Pregnancy in a woman with MPV17-related mitochondrial DNA depletion syndrome: A Case and Perspective.


Clinical Management

Poster Number: 31


Mai Yamakawa, MD, University of California Los Angeles, Perry Shieh, MD, PhD, University of California, Los Angeles

29-year-old woman of Armenian descent presented for slowly progressive weakness, numbness, and imbalance since age of 9 years, associated with asymmetric ptosis, migraines, neuropathic pain, and muscle cramps. Family history was significant for mildly affected brother. She was diagnosed as CMT in 1996 without genetic diagnosis. Neurological exam revealed anisocoria, left ptosis, symmetric distal weakness, areflexia, and stocking-and-glove pattern of sensory loss in all modality. EMG/NCS showed severe sensorimotor axonal polyneuropathy. Targeted genetic testing for CMT in 1999 and clinical whole exome sequencing in 2014 did not reveal causative mutations. Whole genome sequencing in 2017 revealed compound heterozygous mutation in MPV17 gene (c. 206G>A (p. Trp69*), c. 376-9T>G (3’- splice site mutation that results in in-frame deletion of 11 amino acids)). MPV17 is nuclear DNA that encodes a putative channel-forming protein that localizes in the inner mitochondrial membrane and is involved in mitochondrial deoxynucleotide homeostasis. MPV17 mutations are associated with mitochondrial DNA depletion syndrome 6 with reported multiple mtDNA deletions 6. One of the reported phenotypes is an axonal sensorimotor polyneuropathy (CMT2EE) as in this patient. Our patient pursued in vitro fertilization with a sperm donor who was confirmed negative for mutations in MPV17, followed by routine prenatal genetic testing. It is possible, however, that the fertilized oocyte may have mitochondria with mtDNA deletions due to the mother’s mutation, and thus the embryo may have inherited mtDNA deletions. There are no reported cases of symptomatic mitochondrial DNA depletion syndrome patients who pursued pregnancy, as most patients are severely affected by infancy. Prenatal genetic counseling for mitochondrial diseases is based on guidelines for asymptomatic carriers and mildly affected mothers by mtDNA mutations, and not for mitochondrial DNA depletion syndrome. Appropriate pre-pregnancy consultation by a multidisciplinary team is needed to deliver optimal genetic counseling throughout pregnancy due to the unique pathophysiology.