FBXL4-Related Early Onset Mitochondrial Encephalopathy

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This entry is adapted from the peer-reviewed paper https://medlineplus.gov/genetics/condition/fbxl4-related-encephalomyopathic-mitochondrial-dna-depletion-syndrome

FBXL4-related encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome is a severe condition that begins in infancy and affects multiple body systems. It is primarily associated with brain dysfunction combined with muscle weakness (encephalomyopathy).

genetic conditions

1. Introduction

Infants with FBXL4-related encephalomyopathic mtDNA depletion syndrome have weak muscle tone (hypotonia) and a failure to grow or gain weight at the expected rate (failure to thrive). Children with FBXL4-related encephalomyopathic mtDNA depletion syndrome have delayed development of mental and motor skills and severely impaired speech development. Many affected individuals have seizures, movement abnormalities, and an unusually small head size (microcephaly) with a loss of nerve cells in the brain (cerebral atrophy).

All individuals with FBXL4-related encephalomyopathic mtDNA depletion syndrome have a buildup of a chemical called lactic acid in the body (lactic acidosis), and about half of individuals have an accumulation of ammonia in the blood. Buildup of these substances can be life-threatening. Many affected individuals also have heart abnormalities, such as congenital heart defects or heart rhythm abnormalities (arrhythmias). In addition, individuals with this condition can have vision problems, hearing loss, liver abnormalities (hepatopathy), and immune deficiency due to a decrease in white blood cells. Many children with FBXL4-related encephalomyopathic mtDNA depletion syndrome have distinctive facial features that can include thick eyebrows; outside corners of the eyes that point upward (upslanting palpebral fissures); a broad nasal bridge and tip; and a long, smooth space between the upper lip and nose (philtrum).

Because the encephalomyopathy and other signs and symptoms are so severe, people with FBXL4-related encephalomyopathic mtDNA depletion syndrome usually live only into early childhood.

2. Frequency

FBXL4-related encephalomyopathic mtDNA depletion syndrome is a rare condition; the exact prevalence is unknown. At least 50 affected individuals have been described in the medical literature.

3. Causes

As its name suggests, FBXL4-related encephalomyopathic mtDNA depletion syndrome is caused by mutations in the FBXL4 gene. This gene provides instructions for producing a protein that is found within cell structures called mitochondria. Mitochondria are involved in a wide variety of cellular activities, including energy production, chemical signaling, and regulation of cell growth and division (proliferation) and cell death (apoptosis). Mitochondria contain their own DNA, known as mitochondrial DNA (mtDNA), which is essential for the normal function of these structures. The FBXL4 protein is likely involved in the maintenance of mtDNA. Having an adequate amount of mtDNA is essential for normal energy production within cells.

FBXL4 gene mutations that cause FBXL4-related encephalomyopathic mtDNA depletion syndrome lead to a loss of FBXL4 protein function. A lack of this protein's activity leads to problems with the maintenance of mtDNA, which can reduce the amount of mtDNA in cells (known as mtDNA depletion). Depletion of mtDNA impairs mitochondrial function in many of the body's cells and tissues. Reduced mitochondrial function eventually leads to cell dysfunction, most noticeably affecting the brain, muscles, and other tissues that have high-energy requirements. This cell dysfunction leads to encephalomyopathy and other features of FBXL4-related encephalomyopathic mtDNA depletion syndrome.

4. Inheritance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

5. Other Names for This Condition

FBXL4 deficiency
mitochondrial DNA depletion syndrome 13, encephalomyopathic type
MTDPS13
FBXL4-related encephalomyopathic mitochondrial DNA depletion syndrome

References

Almannai M, Dai H, El-Hattab AW, Wong LJC. FBXL4-Related EncephalomyopathicMitochondrial DNA Depletion Syndrome. 2017 Apr 6. In: Adam MP, Ardinger HH, PagonRA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews®[Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Availablefrom http://www.ncbi.nlm.nih.gov/books/NBK425540/
Antoun G, McBride S, Vanstone JR, Naas T, Michaud J, Redpath S, McMillan HJ,Brophy J, Daoud H, Chakraborty P, Dyment D, Holcik M, Harper ME, Lines MA.Detailed Biochemical and Bioenergetic Characterization of FBXL4-RelatedEncephalomyopathic Mitochondrial DNA Depletion. JIMD Rep. 2016;27:1-9. doi:10.1007/8904_2015_491.
Bonnen PE, Yarham JW, Besse A, Wu P, Faqeih EA, Al-Asmari AM, Saleh MA, Eyaid W, Hadeel A, He L, Smith F, Yau S, Simcox EM, Miwa S, Donti T, Abu-Amero KK, WongLJ, Craigen WJ, Graham BH, Scott KL, McFarland R, Taylor RW. Mutations in FBXL4cause mitochondrial encephalopathy and a disorder of mitochondrial DNAmaintenance. Am J Hum Genet. 2013 Sep 5;93(3):471-81. doi:10.1016/j.ajhg.2013.07.017.Oct 3;93(4):773.
Dai H, Zhang VW, El-Hattab AW, Ficicioglu C, Shinawi M, Lines M, Schulze A,McNutt M, Gotway G, Tian X, Chen S, Wang J, Craigen WJ, Wong LJ. FBXL4 defectsare common in patients with congenital lactic acidemia and encephalomyopathicmitochondrial DNA depletion syndrome. Clin Genet. 2017 Apr;91(4):634-639. doi:10.1111/cge.12894.
Gai X, Ghezzi D, Johnson MA, Biagosch CA, Shamseldin HE, Haack TB, Reyes A,Tsukikawa M, Sheldon CA, Srinivasan S, Gorza M, Kremer LS, Wieland T, Strom TM,Polyak E, Place E, Consugar M, Ostrovsky J, Vidoni S, Robinson AJ, Wong LJ,Sondheimer N, Salih MA, Al-Jishi E, Raab CP, Bean C, Furlan F, Parini R, LampertiC, Mayr JA, Konstantopoulou V, Huemer M, Pierce EA, Meitinger T, Freisinger P,Sperl W, Prokisch H, Alkuraya FS, Falk MJ, Zeviani M. Mutations in FBXL4,encoding a mitochondrial protein, cause early-onset mitochondrialencephalomyopathy. Am J Hum Genet. 2013 Sep 5;93(3):482-95. doi:10.1016/j.ajhg.2013.07.016.
Huemer M, Karall D, Schossig A, Abdenur JE, Al Jasmi F, Biagosch C,Distelmaier F, Freisinger P, Graham BH, Haack TB, Hauser N, Hertecant J,Ebrahimi-Fakhari D, Konstantopoulou V, Leydiker K, Lourenco CM, Scholl-Bürgi S,Wilichowski E, Wolf NI, Wortmann SB, Taylor RW, Mayr JA, Bonnen PE, Sperl W,Prokisch H, McFarland R. Clinical, morphological, biochemical, imaging andoutcome parameters in 21 individuals with mitochondrial maintenance defectrelated to FBXL4 mutations. J Inherit Metab Dis. 2015 Sep;38(5):905-14. doi:10.1007/s10545-015-9836-6.

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Peter Tang

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Table of Contents

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1. Introduction

2. Frequency

3. Causes

4. Inheritance

5. Other Names for This Condition

References

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1. Introduction

2. Frequency

3. Causes

3.1. The gene associated with FBXL4-related encephalomyopathic mitochondrial DNA depletion syndrome

4. Inheritance

5. Other Names for This Condition

References