Figure 2: Contents of the MACCR dataset.

(a) Concept overlap among CCRs in the MACCR set. We assigned each report to one or more disease categories based on involvement of particular organ systems. Reports describing presentations of rare diseases, including mitochondrial rare diseases, were assigned to the Rare Disease category as well. Here, we show the total count of reports labeled with single or multiple disease categories (Disease Category Overlap, top) as an UpSet plot⁵⁹. Counts of reports involving rare diseases (n = 751) are highlighted in red. Total counts irrespective of overlap with other categories are also shown at right. For example, 435 CCRs involve cardiovascular disease (CVD) without specific involvement of other organ systems, yet 967 CCRs involve CVD alone or along with other disease categories. Otorhinolaryngologic reports constitute the smallest category in the MACCR set (n = 58); their counts are omitted here. (b) Distribution of disease categories across all published case reports. Here, we determined disease category assignment across all 1.89 million published CCRs (as of August 2018) using sets of MeSH terms corresponding to each category. As in Part A, a report may belong to multiple categories. More than a quarter of all reports in this broad set involve cancer, differing from the report distribution in the MACCR set, though in both sets, cancer, cardiovascular disease, and neuronal disease are the most common three disease categories. (c) Contribution of mitochondrial disease CCRs. 246 CCRs cover a sample of rare mitochondrial diseases, including Barth syndrome, carnitine deficiency, and deficiencies of the respiratory chain complexes. The distribution of CCR publication year is displayed on the left for each disease, and the affected components of the mitochondrion are represented in the diagram to the right. Complex I, II, III, IV, and V deficiencies each cause impairment in their respective component of the respiratory chain, resulting in a range of cardiovascular, neurological, muscular, and metabolic phenotypes. Barth syndrome is caused by a mutation in the tafazzin protein that renders it incapable of creating properly formed cardiolipin (CL) for the inner mitochondrial membrane (IMM). Phosphatidylcholine (PC) is unable to form the tight bends of the cristae, severely limiting energy generation and leading to cardiovascular complications. The timeline below depicts key advancements and discoveries relating to rare mitochondrial disease diagnosis. OMM: outer mitochondrial membrane. IMS: intermembrane space.