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LAMA2-related dystrophies (LAMA2-RD) constitute a rare neuromuscular disorder with a broad spectrum of phenotypic severity. Our understanding of the genotype-phenotype correlations in this condition remains incomplete, and reliable clinical data for clinical trial readiness is limited. In this retrospective study, we reviewed the genetic data and medical records of 114 LAMA2-RD patients enrolled at seven research centers in Brazil. We identified 58 different pathogenic variants, including 21 novel ones. Six variants were more prevalent and were present in 81.5% of the patients. Notably, the c.1255del, c.2049_2050del, c.3976 C>T, c.5234+1G>A, and c.4739dup variants were found in patients unable to walk and without cortical malformation. In contrast, the c.2461A>C variant was present in patients who could walk unassisted. Among ambulatory patients, missense variants were more prevalent (p < 0.0001). Although no specific hotspot regions existed in the LAMA2, 51% of point mutations were in the LN domain, and 88% of the missense variants were found within this domain. Functional analysis was performed in one intronic variant (c.4960-17C>A) and revealed an out-of-frame transcript, indicating that the variant creates a cryptic splicing site (AG). Our study has shed light on crucial phenotype-genotype correlations and provided valuable insights, particularly regarding the Latin American population.
Assuntos
Estudos de Associação Genética , Laminina , Humanos , Laminina/genética , Masculino , Brasil/epidemiologia , Feminino , Criança , Pré-Escolar , Adolescente , Adulto , Perfil Genético , Fenótipo , Estudos Retrospectivos , Distrofias Musculares/genética , Mutação , Adulto Jovem , Predisposição Genética para Doença , Lactente , Genótipo , Pessoa de Meia-IdadeRESUMO
BACKGROUND: LAMA2-related dystrophies (LAMA2-RD) are a rare group of neuromuscular disorders with a broad spectrum of phenotype severity, ranging from mild to severe. We performed a cross-sectional study of LAMA2-RD through motor function and pulmonary tests to establish the disease's natural history. METHODS: Forty-four individuals with LAMA2-RD were included and evaluated once through functional outcome measures including Motor Function Measure 32 (MFM32), Revised Upper Limb Module (RULM), goniometry, and Forced Vital Capacity (FVC). Fixed Effect Regression Model (ERM) and Kaplan-Meier curve were used for calculating the rate of the disease progression RESULTS: Patients were between 2 and 25 years old (mean 11.4), the most frequent phenotype presentation was non-ambulant (N=36, 81.8%) while eight patients (18,2â¯%) were ambulant. The non-ambulant group presented a more severe progression of the disease. Non-ambulant patients had a 1.85â¯% decrease in FVC/year against 1.32â¯%/year among ambulant patients. In the non-ambulant group, there was a 4.2â¯% drop/year in the MFM32-D2 domain (p<0.00001), a 2.6â¯% drop/year in the D3 domain (p<0.0001), and a 2.7â¯% drop/year in the MFM32 global assessment (p<0.0001). However, the non-ambulant group's evaluation of upper limb function through the RULM scale did not show a statistically significant reduction. In the non-ambulant group, elbow and knee retractions worsened 3.22 degrees/year (p=0.00087) and 1.92 degrees/year, respectively. While in those patients who acquired gait, elbow and knee retractions worsened 2.45 degrees/year (p=0.0003) and 1.73 degrees/year (p=0.01), respectively. CONCLUSION: This study confirmed the progressive nature of LAMA2-RD, both in ambulant and non-ambulant patients. MFM32, FVC, and goniometry were identified as promising outcome measures for natural history studies and clinical trials in LAMA2-RD.
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Introduction: Inflammatory myopathy with mitochondrial pathology (IM-Mito) is a rare condition described in a few case series, and it is not clear whether it is a specific disease or a variant of Inclusion Body Myositis (IBM). Radiological data of IM-Mito patients has only been evaluated in one study. Aim: To analyze whole-body muscle magnetic resonance imaging (MRI) features in patients with IM-Mito compared with individuals with IBM. Methods: Fourteen IM-Mito and ten IBM patients were included. IM-Mito was defined by endomysial inflammatory infiltrate, presence of at least 1% of Cytochrome C Oxidase negative fibers, and absence of rimmed vacuoles in muscle biopsy; and IBM was defined by the presence of dystrophic muscular abnormalities, endomysial inflammatory infiltrate, and rimmed vacuoles. Patients underwent clinical evaluation and whole-body muscle MRI to determine the presence of edema, and fatty infiltration in various muscles. Results: Muscle imaging abnormalities were asymmetric in most patients with IM-Mito and IBM. Muscles with the highest average degree of fatty infiltration in both conditions were the quadriceps and medial gastrocnemius. Most patients with IM-Mito and IBM showed imaging patterns of rectus femoris relatively spared compared to other quadriceps muscles. The flexor digitorum profundus was the most affected muscle of the upper limbs in both IBM and IM-Mito. Discussion: Although the results suggest some similarities in muscle imaging features between IM-Mito and IBM, there remains uncertainty whether these two conditions are part of the same clinical spectrum.
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To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.
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Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/genética , Estudo de Associação Genômica Ampla/métodos , Cinesinas/genética , Mutação com Perda de Função/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Esclerose Lateral Amiotrófica/epidemiologia , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Nemaline myopathy is a rare congenital disease of skeletal muscle characterized by muscle weakness and hypotonia, as well as the diagnostic presence of nemaline rods in skeletal muscle fibers. Nemaline myopathy is genetically and phenotypically heterogeneous and, so far, mutations in 11 different genes have been associated with this disease. Dominant mutations in ACTA1 are the second most frequent genetic cause of nemaline myopathy and can lead to a variety of clinical and histologic phenotypes. PATIENTS AND METHODS: We present a series of ACTA1-related cases from a Brazilian cohort of 23 patients with nemaline myopathy, diagnosed after Sanger sequencing the entire coding region of ACTA1, and review the literature on ACTA1-related nemaline myopathy. RESULTS: The study confirmed ACTA1 mutations in four patients, including one with intranuclear rods, one with large intracytoplasmic aggregates, and two with nemaline intracytoplasmic rods. A repeat muscle biopsy in one patient did not show histological progression. CONCLUSION: Despite the recognized phenotypic variability in ACTA1-related nemaline myopathy, clinical and histological presentations appear to correlate with the position of the mutation, which confirms emerging genotype/phenotype correlations and better predict the prognosis of affected patients.
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Actinas/genética , Músculo Esquelético/patologia , Mutação/genética , Miopatias da Nemalina/genética , Adolescente , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Mutations in RYR1 give rise to diverse skeletal muscle phenotypes, ranging from classical central core disease to susceptibility to malignant hyperthermia. Next-generation sequencing has recently shown that RYR1 is implicated in a wide variety of additional myopathies, including centronuclear myopathy. In this work, we established an international cohort of 21 patients from 18 families with autosomal recessive RYR1-related centronuclear myopathy, to better define the clinical, imaging, and histological spectrum of this disorder. Early onset of symptoms with hypotonia, motor developmental delay, proximal muscle weakness, and a stable course were common clinical features in the cohort. Ptosis and/or ophthalmoparesis, facial weakness, thoracic deformities, and spinal involvement were also frequent but variable. A common imaging pattern consisted of selective involvement of the vastus lateralis, adductor magnus, and biceps brachii in comparison to adjacent muscles. In addition to a variable prominence of central nuclei, muscle biopsy from 20 patients showed type 1 fiber predominance and a wide range of intermyofibrillary architecture abnormalities. All families harbored compound heterozygous mutations, most commonly a truncating mutation combined with a missense mutation. This work expands the phenotypic characterization of patients with recessive RYR1-related centronuclear myopathy by highlighting common and variable clinical, histological, and imaging findings in these patients.