Primary mitochondrial disease as a rare cause of unclear breathlessness and distinctive performance degradation – a case report 2023 Ewert et al

[Andy]

Abstract

Background
Primary muscular disorders (metabolic myopathies, including mitochondrial disorders) are a rare cause of dyspnea. We report a case of dyspnea caused by a mitochondrial disorder with a pattern of clinical findings that can be classified in the known pathologies of mitochondrial deletion syndrome.

Case presentation
The patient presented to us at 29 years of age, having had tachycardia, dyspnea, and functional impairment since childhood. She had been diagnosed with bronchial asthma and mild left ventricular hypertrophy and treated accordingly, but her symptoms had worsened. After more than 20 years of progressive physical and social limitations was a mitochondrial disease suspected in the exercise testing. We performed cardiopulmonary exercise testing (CPET) with right heart catheterization showed typical signs of mitochondrial myopathy. Genetic testing confirmed the presence of a ~ 13 kb deletion in mitochondrial DNA from the muscle. The patient was treated with dietary supplements for 1 year. In the course of time, the patient gave birth to a healthy child, which is developing normally.

Conclusion
CPET and lung function data over 5 years demonstrated stable disease. We conclude that CPET and lung function analysis should be used consistently to evaluate the cause of dyspnea and for long-term observation.

Open access, https://bmcpulmmed.biomedcentral.com/articles/10.1186/s12890-023-02391-x

 

[RedFox]

Wow, she lost 13kb of her mtDNA; a healthy person has 16kb. I can't believe that's survivable. If before I saw this article, you asked me what would happen to someone who didn't inherit 80% of their mitochondrial DNA, I would have said they wouldn't even be born. How is this possible?

 

[SNT Gatchaman]

Mitochondrial DNA from the muscle showed a deletion of bases 3,261 to 16,068 with 36% heteroplasmy.

From Mitochondria and Diseases (ScienceDirect)

Heteroplasmy describes the situation in which two or more mtDNA variants exist within the same cell. Heteroplasmies are often caused by de novo mutations occurring either in the germline or in the somatic tissues. In fact, heteroplasmy levels often vary even between the cells or somatic tissues of the same individual, leading to situations where only specific cells, tissues, or organs are affected by mitochondrial dysfunction. The accumulation of these mutations in somatic tissues over time may be a central factor in aging.

Instead of the discrete allele frequencies of 0%, 50%, or 100% observed for alleles of nuclear genes, allele frequencies for mtDNA loci have a continuous distribution ranging from 0% to 100% (“homoplasmy”). The threshold for the disease phenotypes can be anywhere along that distribution, depending on the gene and tissue in question. Thus, as we will see in the discussion of primary mitochondrial diseases later, low-mutation heteroplasmy is unlikely to cause a discernible phenotype, whereas high-mutation heteroplasmy is very likely to cause problems, especially when present in an energy-sensitive organ like the brain or muscles. The lack of paternal contribution precludes compensation for a defective allele inherited from the mother by a functional “wild-type” allele from the father. Furthermore, even if a heteroplasmy is subthreshold for disease presentation in the mother, the disease may occur in her offspring depending on how the mtDNA molecules are apportioned to her oocytes during gametogenesis.

 

[RedFox]

Oh, so this person had the deletion in only 36% of her cells?