Fact: As few as 50 individuals have been affected by this disorder
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).
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.
Survival varies; the median age of reported deaths was two years (range 2 days - 75 months), although surviving individuals as old as 36 years have been reported. To date FBXL4-related mtDNA depletion syndrome has been reported in 50 individuals.
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.
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.
The diagnosis of FBXL4-related mtDNA depletion syndrome is established in a proband by identification of biallelic pathogenic variants in FBXL4 on molecular genetic testing.
Management is best provided by a multidisciplinary team including neurology, nutrition, clinical genetics/metabolism, and developmental pediatrics. Other specialties may be involved as needed. To date no definite treatment is available; thus, treatment is mainly supportive: assuring adequate nutrition and standard treatment of neurologic complications including developmental delay/intellectual disability, seizures, cardiac complications, eye involvement, and hearing loss.
Administration of cofactors and antioxidants, used in mitochondrial disorders with (generally) limited evidence of benefit, may be considered.
FBXL4-related mtDNA depletion syndrome is inherited in an autosomal recessive manner. When both parents are heterozygous carriers, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier (heterozygote), and a 25% chance of being unaffected and not a carrier.
Once the FBXL4 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic diagnosis are possible.
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The following are organizations and/or websites dedicated to providing information and education surrounding Mitochondrial DNA Depletion Syndrome 13. These organizations are dedicated to research, education, awareness, and/or support. They are listed in Alphabetical order without any preference or prejudice. Listing these organizations is not a recommendation or referral in any regard for seeking treatment or consultation or support for treatment.
Genetics Home Reference
Kennedy Krieger Institute
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Genetics Home Reference