Background Spinal muscular atrophy, lower extremity predominant (SMALED) is a type of non-5q spinal muscular atrophy characterised by weakness and atrophy of lower limb muscles without sensory abnormalities. SMALED1 can be caused by dynein cytoplasmic 1 heavy chain 1 (DYNC1H1) gene variants. However, the phenotype and genotype of SMALED1 may overlap with those of other neuromuscular diseases, making it difficult to diagnose clinically. Additionally, bone metabolism and bone mineral density (BMD) in patients with SMALED1 have never been reported. Methods We investigated a Chinese family in which 5 individuals from 3 generations had lower limb muscle atrophy and foot deformities. Clinical manifestations and biochemical and radiographic indices were analysed, and mutational analysis was performed by whole-exome sequencing (WES) and Sanger sequencing. Results A novel mutation in exon 4 of the DYNC1H1 gene (c.587T > C, p.Leu196Ser) was identified in the proband and his affected mother by WES. Sanger sequencing confirmed that the proband and 3 affected family members were carriers of this mutation. As leucine is a hydrophobic amino acid and serine is hydrophilic, the hydrophobic interaction resulting from mutation of amino acid residue 196 could influence the stability of the DYNC1H1 protein. Leg muscle magnetic resonance imaging of the proband revealed severe atrophy and fatty infiltration, and electromyographic recordings showed chronic neurogenic impairment of the lower extremities. Bone metabolism markers and BMD of the proband were all within normal ranges. None of the 4 patients had experienced fragility fractures. Conclusion This study identified a novel DYNC1H1 mutation and expands the spectrum of phenotypes and genotypes of DYNC1H1-related disorders. This is the first report of bone metabolism and BMD in patients with SMALED1.

PurposeNearly 85%-90% of osteogenesis imperfecta (OI) cases are caused by autosome dominant mutations of COL1A1 and COL1A2 genes, of which de novo mutations cover a large proportion, whereas their characteristics remain to be elucidated. This study aims to compare the differences in clinical and genetic characteristics of de novo and inherited COL1A1/COL1A2 mutations of OI, assess the average paternal and maternal age at conception in de novo mutations, and research the rate of nonpenetrance in inherited mutations.Materials and MethodsA retrospective comparison between de novo and inherited mutations was performed among 135 OI probands with COL1A1/COL1A2 mutations. Mutational analyses of all probands and their family members were completed by Sanger sequencing. A new clinical scoring system was developed to assess the clinical severity of OI quantitatively.ResultsA total of 51 probands (37.78%) with de novo mutations and 84 probands (62.22%) with inherited mutations were grouped by the results of the parental gene verification. The proportion of clinical type III (P<0.001) and clinical scores (P<0.001) were significantly higher in de novo mutations. Missense mutations covered a slightly higher proportion of de novo COL1A1 mutations (46.34%) compared with inherited COL1A1 mutations (33.33%), however, lacking a significant difference (P=0.1923). The mean BMD Z/T-score at the lumbar spine in de novo mutations was -2.3 ± 1.5, lower than inherited mutations (-1.7 ± 1.8), but lacking statistical significance (P=0.0742). There was no significant difference between the two groups in OI-related phenotypes (like fracture frequency, blue sclera, and hearing loss) and biochemical indexes. In de novo mutations, the average paternal and maternal age at conception was 29.2 (P<0.05) and 26.8 (P<0.0001), respectively, which were significantly younger than the average gestational age of the population. Additionally, 98.04% of pedigrees (50/51) with de novo mutations were spontaneous conception. The rate of nonpenetrance of parents with pathogenic variants in the inherited mutation group was 25.64% (20/78).ConclusionsOur data revealed that the proportion of clinical type III and clinical scores were significantly higher in de novo mutations than in inherited mutations, demonstrating that de novo mutations are more damaging because they have not undergone purifying selection.