Muscle and bone characteristics of a Chinese family with spinal muscular atrophy, lower extremity predominant 1 (SMALED1) caused by a novel missense DYNC1H1 mutation

Figures

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  Fig. 1. Pedigree of the family with SMALED1. Filled and open symbols represent affected and open symbols unaffected individuals, respectively; and squares and circles indicate males and females, respectively. The proband is indicated by an arrow. Slashes indicate deceased individuals. *DNA available

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  Fig. 2. Photographs of the proband, his mother, and 2 uncles. (a–d) The proband had predominant lower limb atrophy, talipes calcaneovarus, and knee flexion contractures. He stood on the ground with his heels and could only walk with the assistance of ankle fixation braces. (e, f) The proband’s mother had milder lower limb atrophy and clubfeet. She was able to walk independently with a waddling gait starting from the age of 8 years old. (g, h) The proband’s 2 uncles had lower limb atrophy and clubfeet

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  Fig. 3. X-ray radiography and leg muscle MRI of the proband. (a, b, e) X-ray radiography of thoracic and lumbar vertebrae as well as hips was normal and showed no fractures. (c, d, f, g) X-ray radiography of the knees showed soft tissue swelling and ankles showed talipes calcaneovarus and poor alignment of the tibial talus joints. (h) Coronal T1W MRI of calf muscle with severe atrophy and fatty infiltration. Bone marrow oedema of the left calcaneus resulting from the ankle fixation braces that the proband had worn for a long time can be seen. (i) Coronal T1W MRI of distal thigh muscle with severe atrophy and fatty infiltration in posterior thigh muscles. (j) Axial T2W MRI of calves with severe atrophy and subcutaneous fat thickening

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  Fig. 4. Sanger sequencing of the DYNC1H1 variant. (a) Results of Sanger sequencing show the DYNC1H1 mutation (c.587T > C, p.Leu196Ser) in the proband, his mother, and 2 uncles. (b) Amino acid sequence alignment of DYNC1H1 protein from different species reveals that the Leu196 residue is highly conserved. (c) Three-dimensional structure of the analogous region of the human cytoplasmic dynein N-terminal dimerisation domain. The yellow dotted lines represent the hydrogen bond

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  Fig. 5. Schematic representation of DYNC1H1 protein structure and 105 likely pathogenic or pathogenic missense variants in the ClinVar database. DYNC1H1-NMD variants (dark red) are mainly located in the tail region, predominantly within the dimerisation domain, whereas DYNC1H1-NDD variants (blue) are primarily distributed in the motor region. Four variants (p.R598C, p.Y1057C, p.R1201S, and p.R1962H) are shown in both colours because their phenotypes overlap. Variants that are not associated with definitive phenotypes were shown in black. The novel variant (p.L196S) identified in this study is shown in red bold type. Abbreviations: DYNC1H1-NMD, DYNC1H1 neuromuscular disorder; DYNC1H1-NDD, DYNC1H1 neurodevelopmental disorder; MTBD, microtubule-binding domain