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.

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.

Normal Function

The FBXL4 gene provides instructions for making a member of a family of proteins called F-box and leucine rich repeat proteins. Like other members of this family, FBXL4 associates with a group of proteins to form a complex. The protein complex that contains FBXL4 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. As part of the protein complex, 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.

Health Conditions Related to Genetic Changes

FBXL4-related encephalomyopathic mitochondrial DNA depletion syndrome

More than 47 mutations in the FBXL4 gene have been found to cause FBXL4-related encephalomyopathic mtDNA depletion syndrome. This condition affects multiple body systems and is often fatal in early childhood. It is primarily associated with brain dysfunction combined with muscle weakness (encephalomyopathy).

Many of the mutations that cause FBXL4-related encephalomyopathic mtDNA depletion syndrome impair the FBXL4 protein's ability to attach (bind) to other proteins, disrupting the formation of the protein complex, which impairs normal maintenance of mtDNA. Problems with mtDNA maintenance can reduce the amount of mtDNA (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.

Leigh syndrome

MedlinePlus Genetics provides information about Leigh syndrome

Other Names for This Gene

• F-box/LRR-repeat protein 4
• FBL4
• FBL5

Genomic Location

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.

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.