changes in the existing standards of care.
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Cardiopatías/diagnóstico , Cardiopatías/etiología , Atrofias Musculares Espinales de la Infancia/complicaciones , Adolescente , Adulto , Anciano , Niño , Preescolar , Estudios de Cohortes , Electrocardiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
The 270th ENMC workshop aimed to develop a common procedure to optimize the reliability of SMN2 gene copy number determination and to reinforce collaborative networks between molecular scientists and clinicians. The workshop involved neuromuscular and clinical experts and representatives of patient advocacy groups and industry. SMN2 copy number is currently one of the main determinants for therapeutic decision in SMA patients: participants discussed the issues that laboratories may encounter in this molecular test and the cruciality of the accurate determination, due the implications as prognostic factor in symptomatic patients and in individuals identified through newborn screening programmes. At the end of the workshop, the attendees defined a set of recommendations divided into four topics: SMA molecular prognosis assessment, newborn screening for SMA, SMN2 copies and treatments, and modifiers and biomarkers. Moreover, the group draw up a series of recommendations for the companies manufacturing laboratory kits, that will help to minimize the risk of errors, regardless of the laboratories' expertise.
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Atrofia Muscular Espinal , Proteína 2 para la Supervivencia de la Neurona Motora , Humanos , Biomarcadores/análisis , Conferencias de Consenso como Asunto , Dosificación de Gen , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/genética , Pronóstico , Proteína 2 para la Supervivencia de la Neurona Motora/genéticaRESUMEN
A wide variety of non-invasive and invasive techniques for SCD risk stratification in non ischemic cardiomyopathy (NICM) have been proposed, including left ventricular (LV) ejection fraction, QRS duration, late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) and invasive electrophysiologic study with or without three-dimensional electroanatomic mapping (3D-EAM), to identify and characterize the arrhythmogenic substrate. There is still no clear consensus on the risk stratification in this clinical setting. The aim of our study is to characterize the 3D-EAM substrate in patients with the same clinical presentation of unexplained complex VAs and NICM using CMR, three-dimensional electranatomic mapping (3D-EAM) in association with endomyocardial biopsy (EMB) and genetic screening, as a more precise and early diagnostic assessment may provide important subsequent prognostic impact. The study was designed as a prospective multi-center observational evaluation and the patient follow-up was scheduled at 6 months interval. We enrolled 125 patients distinct into four different group by complete diagnostic work-up: myocarditis, non-dilated left ventricular cardiomyopathy, arrhythmogenic cardiomyopathy and control group. The four groups were compared in terms of clinical, imaging and 3D-EAM data. At multivariate analysis sustained VT/VF on admission [HR: 3.64 (1.79-7.4), p < 0.001], total bipolar scar area of left and right ventricle detected by 3D-EAM [HR: 2.24 (1.13-4.49), p = 0.02], histological diagnosis of myocarditis by 3D-EAM guided endomyocardial biopsy (EBM) [HR: 2.79 (1.04-7.44), p = 0.01] were independent predictors of complex VAs or death at follow-up. 3D-EAM guided EMB represent not only a valid diagnostic tool to identify the arrhythmogenic substrate in patients with NICM and ventricular arrhythmic phenotype but also an important predictor of complex Vas at long term follow-up.
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Introduction: High repeat expansion (HRE) alleles in C9orf72 have been linked to both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD); ranges for intermediate allelic expansions have not been defined yet, and clinical interpretation of molecular data lacks a defined genotype-phenotype association. In this study, we provide results from a large multicenter epidemiological study reporting the distribution of C9orf72 repeats in healthy elderly from the Italian population. Methods: A total of 967 samples were collected from neurologically evaluated healthy individuals over 70 years of age in the 13 institutes participating in the RIN (IRCCS Network of Neuroscience and Neurorehabilitation) based in Italy. All samples were genotyped using the AmplideXPCR/CE C9orf72 Kit (Asuragen, Inc.), using standardized protocols that have been validated through blind proficiency testing. Results: All samples carried hexanucleotide G4C2 expansion alleles in the normal range. All samples were characterized by alleles with less than 25 repeats. In particular, 93.7% of samples showed a number of repeats ≤10, 99.9% ≤20 repeats, and 100% ≤25 repeats. Conclusion: This study describes the distribution of hexanucleotide G4C2 expansion alleles in an Italian healthy population, providing a definition of alleles associated with the neurological healthy phenotype. Moreover, this study provides an effective model of federation between institutes, highlighting the importance of sharing genomic data and standardizing analysis techniques, promoting translational research. Data derived from the study may improve genetic counseling and future studies on ALS/FTD.
RESUMEN
Spinal muscular atrophy (SMA) is an autosomal recessive, lower motor neuron disease. Clinical heterogeneity is pervasive: three infantile (type I-III) and one adult-onset (type IV) forms are recognized. Type I SMA is the most common genetic cause of death in infancy and accounts for about 50% of all patients with SMA. Most forms of SMA are caused by mutations of the survival motor neuron (SMN1) gene. A second gene that is 99% identical to SMN1 (SMN2) is located in the same region. The only functionally relevant difference between the two genes identified to date is a C â T transition in exon 7 of SMN2, which determines an alternative spliced isoform that predominantly excludes exon 7. Thus, SMN2 genes do not produce sufficient full length SMN protein to prevent the onset of the disease. Since the identification of the causative mutation, biomedical research of SMA has progressed by leaps and bounds: from clues on the function of SMN protein, to the development of different models of the disease, to the identification of potential treatments, some of which are currently in human trials. The aim of this review is to elucidate the current state of knowledge, emphasizing how close we are to the solution of the puzzle that is SMA, and, more importantly, to highlight the missing pieces of this puzzle. Filling in these gaps in our knowledge will likely accelerate the development and delivery of efficient treatments for SMA patients and be a prerequisite towards achieving our final goal, the cure of SMA.
Asunto(s)
Atrofia Muscular Espinal/genética , Animales , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/tratamiento farmacológico , Proteína 1 para la Supervivencia de la Neurona Motora/genética , Proteína 1 para la Supervivencia de la Neurona Motora/metabolismo , Proteína 2 para la Supervivencia de la Neurona Motora/genética , Proteína 2 para la Supervivencia de la Neurona Motora/metabolismo , Resultado del TratamientoRESUMEN
BACKGROUND: Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by mutations of the SMN1 gene. Based on severity, three forms of SMA are recognised (types I-III). All patients usually have 2-4 copies of a highly homologous gene (SMN2) which produces insufficient levels of functional survival motor neuron (SMN) protein. Recently, evidence has been provided that SMN2 expression can be enhanced in vitro by salbutamol, a ß2-adrenergic agonist. This compound has also been shown to improve motor function of SMA patients in two different pilot trials. AIM: To evaluate the in vivo molecular efficacy of salbutamol in SMA patients. METHODS: Twelve type II-III patients took salbutamol orally for 6 months. SMN2 full length transcript levels were determined in peripheral blood leucocytes by absolute real-time PCR, at baseline and after 3 and 6 months of treatment. RESULTS: A significant and constant increase in SMN2 full length transcript levels was detected; the response was directly proportional to SMN2 gene copy number. CONCLUSIONS: The data strongly support salbutamol as a candidate for treating SMA, and suggest that SMN2 copy number may predict the molecular response to treatment and may be a useful randomisation parameter in a double blind placebo controlled clinical trial design.