Caracterização clínica, genética e radiológica das disferlinopatias
Data
2021
Autores
Farias, Igor Braga 
Orientadores
Oliveira, Acary Souza Bulle
Tipo
Dissertação de mestrado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Objetivos: O objetivo primário desse estudo foi realizar a caracterização clínica de aspectos motores e não-motores relacionados a pacientes com diagnóstico de disferlinopatias acompanhados no setor de investigação de doenças neuromusculares da UNIFESP e avaliar se há diferença entre os fenótipos. Os objetivos secundários incluem: (i) caracterizar o efeito do tempo sobre a força muscular, escalas de funcionalidade e valores de creatinoquinase (CK); (ii) caracterizar a base genética; (iii) caracterizar os músculos com maior lipossubstituição em ressonância magnética de coxas e pernas (iv) Avaliar se há correlação entre a escala de funcionalidade e valores de creatinoquinase e lipossubstituição nos pacientes da amostra. Métodos: Foi realizado estudo retrospectivo dos prontuários de pacientes acompanhados no ambulatório de miopatias do setor entre janeiro de 1995 e dezembro de 2020. Os critérios de inclusão foram: (i) Identificação de variante definida como patogênica em homozigose ou heterozigose composta no gene Dysf; ou (ii) quadro clínico compatível com um dos fenótipos da doença e diminuição da expressão da disferlina em imunoistoquímica em biópsia muscular. Foram transcritos dos prontuários dados clínicos, história familiar, exames complementares e exames físicos. A força muscular foi graduada segundo a escala Medical Research Council. A classificação segundo o fenótipo foi realizada com base nas primeiras manifestações e avaliações. O grau de funcionalidade foi definido pela escala de Gardner–Medwin & Walton (GMW) modificada para disferlinopatias. A lipossubstituição em ressonância de coxas e pernas foi classificada segundo a escala de Mercuri. Para a avaliação da progressão, um modelo linear misto foi utilizado. Resultados: 23 pacientes de 21 famílias distintas foram incluídos no estudo. 19 possuíam exame genético e 8 tinham exame de imagem arquivado em prontuário eletrônico. 16 foram classificados como distrofia muscular de cintura e membros autossômica recessiva 2, 4 como miopatia distal de Miyoshi tipo 1, 2 com comprometimento próximo-distal e 1 como hiperCK assintomática. A idade média de início da primeira manifestação foi 23,93 anos, sendo a diminuição da força na região proximal dos membros inferiores a mais comum (65,21%). A adução das coxas foi o movimento com menor força na primeira consulta (média=3,27). A flexão plantar foi o movimento com maior declínio na força (média=0,10 pontos na escala MRC por ano; p<0,001). O declínio funcional médio foi 0,2987 pontos na escala GMW por ano (p<0,001). As variantes mais comuns foram a c.6124C>T, p.Arg2042Cys e c.2643+1G>A, p.?(splicing), encontradas 3 vezes cada. O valor médio da creatinoquinase na primeira avaliação foi 6096,58 μmol/L, tendo o declínio médio sido estimado em 189,16 μmol/L por ano (p=0,02). Nos exames de imagem, os músculos glúteo mínimo, adutor longo e sóleo foram os com maior grau de lipossubstituição na pelve, coxas e pernas, respectivamente (média=2,56, 3,62 e 3,75 respectivamente). Não houve diferença estatística na idade de início, força, declínio motor, funcional, valores de creatinoquinase ou lipossubstituição em exames de imagem entre os fenótipos dos pacientes da amostra. Conclusões: Este estudo corrobora com achados recentes que propõe que as disferlinopatias não são doenças diferentes, mas sim um contínuo de uma única condição
Objectives: The primary objective of this study was to carry out the clinical characterization of motor and non-motor aspects related to patients diagnosed with dysferlinopathy followed up in the neuromuscular disease investigation sector at UNIFESP and to assess whether there is a difference between the phenotypes. Secondary objectives include:(i) characterize the effect of time on muscle strength, functionality scales and serum levels of creatine phosphokinase (CK);(ii) characterize the genetic basis for the disorders;(iii) characterize the muscles with the highest liposubstitution on magnetic resonance imaging exam of the thighs and legs;(iv) Assess whether there is a correlation between the functionality scales and serum levels of creatinophosphokinase and liposubstitution. Methods: A retrospective study of the medical records of patients followed up at the myopathies clinic of the institution between January of 1995 and December of 2020 was performed. The inclusion criteria were:(i) Identification of a mutation defined as pathogenic in homozygosis or compound heterozygosis in the Dysf gene; or (ii) compatible clinical manifestations with one of the disease phenotypes and decreased expression of dysferlin in immunohistochemistry on muscle biopsy. Clinical data, family history, complementary exams and physical exams were transcribed from medical records. Muscle strength was graded according to the Medical Research Council scale. Classification according to the phenotype was carried out based on the first manifestations and evaluations. The degree of functionality was defined by the Gardner–Medwin & Walton (GMW) scale modified for dysferlinopathy. Liposubstitution in magnetic resonance imaging of the thighs and legs were classified according to the Mercuri scale. For the evaluation of progression, a mixed linear model was used. Results: 23 patients from 21 distinct families were included. 19 had a genetic test and 8 had imaging exam filed in the electronic medical record. 16 were classified as limb-girdle muscular dystrophy autosomal recessive 2, 4 as Miyoshi muscular dystrophy 1, 2 as proximo-distal onset and 1 as asymptomatic hyperCKemia. The mean age of onset was 23.93 years. Reduced proximal strength in the lower limbs was the most common first symptom (65.21%). Thighs adduction was the most affected movement in the first evaluation (mean strength=3.27). Plantar flexion was the movement with the greatest decline in strength (mean=0.10 points on the MRC scale per year; p<0.001). The average functional decline was 0.2987 points on the GMW scale per year (p<0.001). The most common mutations were c.6124C>T,Arg2042Cys and c.2643+1G>A, p.?(splicing), found 3 times each. The mean value of creatinophosphokinase in the first evaluation was 6096.58 μmol/L, with a mean rate of decline of 189.16 μmol/L per year (p=0.02). In imaging exams, the gluteus minimus, adductor longus and soleus muscles were those with the highest degree of liposubstitution in the pelvis, thighs and legs, respectively (mean=2.56, 3.62 and 3.75 respectively). There was no statistical difference in the age of onset, strength, motor and functional decline, serum creatinophosphokinase levels or liposubstitution in imaging exams between the phenotypes in the sample. Conclusion: This study corroborates with recent findings that proposes that dysferlinopathies are not different diseases, but a continuum of a single condition.
Objectives: The primary objective of this study was to carry out the clinical characterization of motor and non-motor aspects related to patients diagnosed with dysferlinopathy followed up in the neuromuscular disease investigation sector at UNIFESP and to assess whether there is a difference between the phenotypes. Secondary objectives include:(i) characterize the effect of time on muscle strength, functionality scales and serum levels of creatine phosphokinase (CK);(ii) characterize the genetic basis for the disorders;(iii) characterize the muscles with the highest liposubstitution on magnetic resonance imaging exam of the thighs and legs;(iv) Assess whether there is a correlation between the functionality scales and serum levels of creatinophosphokinase and liposubstitution. Methods: A retrospective study of the medical records of patients followed up at the myopathies clinic of the institution between January of 1995 and December of 2020 was performed. The inclusion criteria were:(i) Identification of a mutation defined as pathogenic in homozygosis or compound heterozygosis in the Dysf gene; or (ii) compatible clinical manifestations with one of the disease phenotypes and decreased expression of dysferlin in immunohistochemistry on muscle biopsy. Clinical data, family history, complementary exams and physical exams were transcribed from medical records. Muscle strength was graded according to the Medical Research Council scale. Classification according to the phenotype was carried out based on the first manifestations and evaluations. The degree of functionality was defined by the Gardner–Medwin & Walton (GMW) scale modified for dysferlinopathy. Liposubstitution in magnetic resonance imaging of the thighs and legs were classified according to the Mercuri scale. For the evaluation of progression, a mixed linear model was used. Results: 23 patients from 21 distinct families were included. 19 had a genetic test and 8 had imaging exam filed in the electronic medical record. 16 were classified as limb-girdle muscular dystrophy autosomal recessive 2, 4 as Miyoshi muscular dystrophy 1, 2 as proximo-distal onset and 1 as asymptomatic hyperCKemia. The mean age of onset was 23.93 years. Reduced proximal strength in the lower limbs was the most common first symptom (65.21%). Thighs adduction was the most affected movement in the first evaluation (mean strength=3.27). Plantar flexion was the movement with the greatest decline in strength (mean=0.10 points on the MRC scale per year; p<0.001). The average functional decline was 0.2987 points on the GMW scale per year (p<0.001). The most common mutations were c.6124C>T,Arg2042Cys and c.2643+1G>A, p.?(splicing), found 3 times each. The mean value of creatinophosphokinase in the first evaluation was 6096.58 μmol/L, with a mean rate of decline of 189.16 μmol/L per year (p=0.02). In imaging exams, the gluteus minimus, adductor longus and soleus muscles were those with the highest degree of liposubstitution in the pelvis, thighs and legs, respectively (mean=2.56, 3.62 and 3.75 respectively). There was no statistical difference in the age of onset, strength, motor and functional decline, serum creatinophosphokinase levels or liposubstitution in imaging exams between the phenotypes in the sample. Conclusion: This study corroborates with recent findings that proposes that dysferlinopathies are not different diseases, but a continuum of a single condition.