Explain the current general diagnostic algorithm for suspected mitochondrial diseases.

What
are its major limitations? How do you foresee a future diagnostic algorithm?

Mitochondrial diseases are a diverse group of disorders caused by dysfunction of the

mitochondria, which are cellular organelles responsible for generating energy. Understanding
the underlying causes of mitochondrial diseases is critical for developing effective treatments
and cures for affected individuals. Additionally, because mitochondrial diseases are often
inherited maternally and can affect multiple generations, understanding their genetic basis is
essential for developing genetic counseling and family planning options for affected families.

The key to a successful diagnostic algorithm of mitochondrial diseases is thorough clinical

observation and awareness, which includes a insightful medical history, physical examination,
and laboratory tests.. The next step in the algorithm should be biochemical exams of the
patients. This includes laboratory work of different substances associated with the work of
mitochondria including blood lactate, creatine, kinase, amino acids etc. Genetic testing is an
essential component of the diagnostic algorithm for mitochondrial diseases. It can involve not
only the analysis mitochondrial DNA but also the investigation of nucleic DNA. Sequencing of
mitochondrial DNA (mtDNA) can be very difficult, because mtDNA is present in multiple copies
per cell, and mutations may be heteroplasmic (i.e., present in only a subset of mtDNA
molecules). Genetic testing may also involve testing of family members to help confirm a genetic
diagnosis. Genetic testing can be sometimes misleading due to technological limits. It is implied
that not every mutation can be yet detected. Detailed clinical and laboratory test are relevant
for the accurate interpretation of new genetic mutations that are identified through next
generation sequencing technologies. The patient's age, presence of consanguinity, and common
genetic founder mutations in certain regions also play a significant role in the diagnostic
algorithm. When no diagnosis is made, further genetic studies such as exome sequencing or
genome sequencing for detecting nDNA mutations or clinically relevant or affected tissue testing
should be performed.

The current development of a general diagnostic algorithm is complicated because of a diverse

amount of phenotypes that imply dysfunction in almost any type of tissue in the organism. Many
times the genotype and the phenotype have an unclear relationship. Some of the mtDNA
mutations can cause many different diseases or vice versa, many mutation can cause the same.

In the future the development of technologies like genome sequencing and bioinformatics will
be crucial when it comes to diagnostics of mitochondrial diseases. This can help in being more
specific and will make the identification easier. Another important thing are biomarkers. The
development of markers that can be measured in the blood of patients would make a big
difference in non-invasive and reliable results. Lastly AI will probably revolutionise not only the
way that mitochondrial diseases are diagnosed, but the whole medical world. Patterns that are
impossible to see for a human eye could be easily found with artificial intelligence.

Katharina Hӓusler