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case_images: Distinct LDHA peptides identified in the proteomics experiment. (A)  Peptides are represented by lines showing their start and end amino acid position in the LDHA protein sequence (x-axis). In box 2 patient, only two peptides were found, shown in red. (B) Boxplot showing the distribution of the number of distinct LDHA peptides found in other individuals (N = 216).
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case_images: Mapping of precursor peptides on the protein sequence indeed indicated the expression of a truncated protein compared to controls, where identified unique peptides span the entire amino acid sequence of LDHA (Figure A2).
case_images: PMC11763865_02
case_images: Histology and proteomics results of the case example presented in box 3. (A) Hematoxylin-eosin stain of patient-derived muscle biopsy specimen shows reduced muscle fiber caliber. (B) The gomori-trichrome stain of the patient-derived muscle biopsy specimen shows no indications of mitochondrial disease in terms of ragged red fibers. (C) The NADH-trichrome stain of the patient-derived muscle biopsy specimen does not reveal significant indications of abnormal mitochondrial distribution and/or activity. Scale bars = 75 microm. (D) Volcano plot showing the proteomics outliers of the patient presented in this box. Horizontal dotted lines represent nominal and proteome-wide significance thresholds. Vertical dotted lines represent fold changes 0.6 and 1.67.
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case_images: Quadriceps muscle biopsy showed reduced muscle fiber caliber, but no pathological changes strongly indicative of the presence of a mitochondriopathy (Figure A3A-C). This approach revealed the significant dysregulation of 38 proteins of complex I of the mitochondrial respiratory chain, raising suspicion of a primary defect in a gene that encodes a component of this complex (Figure A3D).
case_images: Percentages of coverage of proteins relevant for CMS, SMA, and myopathies in SMO. Numbers above the respective stacked bars refer to the total number of proteins attributed to these diseases based on pathogenic variants in the corresponding genes.
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case_images: These proteins cover 41% of the proteins attributed to the manifestation of subtypes of congenital myasthenic syndromes (CMS; Figure A4), based on pathogenic variants in the corresponding genes, as well as 84% and 69% of proteins responsible for the manifestation of spinal muscular atrophy and myopathies, respectively (for more details see Supplementary Table S1). This protein catalog may aid in the selection of neuromuscular diseases that are suitable for analysis in human SMOs.