ESPE Yearbook of Paediatric Endocrinology

Endocr Rev. 2021 Oct 13;bnab036. PMID: 34644386 doi: 10.1210/endrev/bnab036

Brief Summary: This comprehensive review summarizes the current knowledge on the spectrum of endocrine disorders associated with mitochondrial disease. It provides essential information on the basics and genetics of mitochondrial diseases and details the clinical characteristics, focusing on endocrine and important non-endocrine features. It also provides guidelines/algorithms for diagnosis and management, e.g. for diabetes care and reproductive options.

30 years ago, maternal-inherited diabetes mellitus was first linked to mitochondrial DNA (mtDNA) pathogenic variants in 2 independent pedigrees, where it was found in combination with premature deafness across generations because of either a long mtDNA duplication/deletion (DOI: 10.1038/ng0892-368) or the m.3243A>G variant in the MT-TL1 gene (DOI: 10.2337/diab.43.6.746). Meanwhile large cohort studies have shown that endocrine disorders, such as diabetes mellitus, adrenal and gonadal insufficiency, and hypoparathyroidism, may be prevalent and may precede other classic, clinical manifestations of mitochondrial disorders. On the other hand, in those affected patients with severe, complex other organ system failure (e.g. central or peripheral nervous system (prevalent in 80%), cardiac or kidney), the endocrine effects might be overlooked. Thus, as an endocrinologist it is important to recognize the “red flags” that hint at a mitochondrial origin to endocrine disorders, and to provide expertise on the optimal multi-disciplinary care to individual patients with often multiple organ failure.

Fortunately, the genetic revolution seen with NGS techniques has immensely improved the diagnostic yield of mitochondrial disease. Mitochondrial disorders occur in about 1:5000 of the general population with pathogenic variants in nuclear genes more prominent in childhood-onset forms (80%), and mtDNA variants more common in adult-onset cases. Overall, endocrine manifestations often relate to specific subtypes (genes) of mitochondrial disease and defects of oxidative phosphorylation (OXPHOS). But importantly, mitochondrial DNA genetics differs fundamentally from nuclear DNA genetics. In brief: a) maternal inheritance only, b) cells contain multiple (hundreds to thousands) of mtDNA copies, c) pathogenic mtDNA variants can affect all copies (homoplasmy) or only some (heteroplasmy), thus heteroplasmic defects are mostly functionally recessive and require a threshold to become disease-causing, d) heteroplasmy may be tissue specific and change over time. Thus testing for pathogenic mtDNA variants has to be done with great care using blood, urine sediment or tissue (i.e. muscle) and techniques, such as either targeted pyrosequencing or amplification of mtDNA followed by NGS, which allow sensitive detection of single nucleotide changes and large-scale deletions, as well as quantification of mutant load.

Reproductive options to avoid mitochondrial disease include preimplantation and prenatal testing as well as mitochondrial replacement therapy from healthy donors, but the latter is still an experimental technique in embryos and not in routine use.