Analysis of diagnostic pitfalls in 125 genetically confirmed cases of distal myopathies

Figures

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  Figure 1.. Patient cohort representation. (A) Pie chart showing the proportion of cases with causative variants identified by different molecular genetic studies. WES, whole exome sequencing; WGS, whole genome sequencing; qPCR, quantitative polymerase chain reaction; FSHD, facioscapulohumeral muscular dystrophy (B) Venn diagram showing the overlap of cases with available clinical examination, muscle MRI, and EMG data.

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  Figure 2.. Genetic studies results. (A) Genes causative of DM in our cohort. Percentages indicate the proportion of families with the variants in this gene among 103 families with DM. (B) The distribution of causative variants in the cohort according to ACMG criteria.

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  Figure 3.. Clinical and muscle MRI findings in patients with some DMs. (A, B) A 50-year-old female with COL6A1-myopathy (A) Distal muscle atrophy, classical “inverted champagne bottle” appearance of the lower legs, pes cavus, and mild hand muscle atrophy. (B) Axial T1-WI muscle MRI demonstrating the “sandwich” pattern and “target” sign typical for collagen VI-related myopathies. (C) Axial T1-WI muscle MRI of a 52-year-old female with COL6A1-myopathy showed a “sandwich” and target sign in vasti muscles and rectus femoris, respectively. (D, E) A 17-year-old female (D) and a 38-year-old female (E) with ACTA1-related myopathy showing a clearly distal phenotype, including hand and lower leg muscle atrophy. (F) A 36-year-old male with NEB-related myopathy presenting with lower leg muscle atrophy, pes cavus, and hammertoes. Axial T1-WI muscle MRI of the lower legs shows mild involvement of the soleus muscles. (G) A 44-year-old female with NEB-related myopathy showing lower leg muscle atrophy. Axial T1-WI muscle MRI demonstrates predominant fatty replacement of the lower leg muscles. (H, I) A 22-year-old male with CAPN3-related myopathy presented clinically predominant lower leg muscles…

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  Figure 4.. Characterization of needle EMG findings. (A) Identified patterns of needle muscle MRI and probable causes of incorrect EMG conclusions. The pie chart demonstrates the proportion of cases in which the EMG pattern was consistently interpreted as myogenic versus other patterns on protocol review. The bar chart indicates the most frequent factors to an initial neurogenic interpretation in EMG reports (high MUP amplitudes, examination of a wrong muscle, and significant spontaneous activity). (B) Spontaneous activity on needle EMG across genetically confirmed DMs. Stacked bar chart showing the distribution of spontaneous activity grades (no, 1+, 2+, 3+) on needle EMG by gene. Segment height reflects the number of patients per gene, with gene-specific colors consistent across all bars. Within each bar, genes are arranged from the most frequent at the bottom to the least frequent at the top. The total number of patients in each category is shown above the bars.

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  Figure 5.. Analysis of muscle MRI studies in the DM cohort (A) Heatmap of modified Mercuri scores across 44 muscles (bilateral thigh and lower leg muscles) in patients with molecularly confirmed DMs. Patients are grouped by gene (ordered by gene frequency), and within each gene group are ordered by overall MRI severity. The blue side stripe demonstrates disease duration (years) for each patient (light to dark indicates shorter to longer disease duration). Color scales for Mercuri scores and disease duration are shown on the right and bottom. (B) Mean modified Mercuri grade (0-4) for each bilaterally assessed muscle, ranked from the most to the least affected. Dots indicate the cohort mean; error bars show bootstrap 95% confidence intervals based on 10,000 resamples (B=10,000).

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  Figure 6.. Comparison of a group of patients with a discordant referral clinical diagnosis and a group of patients in which the referral diagnosis coincided with the molecular diagnosis. The results of the comparison of clinical characteristics (A), neurophysiological (B) and lower limb muscle MRI data (C). The values of the MRC scale were used to calculate the MMT score of the upper limb muscles (arm abduction, wrist flexion and wrist extension, forearms flexor and forearms extensor muscles), hand muscles (dorsal interossei and opponens pollicis muscles), and thigh muscles (thigh flexion, adduction and abduction, lower leg flexion and extension).