Mitochondrial Factors and VACTERL Association-Related Congenital Malformations

Abstract

VACTERL/VATER association is a group of congenital malformations characterized by at least 3 of the following findings: vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities. To date, no unifying etiology for VACTERL/VATER association has been established, and there is strong evidence for causal heterogeneity. VACTERL/VATER association has many overlapping characteristics with other congenital disorders that involve multiple malformations. In addition to these other conditions, some of which have known molecular causes, certain aspects of VACTERL/VATER association have similarities with the manifestations of disorders caused by mitochondrial dysfunction. Mitochondrial dysfunction can result from a number of distinct causes and can clinically manifest in diverse presentations; accurate diagnosis can be challenging. Case reports of individuals with VACTERL association and confirmed mitochondrial dysfunction allude to the possibility of mitochondrial involvement in the pathogenesis of VACTERL/VATER association. Further, there is biological plausibility involving mitochondrial dysfunction as a possible etiology related to a diverse group of congenital malformations, including those seen in at least a subset of individuals with VACTERL association.

Keywords: Congenital malformations; Inborn errors of metabolism; Mitochondrial dysfunction; Respiratory chain; VACTERL; VATER.

Fig. 1

Overview of mitochondrial location and anatomy, showing a human cell containing multiple mitochondria, as well as the respiratory chain complexes. Many mitochondrial proteins are encoded by nuclear DNA and transported into the mitochondria by specialized transport systems (arrow). Multiple mtDNA molecules are located within the mitochondrial matrix. Each mtDNA molecule encodes 37 proteins, of which 13 are part of the respiratory chain. The respiratory chain, shown in more detail in the bottom portion of the figure, is located on the inner mitochondrial membrane, and consists of 5 different complexes. Within the mitochondrial matrix, pyruvate enters the tricyclic acid cycle, which is linked with the respiratory chain through complex II. Except for complex II, all complexes of the respiratory chain are encoded by both nuclear and mtDNA.

Fig. 2

Key features and concepts involved in mitochondrial inheritance. A maternal cell may be heteroplasmic for mutant mtDNA and wildtype mtDNA. During mitotic segregation, mutant and wildtype mtDNA are distributed randomly among the daughter cells, resulting in a distribution of the degree of heteroplasmy in daughter cells. Selective mtDNA replication and amplification further increases the level of heteroplasmy in mature oocytes. As only oocytes contribute mitochondria to the zygote, the level of mutant mtDNA depends on the mtDNA mutant load inherited from the mother. If the mutant load remains below a tissue-specific threshold, the offspring may not demonstrate a detectable disease phenotype. However, depending on the proportion of mutant mtDNA, the offspring may show a variable phenotype, with the severity of manifestations as least partially related to the mutant load.

Fig. 3

Involvement of multiple organ systems in mitochondrial disorders as well as related inborn errors of metabolism. Organ systems underlined/in bold indicate those in which there is most frequently a clinical overlap between individuals with VACTERL association and mitochondrial disorders/related IEM.