Genetic Counselling for Maternally Inherited Mitochondrial Disorders

Abstract

The aim of this review was to provide an evidence-based approach to frequently asked questions relating to the risk of transmitting a maternally inherited mitochondrial disorder (MID). We do not address disorders linked with disturbed mitochondrial DNA (mtDNA) maintenance, causing mtDNA depletion or multiple mtDNA deletions, as these are autosomally inherited. The review addresses questions regarding prognosis, recurrence risks and the strategies available to prevent disease transmission. The clinical and genetic complexity of maternally inherited MIDs represent a major challenge for patients, their relatives and health professionals. Since many of the genetic and pathophysiological aspects of MIDs remain unknown, counselling of affected patients and at-risk family members remains difficult. MtDNA mutations are maternally transmitted or, more rarely, they are sporadic, occurring de novo (~25%). Females carrying homoplasmic mtDNA mutations will transmit the mutant species to all of their offspring, who may or may not exhibit a similar phenotype depending on modifying, secondary factors. Females carrying heteroplasmic mtDNA mutations will transmit a variable amount of mutant mtDNA to their offspring, which can result in considerable phenotypic heterogeneity among siblings. The majority of mtDNA rearrangements, such as single large-scale deletions, are sporadic, but there is a small risk of recurrence (~4%) among the offspring of affected women. The range and suitability of reproductive choices for prospective mothers is a complex area of mitochondrial medicine that needs to be managed by experienced healthcare professionals as part of a multidisciplinary team. Genetic counselling is facilitated by the identification of the underlying causative genetic defect. To provide more precise genetic counselling, further research is needed to clarify the secondary factors that account for the variable penetrance and the often marked differential expressivity of pathogenic mtDNA mutations both within and between families.

Increased mtDNA Copy Number Does Not Protect Against LHON

“…2 We also do not agree with the notion that mtDNA itself contributes to the copy number and the heteroplasmy rate. The heteroplasmy rate is predominantly influenced by the bottleneck effect during early oogenesis and probably also during mitotic segregation of the mutation in postmitotic tissues.…”

Assisted reproductive technologies to prevent human mitochondrial disease transmission

“…Homoplasmy for abnormal mtDNA is generally associated with the most severe disease, although sometimes it is compatible with life and associated with less severe symptoms. For example, Leber hereditary optic neuropathy ( Table 1) is typically caused by homoplasmy for mutated mtDNA and causes blindness in early adulthood with relatively low penetrance [12][13][14] .…”

Kearns-Sayre syndrome is genetically and phenotypically heterogeneous

“…Though KSS is usually sporadic, in about 4% of the cases there is transmission via the maternal line. 3 If cerebral lesions in KSS also occur bilaterally in the substantia nigra, as mentioned in the discussion, we can expect that at least some KSS patients present with Parkinsonism. However, no reports about KSS and Parkinsonism have been published.…”