Mitochondrial DNA maintenance defects

Article Reviews
, , , , ,
1

Read Full Text: Mitochondrial DNA maintenance defects (Free to access)
Journal: Biochimica et Biophysica Acta - Molecular Basis of Disease
Year Published: 2017
Ranked 36th on our 2015-2020 list of the 100 most influential OT-related articles

This is one of those groups of diagnoses that you want to keep stowed in the back of your mind.

Mitochondrial DNA maintenance defects (MDMDs) are a group of genetic disorders that can present at any age. Even though symptoms and severity can vary, there are several systems that are commonly affected.

MDMDs are currently underdiagnosed—but there’s a good chance you’ll come across them at some point, as manifestations range from developmental delays to dementia-like symptoms. So, it’s essential to work with your team to ensure you raise the flag if you see patterns associated with genetic conditions like MDMDs.

Occupational therapy is one of the few treatment options available to these patients—and, in the absence of a cure, you’ll be called upon to really focus on the individual and what matters most to them.

Let’s dive in.

What was the aim of this article?

The authors stated four main goals for this article:

  1. To discuss the roles mitochondrial DNA play in the function and maintenance of the organelle
  2. To discuss some of the issues that arise when there is mtDNA deletion or depletion
  3. The presentation and clinical features of currently recognized MDMD diagnoses
  4. Available treatment options for these disorders

What are mitochondrial DNA maintenance defects?

Mitochondrial DNA maintenance defects (MDMDs) comprise a large group of diseases that present when the mechanism of maintaining and proliferating mitochondrial DNA is impaired.

But, what does that even mean?

Let’s back up a second and do a quick biology review. Mitochondria are organelles found in almost all cells in the human body. They are the powerhouses of those cells—they make the energy that each cell needs to do its job. Plus, they impact hormone synthesis, calcium homeostasis, and cell cycle regulation. All together, mitochondria produce about 90% of the energy needed by the body! So, it stands to reason that when something goes wrong with mitochondria, there can be a widespread and devastating impact.

Mitochondria have their own DNA, known as mtDNA. And, during the process of replicating and maintaining this mtDNA, things can go wrong (as they can in other genetic disorders). Proteins can be deleted or depleted, or they can function incorrectly.

What do MDMDs look like?

The presentation of each specific disorder can vary greatly, but there were main clinical features that popped up again and again.

This seems to be because systems with high energy demands are the ones that show the first signs that energy production is being impaired.

Common signs and symptoms include:

  • Motor Impairments: Most diagnoses included some type of ataxia or sensorimotor impairment, tonal issues, and fatigue
  • Neurological Impairments: Many people present with encephalopathy, seizures, dementia-like symptoms, parkinsonism, developmental delays, autism like symptoms, and migraines
  • Visual Impairments: Optic atrophy and ptosis came up multiple times
  • Hearing Impairments: Hearing loss is not uncommon
  • Gastrointestinal Impairments: These included vomiting, nutritional deficits, and dysmotility
  • Kidney, Liver, and Cardiac Impairments: Many patients develop cardiomyopathy, renal failure, and glycemic issues

It’s important to note that the authors emphasized how most diagnoses involved multisystem or multiorgan impairment.

What diagnoses make up this group?

Mitochondrial DNA maintenance defects, or MDMDs, are a broad group of diagnoses in every sense of the word.

Onset can range from infancy to adulthood. Some sources state that, in general, mitochondrial disorders impact approximately 1 in every 5,000 people—but there were some disorders the authors mentioned where only a handful of cases has ever been identified (one specific diagnosis has only been found in two sisters!).

There is a wide variety of diagnoses that make up MDMDs. Many of them are named for the specific biochemicals that are impacted. The authors reviewed 40 different MDMDs.

I’m listing them here so you can see the wide range of diagnoses. (And, just in case any of you have worked with one of them!)

Neonatal Period or Infancy:

  • ABAT-related encephalomyopathic MDMD
  • FBXL4-related encephalomyopathic MDMD
  • Infantile-onset spinocerebellar ataxia
  • MPV17-related hepatocerebral MDMD
  • OPA1-related encephalomyopathic MDMD
  • RRM2B-related encephalomyopathic MDMD
  • Seckel syndrome (DNA2-related)
  • Sengers syndrome (AGK-related)
  • SUCLG1-related encephalomyopathic MDMA
  • TFAM-related hepatocerebral MDMD
  • TWINK-related hepatocerebral MDMD
  • TWNK-related IOSCA

Neonatal Period, Infancy, or Childhood

  • DGUOK-related hepatocerebral MDMD

Infancy or Early Childhood:

  • Behr syndrome (OPA1-related)
  • Navajo neurohepatopathy (MPV17-related)
  • SUCLA2-related encephalomyopathic MDMA
  • TK2-related myopathic MDMD

Infancy to Adulthood:

  • POLG-related MNGIE
  • POLG2-related myopathic MDMD

Early Childhood/Childhood:

  • Alpers-Huttenlocher syndrome (POLG-related)
  • MFN2-related ADOA
  • RRM2B-related ARPEO
  • SLC25A4-related cardiomyopathic MDMD

Childhood or Early Adulthood:

  • DNA2-related myopathic MDMD
    MFN2-related CMT2
  • MGME1-related myopathic MDMD
  • MPV17-related neuromyopathic MDMD
  • OPA1-related ADOA
  • POLG-related ARPEO
  • TYMP-related MNGIE

Early or Mid-Adulthood:

  • DGUOK-related myopathic MDMD
  • POLG-related ANS
  • POLG-related MEMSA
  • RNASEH1-related encephalomyopathic MDMD
  • RRM2B-related MNGIE
  • TK2-related ARPEO
  • TWNK-related ADPEO

Adulthood:

  • POLG-related ADPEO
  • RRM2B-related ADPEO
  • SLC25A4-related ADPEO

What treatment options are currently available?

Unfortunately, there is no cure, and treatment options are usually limited.

  • Therapeutics: Occupational therapy, along with physical therapy and speech therapy, was the first intervention mentioned when addressing the symptoms of MDMDs. The authors specifically mention OT for mitigating some of the more challenging motor-based issues, as well as for feeding.
  • Medical Interventions: These were pretty broad, but they included anti-epileptic medications, surgical interventions for ptosis and cochlear implantation, monitoring of organ systems (such as lung and heart function), and potential liver transplants—although the authors briefly mentioned some ethical questions regarding transplants for patients with poor prognoses.
  • Nutrition Support: Gastrointestinal interventions for dysmotility, as well as nasogastric tubes and gastronomy tube feedings might be necessary for some patients. The intervention of an experienced dietician can be helpful in meeting nutritional needs without triggering hypoglycemic episodes.

What did the authors conclude/discuss?

These are a group of diseases, impacting a variety of organ systems with a highly variable clinical presentation.

The authors spent a great deal of time teasing apart each specific diagnosis. And, while some are incredibly rare (with recorded cases in the single digits multiple times), each diagnosis is distinct from the other. The authors also took great care to explain the highly intricate biochemical processes of mitochondria, as well as the impact on any specific issues that can arise.

There is no cure.

The authors were pretty blunt on this: “No curative therapy is available for any of these disorders, and treatment remains largely symptomatic.” But, there are some treatment options currently available to help with improving comfort and quality of life. And, occupational therapy was explicitly stated as a beneficial therapy for people with MDMDs.

Takeaways for OT practitioners

(These were our personal takeaways, and were not mentioned in the article.)

1.) Given the breadth of challenges patients with MDMDs can face, it’s important to focus on what our clients’ priorities are.

OTs are really great at this! We not only base our interventions on a list of challenges, but also on an occupational profile. And, in the Club, we’ve recently talked about how amazingly prepared OTs are to use participatory medicine. This is a time to do it. When it’s impossible to alleviate or mitigate every symptom, it’s important to meet our clients where they are in a meaningful way.

2.) MDMDs can manifest symptoms at any age, so this isn’t just one for the pediatric crowd.

While every OT works with people who have genetic disorders, it sometimes feels like a lot of focus and resources go toward intervening in the pediatric realm. And, while we are seeing increased focus on the transition to adulthood and providing additional support for adults with disabilities, this article serves as an important reminder: it’s critical that all OTs, in all practice areas, stay informed and find the resources needed for this set of diagnoses.

3.) Like a lot of other rare disorders with no clear and effective treatment, a multidisciplinary team is key.

Disorders like this can be tough. There are a lot of areas to address, and no clear path for effective treatment. That means using the skill set of a large and diverse team can be the key to making sure all areas of concern are being addressed in a safe and cohesive manner.

This review incorporated information regarding background information and clinical presentation from the Genetic and Rare Disease Center of the NIH, as well as the United Mitochondrial Disease Foundation.

Here’s the full APA citation for this article:

El-Hattab AW, Craigen WJ, Scaglia F. Mitochondrial DNA maintenance defects. Biochim Biophys Acta Mol Basis Dis. 2017 Jun;1863(6):1539-1555. doi: 10.1016/j.bbadis.2017.02.017. Epub 2017 Feb 16. PMID: 28215579.

What questions/thoughts does this article raise for you?

3

There was a child at my children’s elementary school with Mitochondrial disease. One of the parents was briefly in my book club and she discussed how difficult it was for others to understand her child’s issues. Her daughter used a wheelchair for energy conservation most of the day. However, she loved gym so would participate then and this was hard for both the kids and parents to understand. The classroom also had to be kept as germ-free as possible (pre-Covid) due to a compromised immune system and parents were annoyed by the rules. Mom tried to come in and do education of the whys but still felt people did not understand and were often making false assumptions and sometimes cruel remarks.
I found this resource Understanding the energy/sensory connection: mitochondrial diseaseSusan N. Schriber Orloff, OTR/L: https://www.mitoaction.org/wp-content/uploads/2019/10/Understanding_mitochondrial_sensory_issues.pdf

3 Likes
4

Hi @tee! Than you for sharing this personal story! As we were working on this piece I kept thinking about how these families not only have the burden of managing this condition- they also have the burden of educating others about it. Just the names of the conditions alone are a huge barrier to sharing about them. Can imagine trying to explain to someone that your loved one has MPV17-related neuromyopathic MDMD??

Thank you so much for sharing that resource!! I had not seen it before. I could definitely see using it if, both as a education resource, but also to communicate that the symptomology is one that we are accustomed to working with. Because, I’m sure the families get so fatigued of people being like “I’ve never heard of that before!”

5

I agree OT is skilled on addressing the functional needs of these clients as I’m sure progress keeps changing. These cases seem multi-layered and would benefit from including the caretakers with a priority list of goals. I’m also curious on if the inclusion of other modalities may enhance treatment sessions specifically Frequency Specific Microcurrent? I know this microcurrent increases the ATP in the mitochondria and wondering if it could helpful?

6 Likes
6

Oh interesting! I hadn’t thought about strategies to just generally boost mitochondrial health and thereby ATP/energy production. (@jennifer1, did you read anything about this?) Simple interventions like sleep, eating healthy fats, and exercise boost cell health- and while this is of course not a cure for this population, it may allow them to have the highest quality of life for as long as possible.

Just based on what I’m reading I think I would focus on the lifestyle interventions I mentioned about, because they have more a system-wide impact, whereas FSM, seems to be pretty localized. But, that is just my gut!! Not a definitive answer!!

This article gave a really simple explanation of lifestyle interventions to boost mitochondrial health:

(Also, welcome to the Club, @rose!!! It is great to have you!!!)

7

I hadn’t seen anything about that in my reading! I think it would be interesting to dive a little deeper into the literature to see what’s there. I wouldn’t think anything that can boost cellular health would be a bad thing, but I do know from what I learned the challenge is that the mitochondrial DNA replication process itself is faulty. I would say that as long as contraindications related to the wide range of systemic challenges as addressed and reviewed by the team, it would be interesting to see what you find!

2 Likes
8

How awful that on top of everything the family had to deal with not just misunderstanding but cruel remarks. This would be such an amazing place for OT to step in to help with classroom education but also for the staff and other parents at the school.
I remember back in college an inclusionary program with puppets for educating students when a child would be in the classroom who had different needs, but of course I can’t for the life of me remember what it was called.

2 Likes
9

Thanks Sarah! This a great club and I love the exchange of ideas!

2 Likes
10

I found this article review fascinating - thank you for sharing, Sarah! I have had no previous experience working or interacting with individuals with MDMDs so this was a completely new diagnostic area for me. I love that this article on a group of such rare diagnoses made the list of 100 most influential articles for OTs. I think your takeaways are obviously applicable for individuals in all settings - we as OTs are in the business of meaningful activity and engagement and with highly complex individuals, it is especially as important to remain client-centered and strength-based.

As someone who is really interested in pediatrics, especially in the school-based setting, my mind instantly transitions to, “how is this impacting kiddos in the classroom and how can we best cultivate a supportive environment for meaningful social and occupational engagement with their peers?”. I found this article (in full disclosure, I haven’t finished it quite yet!) and I am excited to see from the CHILD’s perspective how MDMDs impacts their daily occupations and activities. It’s from a group of OTs in the Netherlands but still believe it is appropriate and generalizable to our pediatric or other population(s) here. :slight_smile:

Citation: Lindenschot, M., de Groot, I., Koene, S., Satink, T., Steultjens, E., & Nijhuis-van der Sanden, M. (2018). Everyday Activities for Children with Mitochondrial Disorder: A Retrospective Chart Review. Occupational therapy international , 2018 , 5716947. https://doi.org/10.1155/2018/5716947

2 Likes
11

Hi @allison5! I finally had time to sit down with the article that you sent! I’m like you- this was a new diagnostic category for me… so I’ve been on a huge learning curve!!

I thought the overall takeaway from you article was really helpful- that these kids are still participating in the same types of activities as their typically developing peers. Then to help these kids participate as fully as possible, it supports the need for personalized and strength-based care, which puts emphasis on involving the children’s perspective in care. Thank you for the read!!!

Your article also reminded me that I forgot to link our other discussion of a specific mitochondrial disorder (MELAS Syndrome.) I’m dropping it here, just in case anyone wants to dive deeper into what a specific mitochondrial defect diagnosis may look like:

1 Like