RESUMO
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.
RESUMO
BACKGROUND: LAMA2-related muscular dystrophy is a disorder that causes muscle weakness and varies in severity, from a severe, congenital type to a milder, late-onset form. However, the disease does not only affect the muscles, but has systemic involvement and can lead to alterations such as brain malformation, epilepsy and intellectual disability. OBJECTIVE: Describe the frequency of cortical malformations, epilepsy and intellectual disability in LAMA2-RD in a Brazilian cohort and correlate the neurological findings to genetic and motor function. METHODS: This is an observational study of 52 LAMA2-RD patients, who were divided into motor function subgroups and compared based on brain MRI findings, epilepsy, intellectual disability, and type of variants and variant domains. RESULTS: 44 patients (84.6%) were only able to sit, and 8 patients (15.4%) were able to walk. 10 patients (19.2%) presented with cortical malformations (polymicrogyria, lissencephaly-pachygyria, and cobblestone),10 patients (19.2%) presented with epilepsy, and 8 (15.4%) had intellectual disability. CNS manifestations correlated with a more severe motor phenotype and none of the patients able to walk presented with cortical malformation or epilepsy. There was a relation between gene variants affecting the laminin-α2 LG-domain and the presence of brain malformation (Pâ=â0.016). There was also a relation between the presence of null variants and central nervous system involvement. A new brazilian possible founder variant was found in 11 patients (21,15%) (c.1255del; p. Ile419Leufs*4). CONCLUSION: Cortical malformations, epilepsy and intellectual disability are more frequent among LAMA2-RD patients than previously reported and correlate with motor function severity and the presence of variants affecting the laminin-α2 LG domain. This brings more insight fore phenotype-genotype correlations, shows the importance of reviewing the brain MRI of patients with LAMA2-RD and allows greater attention to the risk of brain malformation, epilepsy, and intellectual disability in those patients with variants that affect the LG domain.