IVF Frontier: Preventing the Inheritance of Mitochondrial Diseases

Pre-implantation genetic diagnosis (PGD) of IVF embryos has moved into the mainstream of reproductive medicine. Genetic testing of IVF embryos for known genetic diseases allows the clinician to identify, before implantation, those embryos that carry the genetic mutation for disease. Using this information, patients can choose to have transferred only embryos without the disease gene. Because the abnormal embryos are not transferred and are typically discarded or donated to research, PGD has been rejected by those who are opposed to creating embryos outside of intercourse, especially if not every fertilized egg is given the opportunity to implant. But patients determined to short-circuit genetic disease transmission have initiated a tidal wave of clinics rushing to meet this need. Most centers are either already offering PGD as a service or scrambling to offer it, simply to stay competitive. Parents want their kids to be healthy, period. If that is selfishness, it must be the best kind of selfish.

Given the fierce opposition to IVF initially, then continued opposition to every technological tweak involving IVF (with PGD being only the most recent), it might be prudent for IVF clinicians to get a fire suit for the backlash against the newest  potential IVF genetic therapy application on the  horizon. The United Kingdom has taken the first steps to support translational research which would create an embryo which does not have its mother’s mitochondria and  so can not inherit her mitochondrial mutations. Described as gene therapy for eggs, the maternal DNA is moved to a de-nucleated donor egg with healthy mitochondria, effectively removing the mutated mitochondrial DNA from the mother’s lineage.

A little biology background  may be helpful here. Most of us are familiar with the notion of nuclear DNA and the idea that the genetic information that makes us unique comes from our biological parents, half from Mom, half from Dad. Well, that’s true as far as it goes but there is another kind of DNA called mitochondrial DNA which is found predominately in the egg. Sperm have only a very few mitochondria, just enough to power the sperm to the egg but then the sperm mitochondria are destroyed inside the egg.  Fortunately the egg has a large supply of mitochondria. We get the “starter” mitochondrial DNA from Mom in the egg and then as the egg and later the embryo divides, this mitochondrial DNA gets copied and passed on to all of the resulting cells as life goes on so that all of cells in our body “inherit” mitochondrial DNA from Mom.  Mitochondrial DNA doesn’t determine trait like hair color, eye color etc. but it does “power” everything we do so mutations in its DNA can have devastating effects.

Mitochondria are organelles that provide chemical energy for our cells; they are sometimes referred to as  the “powerhouses” of the cell.  Mitochondria contain a kind of circular DNA that actually may have arisen from a collaboration (or parasitic invasion) of an ancestral eukaryotic cell with bacterial DNA. The mitochondrial DNA contains 13 protein-encoding genes which instruct the production of a variety of proteins for the electron transport chain that converts energy from  the food we eat into stored energy called adenosine triphosphate or ATP. You might recognize some of the proteins (NADH Dehydrogenase, ATP synthase, Cytochrome C oxidase, Coenzyme  Q etc.)  from the Krebs cycle which every biology student has memorized (and probably forgotten) numerous times.

The origin of mitochondrial disease. Mitochondrial DNA tends to have more mutations than nuclear DNA because the repair machinery for mitochondrial DNA is not as good. This prevalence of mutations has an upside because geneticists can use the information to identify related individuals through the maternal line. The downside of these mutations is that certain mitochondrial diseases are created which can be passed on through the maternal line. Some of the most common mitochondrial diseases are in the table below, copied from the article,  Mitochondrial Disorders Overview.

Table 1. Clinical Syndromes of Mitochondrial Diseases

Disorder Primary Features Additional Features
Alpers-Huttenlocher syndrome • Hypotonia
• Seizures
• Liver failure
• Renal tubulopathy
Chronic progressive external ophthalmoplegia (CPEO) • External ophthalmoplegia
• Bilateral ptosis
• Mild proximal myopathy
Kearns-Sayre syndrome (KSS) • PEO onset at age <20 years
• Pigmentary retinopathy
• One of the following: CSF protein >1g/L, cerebellar ataxia, heart block
• Bilateral deafness
• Myopathy
• Dysphagia
• Diabetes mellitus
• Hypoparathyroidism
• Dementia
Pearson syndrome • Sideroblastic anemia of childhood
• Pancytopenia
• Exocrine pancreatic failure
• Renal tubular defects
Infantile myopathy and lactic acidosis (fatal and non-fatal forms) • Hypotonia in 1st year of life
• Feeding and respiratory difficulties
• Fatal form may be associated with a cardiomyopathy and/or the Toni-Fanconi-Debre syndrome
Leigh syndrome (LS) • Subacute relapsing encephalopathy
• Cerebellar and brain stem signs
• Infantile onset
• Basal ganglia lucencies
• Maternal history of neurologic disease or Leigh syndrome
Neurogenic weakness with ataxia and retinitis pigmentosa (NARP) • Late-childhood or adult-onset peripheral neuropathy
• Ataxia
• Pigmentary retinopathy
• Basal ganglia lucencies
• Abnormal electroretinogram
• Sensorimotor neuropathy
Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) • Stroke-like episodes at age <40 years
• Seizures and/or dementia
• Ragged-red fibers and/or lactic acidosis
• Diabetes mellitus
• Cardiomyopathy (initially hypertrophic; later dilated)
• Bilateral deafness
• Pigmentary retinopathy
• Cerebellar ataxia
Myoclonic epilepsy myopathy sensory ataxia (MEMSA) 1 • Myopathy
• Seizures
• Cerebellar ataxia
• Dementia
• Peripheral neuropathy
• Spasticity
Myoclonic epilepsy with ragged-red fibers (MERRF) • Myoclonus
• Seizures
• Cerebellar ataxia
• Myopathy
• Dementia
• Optic atrophy
• Bilateral deafness
• Peripheral neuropathy
• Spasticity
• Multiple lipomata
Leber hereditary optic neuropathy (LHON) • Subacute painless bilateral visual failure
• Males:females ~4:1
• Median age of onset 24 years
• Dystonia
• Cardiac pre-excitation syndromes

Given the devastating nature of these diseases, it should be easy to understand why a parent would want to ensure their children would not inherit these mitochondrial DNA mutations , setting into motion a lifetime of suffering for their child.

How can IVF be used to prevent transmission of mitochondrial disease? By creating  a hybrid egg from the intended mother’s nuclear DNA and a donor egg, which substitutes the mother’s mutated mitochondrial DNA with normal mitochondrial DNA from a donor egg.

How it works: Because the DNA is nicely encapsulated in the egg’s nucleus, the entire nucleus can be removed fairly easily using micromanipulation tools similar to the tools routinely used in IVF clinics for  intracytoplasmic sperm injection (ICSI).  The technical aspects of removing a cell nucleus and putting it in an de-nucleated egg has been in use for decades for various research applications.  The nucleus inside the donor egg is removed and discarded, leaving behind a donor egg containing mitochondrial DNA and donor cytoplasm. The nucleus is also removed from the intended mother’s egg but in this case,  the rest of the egg is discarded, saving only the maternal nucleus. Then the maternal nucleus is transplanted into the de-nucleated donor egg, reconstituting a complete egg which then is fertilized via IVF using sperm from the biological father. This nuclear transfer procedure in different from reproductive cloning in that after nuclear transfer, a new haploid egg is created, not an identical cloned person. The reconstituted egg still needs to be fertilized to create a new individual. Another version of this technique has also been proposed in which fertilization occurs between the gametes of the intended parents but then this nucleus from the very early embryo is transferred into a de-nucleated donor egg with normal mitochondria for continued development. This second version is arguably very similar to reproductive cloning in which a nucleus from an existing adult individual is transferred to a de-nucleated egg. Reproductive cloning is highly unpopular and illegal in many countries  so is less likely to ever win acceptance as a clinical procedure.

Neither of these procedures are currently available as clinical procedures, although US scientists at the Oregon Health & Science University’s Oregon National Primate Research Center (ONPRC) are studying the reconstituted egg  technique in primate models and have produced healthy primate offspring. You can learn more about  Shoukhrat Mitalipov, Ph.D’s research from his Oregon Health and Science University website. In addition, the British Wellcome Trust Centre has been given funding specifically for  translational research whose goals is to make these protocols available  for clinical use someday, although currently such nuclear transfer is illegal in both the US and UK due to cloning concerns. If after more research, it still appears as though this form of gene therapy works and is safe, and if patients want it, efforts to revise existing laws would be made to allow these procedures to be adopted clinically.

The article Genetic research: How many parents is too many?, raises concerns that that the resulting embryo would have 3 parents, 2 nuclear parents and a mitochondrial donor parent. Over 99% of the inherited DNA is nuclear (from intended parents, not the donor) so only a miniscule part of the child arises from a third party–arguably a very weak case for establishing parentage.  Furthermore, we’ve always looked to nuclear DNA to define parentage historically, although we have also used mitochondrial DNA in population genetics to trace the maternal lineage back in time to Mitochondrial Eve.

New technology, particularly that involving IVF have always attracted vigorous debate. IVF, by separating the sex act from procreation and then by inviting the participation of “third parties”(donor egg, donor sperm, donor uterus and now donor mitochondria)  seems to reopen debate about what it means to be human. Is  new technology “unnatural”and if it is, does that make it immoral or unethical? Are we required to accept disease as God’s will? If not, how far can we go to eradicate disease? So stay tuned, but have a fire extinguisher at hand,  because the ethical debates about new technologies involving IVF are just heating up.

© 2012, Fertility Lab Insider. All rights reserved.

©2012 Fertility Lab Insider. All Rights Reserved.



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