FBXL4-Associated Mitochondrial Disease (FBXL4-Associated Mito), also known as encephalopathic Mitochondrial DNA (mtDNA) Depletion Syndrome 13 (MTDPS13), is a rare genetic disorder caused by mutations of the FBXL4 gene. Patients present with early-onset encephalopathy, lactic acidosis, developmental delay, growth failure, and hypotonia, affecting multiple organs including the brain, heart, and liver ^[1,2]. FBXL4 was initially thought to regulate mtDNA levels, given that patients present with symptoms associated with a lack of mtDNA. However, recent findings show that at a molecular level, FBXL4 fine-tunes the process of mitochondrial removal, termed mitophagy, by regulating the mitophagy receptors BNIP3 and NIX^[3,4,5]. Specifically, FBXL4 binds to BNIP3 and NIX with the help of another mitochondrial protein, PPTC7, and tags BNIP3 and NIX to be degraded by one of the cell’s degradation systems (the Ubiquitin Proteasome System) ^[6,7,8]. In the case of FBXL4-Associated Mito, FBXL4 loss-of-function mutations result in unregulated mitophagy. The subsequent excessive removal of mitochondria as a whole also results in less cellular levels of mtDNA.

While there are only ~94 documented patients diagnosed with FBXL4-Associated Mito^[9], the exact prevalence is unknown, and prognosis widely varies from patient to patient.

FBXL4-Associated Mito can be diagnosed by in utero testing, and complications can occur during pregnancy. Patients can present with symptoms at birth, with symptoms typically progressing over time. The average survival age for patients with mtDNA depletion syndromes averages around 2 years of age, however lifespans vary between different individuals. Some FBXL4 patients have survived into adulthood.

FBXL4-Associated Mito is an inherited disorder caused by biallelic pathogenic mutations in the FBXL4 gene. This impairs the fine-tuning of mitophagy, leading to the excessive removal of mitochondria. Currently there are ~94 published pathogenic mutation variants of FBXL4.

Symptoms of FBXl4-Associated Mito include:

• • Early-onset encephalopathy
  • Metabolic dysfunction (Lactic acidosis, hyperammonia, mildly elevated transaminases etc.)
  • Heart dysfunction (hypertrophic cardiomyopathy, congenital heart malformations, arrhythmias)
  • Muscular dysfunction (Hypotonia, movement disorders)
  • Developmental delay
  • Bones marrow dysfunction (neutropenia, lymphopenia)
  • Vision dysfunction (cataracts, strabismus, nystagmus, optic atrophy)
  • Hearing loss
  • Seizures
  • Cerebral atrophy

Your loved one’s healthcare provider will determine whether he or she meets the clinical criteria for a diagnosis of FBXL4 –Associated Mito. They may perform or recommend:

• • Molecular genetic testing for a FBXL4 mutation
  • Brain-imaging such as computed tomography (CT) scan or magnetic resonance imaging (MRI)
  • Blood tests and cerebrospinal fluid tests to check for levels of key markers (e.g. lactic acid, ammonia, etc.)
  • A muscle sample (biopsy)

As with all mitochondrial disorders, there is no cure for FBXL4-Associated Mito. Available treatments can help manage symptoms and improve life for individuals and their families. Management is best provided by a multidisciplinary healthcare team including neurology, nutrition, clinical genetics/metabolism, and developmental pediatrics. Treatments are based upon symptom management.

As with other mitochondrial diseases, therapies may include various vitamins, antioxidants, and cofactors, often in a “cocktail” combination.

Since FBXL4-Associated Mito is an inherited disorder, genetic counseling for the family may also be recommended.

We are here to help. UMDF serves a number of families coping with FBXL4. We suggest you reach out to our Support & Education Team – online, via email at  support@umdf.org or phone at (888) 900-6486. They’ll also connect you with a UMDF ambassador, likely a fellow FBXL4 patient or family member, who can help support and guide you through your questions.

• Get Support
  Connect with our Support & Education Team online, via email at support@umdf.org or phone at (888) 900-6486.Check out the FBXL4 parent community group

  Connect with other FBXL4 family stories: Live Like Lorelei by Susan Benjaminson Geoghegan is a novel based on the true story of a girl with FBXL4-Associated Mito and the impact she had on the world. Click here for more info.

• Check our clinical trials finder
  Use our Clinical Trials Finder tool to see if you qualify for any clinical trials.

• Join our patient registry, mitoSHARE
  We are actively recruiting FBXL4 and mtDNA Depletion Syndrome families to participate in our patient registry, mitoSHARE. Patient registries like mitoSHARE are an integral part in charting a course toward treatments and cures for FBXL4-Associated Mito and other mitochondrial diseases. There are currently over 30 active mitochondrial disease clinical trials. Next generation patient registries like mitoSHARE are an integral part of expanding that number.

• Become an advocate
  Ask your representatives to prioritize mitochondrial disease research and support via the UMDF Advocacy Center. We’ll send regular action items so you – and your friends and family – can let Congress know where we need their support. Click here to sign up.

• Join the conversation online
  – UMDF Social Media Support Groups: Facebook Support Group
  – UMDF News & Updates: Facebook | Twitter | Instagram | YouTube

• Get involved
  Join the fight by giving your voice, generosity, time, or energy. Click here to see how you can help.

UMDF is helping chart a path toward treatments and eventual cure of mitochondrial diseases like FBXL4 through:

• Research & Funding: UMDF has provided more than $15 million in research funding to find treatments for diseases like FBXL4 . UMDF advocacy has helped secure an additional $55 million in federal funding via the Department of Defense and National Institutes of Health.
• Data: Over two decades ago, UMDF pioneered patient registries for the mitochondrial disease community. Today, our next generation patient registry, mitoSHARE, is helping chart a path toward the treatment and eventual cure of mitochondrial diseases.
• Patient Support: Thousands of families just like you depend upon UMDF for support and education on diseases like FBXL4 . Attendance at our support meetings annually tops 7,000, including disease specific support meetings for families.
• Clinician Support: To help educate clinicians on diseases like FBXL4 , we feature monthly Bench to Bedside clinician seminars, host the annual Mitochondrial Medicine Symposium, support the Mitochondrial Care Network, and educate clinicians on our Mito U platform.

• NIH: FBXL4-Related Encephalomyopathic Mitochondrial DNA Depletion Syndrome

UMDF is here to help. Contact the Support Line at (888) 900-6486 weekdays from 8:00am to 5:00pm EST to connect with our Patient Concierge. Or, via email contact  support@umdf.org.

1. Bonnen et al., 2013. Mutations in FBXL4 cause mitochondrial encephalopathy and a disorder of mitochondrial DNA maintenance 

2. Gai et al., 2013. Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy 

3. Nguyen-Dien et al., 2023. FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors

4. Elcocks et al., 2023. FBXL4 ubiquitin ligase deficiency promotes mitophagy by elevating NIX levels

5. Cao et al., 2023. A mitochondrial SCF‐FBXL4 ubiquitin E3 ligase complex degrades BNIP3 and NIX to restrain mitophagy and prevent mitochondrial disease

6. Nguyen-Dien et al., 2023. PPTC7 antagonizes mitophagy by promoting BNIP3 and NIX degradation via SCFFBXL4

7. Wei et al., 2023. Dual-localized PPTC7 limits mitophagy through proximal and dynamic interactions with BNIP3 and NIX

8. Sun et al., 2023. A mitophagy sensor PPTC7 controls BNIP3 and NIX degradation to regulate mitochondrial mass

9. Ballout et al., 2019. FBXL4-Related Mitochondrial DNA Depletion Syndrome 13 (MTDPS13): A Case Report With a Comprehensive Mutation Review