It's All In The Genes

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VMP's Dr Fran Kendall Factoid Friday Blog on Rare Diseases


Mitochondrial disease is an umbrella heading that encompasses a number of well described subtypes including MELAS and MERRF and many other nonspecific disorders all affecting the body's ability to adequately produce energy.

The genetics that regulate mitochondrial functioning is as diverse and widespread as the various subtypes it generates. However, many people have limited understanding of the complexities of mitochondrial genetics  leaving them confused and confounded in regards to risks for children, themselves, or other family members.

Because understanding mitochondrial  Genetics has profound implications for an extended family, grasping the basic principles is important to understand your disease or that of your child or family member.

The Power of Two Genomes

Understanding two basic concepts regarding mitochondrial genetics is critical for understanding the principles that govern the inheritance of mitochondrial disease. The first is that there are approximately 1500 different genes that regulate mitochondrial functioning.  These genes encode for a whole host of proteins including the various complexes of the electron transport chain, the biochemical pathway that produces energy, assembly proteins that coalesce the subunits of the complexes, and transport proteins that allow for the movement of various compounds in and out of the mitochondria. Defects in any of these genes and resulting proteins can lead to inadequate energy production and mitochondrial disease. In contrast, many of the commonly known and understood inherited diseases such as cystic fibrosis, Tay-Sachs, and sickle cell anemia are due to an alteration in one gene which results in one damaged protein and subsequent disease. Clearly, having 1500 different players in mitochondrial metabolism makes the disease group broad, extensive and variable.

The second basic principle required to grasp  the genetics of mitochondrial disease is understanding that two sets of genetic material or code are involved in regulating mitochondrial metabolism. The best understood and well described is the maternally inherited mtDNA. Housed within a circular Molecule that resides within the mitochondria themselves, this genetic material is passed from mother to child from generation to generation via the egg cell and encompasses a total of 37 genes. (Remember, that we all begin as an egg cell subsequently fertilized by a sperm. The structure of the egg cell which includes mitochondria comes from our mothers although subsequent replication of that cell requires input from our fathers' genetic blueprint.)   These 37 genes were sequenced a number of years ago and some of the commonly known and understood mitochondrial diseases such as MELAS and MERRF were found to be caused by mutations in these genes in the 1980's.

The remaining 1400+ genes are inherited through both of our parents and are housed in the nucleus or command center of our body's cells.  Together, these mitochondrial and nuclear mitochondrial genes encompass the blueprint or genetic code that regulates our mitochondrial machinery.

The Mitochondrial Genome

While somewhat of a misnomer leading one to believe that this genetic material alone regulates mitochondrial functioning, mitochondrial DNA or mtDNA is merely the subset of genes regulating mitochondrial function that are inherited exclusively through the maternal line.

The mtDNA is a circular molecule present in 5 to 10 copies and each of mitochondria and composed of 16,569 basis or 37 genes. In addition, dependent on the cell type, there are hundreds to thousands of mitochondria per cell. These 37 genes encode for 22 tRNAs, 13 polypeptides or proteins of the respiratory chain including seven subunits of complex one, one subunit of complex III, three subunits of complex IV, two subunits of complex V and two ribosomal RNA's. Essentially, these genes are an integral part of the machinery that allows the mitochondria to be created and to function.

Mutations in the mtDNA arise either de Novo, meaning are present only in the affected individual, or are maternally inherited. In most cases, mtDNA point mutations or mutations that alter just one base pair or bead on the string of a gene, are inherited, whereas large deletions, a loss of big chunks of genetic material, are typically de novo in nature and not passed on from mother to child.

Another unique feature of the mtDNA is heteroplasmy in which mutated mtDNA may be present in varying amounts with wild type or typical DNA within the same cell. When the percentage of mutated DNA (mutation load) reaches a certain threshold the function of the tissue may become impaired.  The mutation load varies by tissue type, age, and specific mutation. Thus, the mutation load varies within and between tissues leading to broad spectrum of clinical symptoms that can range from healthy and asymptomatic to severely impacted. And certain tissues, like blood, there may be selection again some of these mutations with preferential retention of cells with normal mtDNA.

Many of the well-known and well described subtypes of mitochondrial disease to include MELAS, MERRF, Kearns Sayre syndrome, and Pearson syndrome all result from point mutations and deletions in the mtDNA.

The Nuclear Genes

As previously stated, the other remaining 1400+ genes that regulate mitochondrial production and function are encoded by nuclear mitochondrial genes inherited from both parents and are housed within the center of the cell or nucleus.

Hundreds of proteins are in coded for by the nuclear mitochondrial genes and many of these proteins are responsible for the control of electron transport chain function, structure, and assembly. Included in these nuclear genes are 36 subunits of complex I, all for subunits of complex II,  10 subunits of complex III, 10 subunits of complex IV and 14 subunits of complex V.  In addition, there are also a number of very critical assembly genes found among the nuclear mitochondrial genes. For example, SURF 1 is involved in assembling the various components of cytochrome C oxidase or complex IV of the electron transport chain. In some studies, over 75% of Leigh disease patients with cytochrome C oxidase deficiency were found to have SURF 1 mutations.

Overall, the vast majority of pediatric mitochondrial disease is due to autosomal recessive inheritance affecting nuclear mitochondrial genes meaning that each parent contributes a defective or altered gene that when inherited together result in disease. In 1998, Lamont at all demonstrated that mitochondrial DNA mutations account for less than 10% of all mitochondrial disorders in children.

With the advances in molecular biology, many more mitochondrial nuclear gene mutations have been identified in recent years and to include POLG, SURF 1, OPA 1, BCS1L and many others.

The Inheritance Pattern of Mito Genes

Mitochondrial disease inheritance patterns are extensive and lead to considerable confusion in the patient population. Many are under the misperception that mitochondrial disorders are all maternally inherited when in fact only a fraction of mitochondrial disorders are passed on through the mother's line with the vast majority of cases being inherited via the nuclear genes in a host of patterns in including X-linked, autosomal dominant, and autosomal recessive.  A number of mitochondrial disorders also occur sporadically meaning their disease was not inherited from either parent but rather occurred spontaneously in them alone.

MtDNA point mutations are typically maternally inherited although there are reported cases of sporadic occurrence. Unfortunately, Mothers who harbor an mtDNA mutation face up to 100% recurrence risk for each and every pregnancy they consider. However, because of the concept of heteroplasmy each subsequent child can have a variable amount of mutated DNA leading to a broad spectrum of clinical presentation. As such, some children may be severely affected due to a high mutation load while others are clinically spared. MtDNA deletions are generally de novo or occur only in the affected person and our associate it with a very low recurrence risk for offspring.

Alterations in nuclear mitochondrial genes cause the vast majority of mito disease. As previously noted, in the pediatric population studies indicate that 75 to 90% of disease is inherited in an autosomal recessive fashion in which each parent is a carrier of an altered gene that when inherited together result in disease. Others are autosomal dominant in which the presence of only one gene copy change can lead to disease, some are X-linked such as Barth syndrome effecting primarily boys, and yet others are sporadic meaning the genetic change is not found in other family members.

Knowledge of the gene mutation in you or your child is required to predict accurate recurrence risks. Without an identified gene mutation, we can offer only our best guesstimate in regards to your family's risks.

What's in YOUR Genes?

In recent years, advances in molecular genetics and increased commercialization of testing, has allowed many patients access to technology leading to a classification of their mitochondrial disease on a genomic basis. Unfortunately, though, some insurance plans, including many federal and state-based policies do not provide coverage for genetic testing. In addition, many people around the globe also do not have access to advanced genomics due to restrictions in socialized medical programs or simply due to lack of advanced medical care in their countries.  Nonetheless, many patients have had their diseases categorized molecularly utilizing these genomic tools.

Why is understanding your disease on a molecular basis important? First and foremost, finding a causative gene confirms your diagnosis and assures that you are not mis-categorised or classified incorrectly.  I have diagnosed and rediagnosed numerous patients utilizing advanced genomics and on a number of occasions, the diagnosis leads to treatment modalities previously untried or considered and ultimately an improvement in quality of life for that patient. In the case of mitochondrial disease, where treatment is primarily symptomatic, having a clear genetic diagnosis enables patients to participate in clinical treatment trials if they otherwise qualify. Lastly, having a gene diagnosis clearly allows families to understand their recurrence risks and implications for other possibly affected family members.

In summary, and conclusion, the genetics of mitochondrial disease is complex and involves two separate genomes, the mtDNA and the nuclear mitochondrial genes. Inheritance patterns range from the maternal and sporadic inheritance of the mitochondrial genome to a host of possibilities when nuclear genes are involved, most commonly autosomal recessive in the pediatric population.

Aside from allowing for accurate recurrence risk information, a genetic diagnosis can provide confirmation of a specific disease as well as information regarding treatment modalities that may improve quality-of-life.

As such, in our practice, we encourage all patients and families to pursue genetic studies if at all possible.


Fran Kendall, MD

Founder, Managing Director of VMP Genetics, Clinical Biochemical Geneticist


This post is not meant to be a recommendation or a substitute for professional advice and services rendered by qualified doctors, allied medical personnel, and other professional services. The responsibility for any use of this information, or for proper medical treatment, rests with you.