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1.
Artículo en Inglés | MEDLINE | ID: mdl-39230607

RESUMEN

PURPOSE: Although dysphagia is a common symptom among patients with Spinal Muscular Atrophy Type 1 (SMA1), scant data exist on the application of Fiberoptic Endoscopic Evaluation of Swallowing (FEES) in this population. The aim was to analyze FEES feasibility, swallow safety and efficacy, dysphagia phenotype, and agreement with VideoFluoroscopic Swallow Study (VFSS) in children with symptomatic, medication-treated SMA1 and oral feeding. METHODS: 10 children with SMA1 underwent FEES. Six patients had also a VFSS. Two clinicians independently rated FEES and VFSS videos. Swallowing safety was assessed using the Penetration-Aspiration scale (PAS). Dysphagia phenotypes were defined according to the classification defined by Warnecke et al. Swallowing efficacy was evaluated with the Yale Pharyngeal Residue Severity Rating Scale (YPRSRS) in FEES, whereas pharyngeal residue was rated as present or absent in VFSS. RESULTS: FEES was performed in all children without complications. Four children tolerated bolus trials during FEES, in 4 children swallowing characteristics were inferred based on post-swallow residues, while 2 children refused to eat and only saliva management was assessed. The dysphagia phenotype of predominance of residue in the piriform sinuses was documented in 7/8 children. The PAS score was < 3 in 3 children and > 5 in one child. Swallowing efficacy was impaired in 8/8 children. VFSS showed complete agreement with FEES. CONCLUSIONS: FEES is a feasible examination in children with SMA1. Swallowing safety and efficacy are impaired in nearly all patients with strong agreement between FEES and VFSS. Dysphagia is characterized by the predominance of residue in the piriform sinus.

2.
Neurogenetics ; 21(1): 1-18, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31834528

RESUMEN

Over the past 10 years, the increasingly important role played by next-generation sequencing panels in the genetic diagnosis of epilepsy has led to a growing list of gene variants and a plethora of new scientific data. To date, however, there is still no consensus on what constitutes the "ideal panel design," or on the most rational criteria for selecting the best candidates for gene-panel analysis, even though both might optimize the cost-benefit ratio and the diagnostic efficiency of customized gene panels. Even though more and more laboratories are adopting whole-exome sequencing as a first-tier diagnostic approach, interpreting, "in silico," a set of epilepsy-related genes remains difficult. In the light of these considerations, we performed a systematic review of the targeted gene panels for epilepsy already reported in the available scientific literature, with a view to identifying the best criteria for selecting patients for gene-panel analysis, and the best way to design an "ideal," gold-standard panel that includes all genes with an established role in epilepsy pathogenesis, as well as those that might help to guide decisions regarding specific medical interventions and treatments. Our analyses suggest that the usefulness and diagnostic power of customized gene panels for epilepsy may be greatest when these panels are confined to rationally selected, relatively small, pools of genes, and applied in more carefully selected epilepsy patients (those with complex forms of epilepsy). A panel containing 64 genes, which includes the 45 genes harboring a significant number of pathogenic variants identified in previous literature, the 32 clinically actionable genes, and the 21 ILAE (International League Against Epilepsy) recommended genes, may represent an "ideal" core set likely able to provide the highest diagnostic efficiency and cost-effectiveness and facilitate gene prioritization when testing patients with whole-exome/whole-genome sequencing.


Asunto(s)
Epilepsia/diagnóstico , Epilepsia/genética , Pruebas Genéticas/métodos , Epilepsia/patología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mutación , Secuenciación del Exoma
3.
Cephalalgia ; 34(10): 767-76, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24973419

RESUMEN

BACKGROUND: The existence of a correlation and/or comorbidity between sleep disorders and headache, related to common anatomical structures and neurochemical processes, has important implications for the treatment of both conditions. METHODS: The high prevalence of certain sleep disorders in children with migraine and the fact that sleep is disrupted in these patients highlight the importance of a specific therapy targeted to improve both conditions. FINDINGS: The treatment of sleep disorders like insomnia, sleep apnea, sleep bruxism and restless legs syndrome, either with behavioral or pharmacological approach, often leads to an improvement of migraine. Drugs like serotoninergic and dopaminergic compounds are commonly used for sleep disorders and for migraine prophylaxis and treatment: Insomnia, sleep-wake transition disorders and migraine have been related to the serotonergic system abnormality; on the other hand prodromal symptoms of migraine (yawning, drowsiness, irritability, mood changes, hyperactivity) support a direct role for the dopaminergic system that is also involved in sleep-related movement disorders. CONCLUSIONS: Our review of the literature revealed that, beside pharmacological treatment, child education and lifestyle modification including sleep hygiene could play a significant role in overall success of the treatment. Therefore comorbid sleep conditions should be always screened in children with migraine in order to improve patient management and to choose the most appropriate treatment.


Asunto(s)
Cefalea/epidemiología , Trastornos del Sueño-Vigilia/epidemiología , Trastornos del Sueño-Vigilia/terapia , Sueño/fisiología , Niño , Cefalea/complicaciones , Cefalea/fisiopatología , Humanos , Trastornos del Sueño-Vigilia/fisiopatología
4.
Front Neurol ; 15: 1308296, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38487326

RESUMEN

Objective: To review the clinical characteristics and effect of treatment in patients with spinal muscular atrophy (SMA) and three copies of the SMN2 gene. Methods: We conducted a literature search in October 2022 to identify English-language clinical research on SMA that included SMN2 copy number according to PRISMA guidelines. Results: Our search identified 44 studies examining the impact of three SMN2 copies on clinical characteristics (21 on phenotype, 13 on natural history, and 15 on functional status and other signs/symptoms). In children with type I SMA or presymptomatic infants with an SMN1 deletion, three SMN2 copies was associated with later symptom onset, slower decline in motor function and longer survival compared with two SMN2 copies. In patients with SMA type II or III, three SMN2 copies is associated with earlier symptom onset, loss of ambulation, and ventilator dependence compared with four SMN2 copies. Eleven studies examined treatment effects with nusinersen (nine studies), onasemnogene abeparvovec (one study), and a range of treatments (one study) in patients with three SMN2 copies. In presymptomatic infants, early treatment delayed the onset of symptoms and maintained motor function in those with three SMN2 copies. The impact of copy number on treatment response in symptomatic patients is still unclear. Conclusion: SMN2 copy number is strongly correlated with SMA phenotype in patients with SMN1 deletion, while no correlation was found in patients with an SMN1 mutation. Patients with three SMN2 copies show a highly variable clinical phenotype. Early initiation of treatment is highly effective in presymptomatic patients with three SMN2 copies.

5.
Arch Dis Child ; 109(5): 395-401, 2024 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-38290776

RESUMEN

OBJECTIVE: The aim of this study was to assess early language acquisitions in treated individuals with spinal muscular atrophy (SMA) type 1 and in infants identified by newborn screening (NBS). METHODS: Parents of SMA individuals aged between 8 and 36 months were asked to fill in the MacArthur-Bates Communicative Development Inventory (MB-CDI) that assesses comprehension, gesture and expressive skills. A follow-up assessment was performed in 21 of the 36. RESULTS: The MB-CDI was completed by parents of 24 type 1 and 12 infants identified by NBS. Comprehension skills were preserved in 81% of the type 1 SMA and in 87% infants identified by NBS. Gesture abilities were <5th centile in 55% of the type 1 SMA and in none of those identified by NBS. Lexical expressions were <5th centile in more than 80% type 1 SMA and in 50% of infants identified by NBS. At follow-up, despite an increase in lexical expression skills, the scores remained below the fifth centile in 43% type 1 SMA and in 86% of infants identified by NBS. CONCLUSIONS: These results suggest that language and communication development may follow a similar pattern to that observed in motor function with the possibility to develop skills (eg, ability to say clear words) that are not usually present in untreated infants but with a level of performance that does not reach that of their typically developing peers.


Asunto(s)
Atrofia Muscular Espinal , Atrofias Musculares Espinales de la Infancia , Recién Nacido , Lactante , Humanos , Preescolar , Estudios de Cohortes , Atrofia Muscular Espinal/diagnóstico , Atrofias Musculares Espinales de la Infancia/diagnóstico , Desarrollo del Lenguaje , Gestos
6.
Neuromuscul Disord ; 34: 75-82, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38157655

RESUMEN

Duchenne muscular dystrophy (DMD) is a neuromuscular condition characterized by muscle weakness. The Performance of upper limb (PUL) test is designed to evaluate upper limb function in DMD patients across three domains. The aim of this study is to identify frequently lost or gained PUL 2.0 abilities at distinct functional stages in DMD patients. This retrospective study analyzed prospectively collected data on 24-month PUL 2.0 changes related to ambulatory function. Ambulant patients were categorized based on initial 6MWT distance, non-ambulant patients by time since ambulation loss. Each PUL 2.0 item was classified as shift up, no change, or shift down. The study's cohort incuded 274 patients, with 626 paired evaluations at the 24-month mark. Among these, 55.1 % had activity loss, while 29.1 % had gains. Ambulant patients showed the lowest loss rates, mainly in the shoulder domain. The highest loss rate was in the shoulder domain in the transitioning subgroup and in elbow and distal domains in the non-ambulant patients. Younger ambulant patients demonstrated multiple gains, whereas in the other functional subgroups there were fewer gains, mostly tied to singular activities. Our findings highlight divergent upper limb domain progression, partly linked to functional status and baseline function.


Asunto(s)
Distrofia Muscular de Duchenne , Humanos , Distrofia Muscular de Duchenne/complicaciones , Estudios Retrospectivos , Extremidad Superior , Caminata , Debilidad Muscular
7.
EClinicalMedicine ; 59: 101997, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-37197706

RESUMEN

Background: Efficacy and safety of onasemnogene abeparvovec (OA) for Spinal Muscular Atrophy infants under 7 months and <8.5 kg has been reported in clinical trials. This study examines efficacy and safety predictors in a wide age (22 days-72 months) and weight (3.2-17 kg) range, also including patients previously treated with other drugs. Methods: 46 patients were treated for 12 months between January 2020 and March 2022. Safety profile was also available for another 21 patients with at least 6 month follow-up after OA infusion. 19/67 were treatment naïve when treated with OA. Motor function was measured with the CHOP-INTEND. Findings: CHOP-INTEND changes varied among age groups. Baseline score and age at OA treatment best predicted changes. A mixed model post-hoc analysis showed that in patients treated before the age of 24 months the CHOP-INTEND changes were already significant 3 months after OA while in those treated after the age of 24 months the difference was only significant 12 months after OA. Adverse events occurred in 51/67. The risk for elevated transaminases serum levels was higher in older patients. This was also true for weight and for pre-treatment with nusinersen when analysed individually. A binomial negative regression analysis showed that only age at OA treatment had a significant effect on the risk of elevated transaminases. Interpretation: Our paper describes OA 12-month follow-up showing efficacy across various age and weight groups not targeted by clinical trials. The study identifies prognostic factors for safety and efficacy in treatment selection. Funding: None.

8.
Genes (Basel) ; 14(2)2023 01 23.
Artículo en Inglés | MEDLINE | ID: mdl-36833224

RESUMEN

Thanks to advances in gene sequencing, RYR1-related myopathy (RYR1-RM) is now known to manifest itself in vastly heterogeneous forms, whose clinical interpretation is, therefore, highly challenging. We set out to develop a novel unsupervised cluster analysis method in a large patient population. The objective was to analyze the main RYR1-related characteristics to identify distinctive features of RYR1-RM and, thus, offer more precise genotype-phenotype correlations in a group of potentially life-threatening disorders. We studied 600 patients presenting with a suspicion of inherited myopathy, who were investigated using next-generation sequencing. Among them, 73 index cases harbored variants in RYR1. In an attempt to group genetic variants and fully exploit information derived from genetic, morphological, and clinical datasets, we performed unsupervised cluster analysis in 64 probands carrying monoallelic variants. Most of the 73 patients with positive molecular diagnoses were clinically asymptomatic or pauci-symptomatic. Multimodal integration of clinical and histological data, performed using a non-metric multi-dimensional scaling analysis with k-means clustering, grouped the 64 patients into 4 clusters with distinctive patterns of clinical and morphological findings. In addressing the need for more specific genotype-phenotype correlations, we found clustering to overcome the limits of the "single-dimension" paradigm traditionally used to describe genotype-phenotype relationships.


Asunto(s)
Enfermedades Musculares , Canal Liberador de Calcio Receptor de Rianodina , Humanos , Canal Liberador de Calcio Receptor de Rianodina/genética , Enfermedades Musculares/genética , Estudios de Asociación Genética , Genotipo , Fenotipo
9.
J Neuromuscul Dis ; 10(4): 567-574, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37066919

RESUMEN

BACKGROUND: The performance of upper limb 2.0 (PUL) is widely used to assess upper limb function in DMD patients. The aim of the study was to assess 24 month PUL changes in a large cohort of DMD patients and to establish whether domains changes occur more frequently in specific functional subgroups. METHODS: The PUL was performed in 311 patients who had at least one pair of assessments at 24 months, for a total of 808 paired assessments. Ambulant patients were subdivided according to the ability to walk: >350, 250-350, ≤250 meters. Non ambulant patients were subdivided according to the time since they lost ambulation: <1, 1-2, 2-5 or >5 years. RESULTS: At 12 months, the mean PUL 2.0 change on all the paired assessments was -1.30 (-1.51--1.05) for the total score, -0.5 (-0.66--0.39) for the shoulder domain, -0.6 (-0.74--0.5) for the elbow domain and -0.1 (-0.20--0.06) for the distal domain.At 24 months, the mean PUL 2.0 change on all the paired assessments was -2.9 (-3.29--2.60) for the total score, -1.30 (-1.47--1.09) for the shoulder domain, -1.30 (-1.45--1.11) for the elbow domain and -0.4 (-1.48--1.29) for the distal domain.Changes at 12 and 24 months were statistically significant between subgroups with different functional abilities for the total score and each domain (p < 0.001). CONCLUSION: There were different patterns of changes among the functional subgroups in the individual domains. The time of transition, including the year before and after loss of ambulation, show the peak of negative changes in PUL total scores that reflect not only loss of shoulder but also of elbow activities. These results suggest that patterns of changes should be considered at the time of designing clinical trials.


Asunto(s)
Distrofia Muscular de Duchenne , Humanos , Actividades Cotidianas , Extremidad Superior , Caminata
10.
Front Cell Neurosci ; 16: 982760, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36035258

RESUMEN

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.

11.
J Neurol ; 269(1): 437-450, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34487232

RESUMEN

BACKGROUND: Monoallelic variants in the KIF1A gene are associated with a large set of clinical phenotypes including neurodevelopmental and neurodegenerative disorders, underpinned by a broad spectrum of central and peripheral nervous system involvement. METHODS: In a multicenter study conducted in patients presenting spastic gait or complex neurodevelopmental disorders, we analyzed the clinical, genetic and neuroradiological features of 28 index cases harboring heterozygous variants in KIF1A. We conducted a literature systematic review with the aim to comparing our findings with previously reported KIF1A-related phenotypes. RESULTS: Among 28 patients, we identified nine novel monoallelic variants, and one a copy number variation encompassing KIF1A. Mutations arose de novo in most patients and were prevalently located in the motor domain. Most patients presented features of a continuum ataxia-spasticity spectrum with only five cases showing a prevalently pure spastic phenotype and six presenting congenital ataxias. Seventeen mutations occurred in the motor domain of the Kinesin-1A protein, but location of mutation did not correlate with neurological and imaging presentations. When tested in 15 patients, muscle biopsy showed oxidative metabolism alterations (6 cases), impaired respiratory chain complexes II + III activity (3/6) and low CoQ10 levels (6/9). Ubiquinol supplementation (1gr/die) was used in 6 patients with subjective benefit. CONCLUSIONS: This study broadened our clinical, genetic, and neuroimaging knowledge of KIF1A-related disorders. Although highly heterogeneous, it seems that manifestations of ataxia-spasticity spectrum disorders seem to occur in most patients. Some patients also present secondary impairment of oxidative metabolism; in this subset, ubiquinol supplementation therapy might be appropriate.


Asunto(s)
Variaciones en el Número de Copia de ADN , Cinesinas , Paraplejía Espástica Hereditaria , Estudios Transversales , Heterocigoto , Humanos , Cinesinas/genética , Mutación , Fenotipo , Paraplejía Espástica Hereditaria/genética
12.
Acta Neuropathol Commun ; 10(1): 54, 2022 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-35428369

RESUMEN

Mutations in the RYR1 gene, encoding ryanodine receptor 1 (RyR1), are a well-known cause of Central Core Disease (CCD) and Multi-minicore Disease (MmD). We screened a cohort of 153 patients carrying an histopathological diagnosis of core myopathy (cores and minicores) for RYR1 mutation. At least one RYR1 mutation was identified in 69 of them and these patients were further studied. Clinical and histopathological features were collected. Clinical phenotype was highly heterogeneous ranging from asymptomatic or paucisymptomatic hyperCKemia to severe muscle weakness and skeletal deformity with loss of ambulation. Sixty-eight RYR1 mutations, generally missense, were identified, of which 16 were novel. The combined analysis of the clinical presentation, disease progression and the structural bioinformatic analyses of RYR1 allowed to associate some phenotypes to mutations in specific domains. In addition, this study highlighted the structural bioinformatics potential in the prediction of the pathogenicity of RYR1 mutations. Further improvement in the comprehension of genotype-phenotype relationship of core myopathies can be expected in the next future: the actual lack of the human RyR1 crystal structure paired with the presence of large intrinsically disordered regions in RyR1, and the frequent presence of more than one RYR1 mutation in core myopathy patients, require designing novel investigation strategies to completely address RyR1 mutation effect.


Asunto(s)
Miopatías Estructurales Congénitas , Miopatía del Núcleo Central , Canal Liberador de Calcio Receptor de Rianodina , Humanos , Músculo Esquelético/patología , Mutación/genética , Miopatías Estructurales Congénitas/genética , Miopatías Estructurales Congénitas/patología , Miopatía del Núcleo Central/genética , Miopatía del Núcleo Central/patología , Canal Liberador de Calcio Receptor de Rianodina/genética
13.
Children (Basel) ; 8(12)2021 Dec 18.
Artículo en Inglés | MEDLINE | ID: mdl-34943397

RESUMEN

Neuroleptic malignant syndrome (NMS) is a rare, life-threatening, idiosyncratic adverse reaction to antipsychotic drugs. Despite the increasing rates in the prescription of antipsychotics in pediatric patients with autism spectrum disorder (ASD), little is known about the occurrence and hallmarks of NMS in this specific population. NMS appears to be part of the larger catatonia domain, based on the frequent relationship between ASD and catatonia, on the shared, when not overlapping, clinical features with malignant catatonia, and on the effectiveness of catatonia treatments on the NMS/MC symptoms. The intrinsic difficulties of exploring NMS in ASD in controlled studies accounts for the subsequent lack of available information. Based on recent reports and on our case report, clinical features of NMS in the pediatric ASD population appear to be the same as the non-ASD population. Further studies are needed to confirm these results.

14.
J Neurol Sci ; 425: 117441, 2021 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-33866115

RESUMEN

Hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by progressive spasticity and weakness of the lower limbs with a notable phenotypic variation and an autosomal recessive (AR), autosomal dominant (AD), and X-linked inheritance pattern. The recent clinical use of next generation sequencing methods has facilitated the diagnostic approach to HSPs, but the diagnosis remains quite challenging considering its wide clinical and genetic heterogeneity. In this scenario, magnetic resonance imaging (MRI) emerges as a valuable tool in helping to exclude mimicking disorders and to guide genetic testing. The aim of this study is to investigate the presence of possible patterns of morphostructural MRI findings that may provide relevant clues for a specific genetic HSP subtype. In our cohort, for example, white matter abnormalities were the most common finding followed by the thinning of the corpus callosum, which, interestingly, presented different thinning characteristics depending on the HSP subtype.


Asunto(s)
Paraplejía Espástica Hereditaria , Niño , Cuerpo Calloso , Pruebas Genéticas , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mutación , Neuroimagen , Paraplejía Espástica Hereditaria/diagnóstico por imagen , Paraplejía Espástica Hereditaria/genética
15.
J Clin Med ; 10(10)2021 May 12.
Artículo en Inglés | MEDLINE | ID: mdl-34065803

RESUMEN

Movement disorders are increasingly being recognized as a manifestation of childhood-onset mitochondrial diseases (MDs). However, the spectrum and characteristics of these conditions have not been studied in detail in the context of a well-defined cohort of patients. We retrospectively explored a cohort of individuals with childhood-onset MDs querying the Nationwide Italian Collaborative Network of Mitochondrial Diseases database. Using a customized online questionnaire, we attempted to collect data from the subgroup of patients with movement disorders. Complete information was available for 102 patients. Movement disorder was the presenting feature of MD in 45 individuals, with a mean age at onset of 11 years. Ataxia was the most common movement disorder at onset, followed by dystonia, tremor, hypokinetic disorders, chorea, and myoclonus. During the disease course, most patients (67.7%) encountered a worsening of their movement disorder. Basal ganglia involvement, cerebral white matter changes, and cerebellar atrophy were the most commonly associated neuroradiological patterns. Forty-one patients harbored point mutations in the mitochondrial DNA, 10 carried mitochondrial DNA rearrangements, and 41 cases presented mutations in nuclear-DNA-encoded genes, the latter being associated with an earlier onset and a higher impairment in activities of daily living. Among our patients, 32 individuals received pharmacological treatment; clonazepam and oral baclofen were the most commonly used drugs, whereas levodopa and intrathecal baclofen administration were the most effective. A better delineation of the movement disorders phenotypes starting in childhood may improve our diagnostic workup in MDs, fine tuning management, and treatment of affected patients.

16.
Acta Myol ; 39(4): 218-221, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33458577

RESUMEN

Two patients with a paucisymptomatic hyperckemia underwent a skeletal muscle biopsy and massive gene panel to investigate mutations associated with inherited muscle disorders. In the SGCA gene, sequence analyses revealed a homozygous c.850C > T/p.Arg284Cys in patient 1 and two heterozygous variants (c.739G > A/p.Val247Met and c.850C > T/p.Arg284Cys) in patient 2. Combination of histology and immunofluorence studies showed minimal changes for muscular proteins including the α-sarcoglycan. These two cases highlight the advantages of next-generation sequencing in the differential diagnosis of mild myopathic conditions before considering the more invasive muscle biopsy in sarcoglycanopathies.


Asunto(s)
Creatina Quinasa/sangre , Mialgia/etiología , Sarcoglicanopatías/sangre , Sarcoglicanopatías/diagnóstico , Adulto , Femenino , Humanos , Masculino , Mialgia/sangre , Mialgia/patología , Sarcoglicanopatías/complicaciones
17.
Ann Clin Transl Neurol ; 7(4): 595-601, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32237276

RESUMEN

Mutations in the ATPase family 3-like gene (AFG3L2) have been linked to autosomal-dominant spinocerebellar ataxia type 28 and autosomal recessive spastic ataxia-neuropathy syndrome. Here, we describe the case of a child carrying bi-allelic mutations in AFG3L2 and presenting with ictal paroxysmal episodes associated with neuroimaging suggestive of basal ganglia involvement. Studies in skin fibroblasts showed a significant reduction of AFG3L2 expression. The relatively mild clinical presentation and the benign course, in spite of severe neuroimaging features, distinguish this case from data reported in the literature, and therefore expand the spectrum of neurological and neuroradiological features associated with AFG3L2 mutations.


Asunto(s)
Proteasas ATP-Dependientes/genética , ATPasas Asociadas con Actividades Celulares Diversas/genética , Ataxias Espinocerebelosas/congénito , Niño , Humanos , Imagen por Resonancia Magnética , Masculino , Ataxias Espinocerebelosas/diagnóstico , Ataxias Espinocerebelosas/genética , Ataxias Espinocerebelosas/patología , Ataxias Espinocerebelosas/fisiopatología
18.
Neurol Genet ; 5(5): e352, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31517061

RESUMEN

OBJECTIVE: Next-generation sequencing (NGS) was applied in molecularly undiagnosed asymptomatic or paucisymptomatic hyperCKemia to investigate whether this technique might allow detection of the genetic basis of the condition. METHODS: Sixty-six patients with undiagnosed asymptomatic or paucisymptomatic hyperCKemia, referred to tertiary neuromuscular centers over an approximately 2-year period, were analyzed using a customized, targeted sequencing panel able to investigate the coding exons and flanking intronic regions of 78 genes associated with limb-girdle muscular dystrophies, rhabdomyolysis, and metabolic and distal myopathies. RESULTS: A molecular diagnosis was reached in 33 cases, corresponding to a positive diagnostic yield of 50%. Variants of unknown significance were found in 17 patients (26%), whereas 16 cases (24%) remained molecularly undefined. The major features of the diagnosed cases were mild proximal muscle weakness (found in 27%) and myalgia (in 24%). Fourteen patients with a molecular diagnosis and mild myopathic features on muscle biopsy remained asymptomatic at a 24-month follow-up. CONCLUSIONS: This study of patients with undiagnosed hyperCKemia, highlighting the advantages of NGS used as a first-tier diagnostic approach in genetically heterogeneous conditions, illustrates the ongoing evolution of molecular diagnosis in the field of clinical neurology. Isolated hyperCKemia can be the sole feature alerting to a progressive muscular disorder requiring careful surveillance.

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