FOXRED1

FOXRED1 is a nuclear gene that encodes a mitochondrial protein essential for the assembly and function of Complex I, the largest enzyme complex of the mitochondrial electron transport chain. 

Mutations in FOXRED1 disrupt energy production, leading to mitochondrial complex I deficiency and a spectrum of severe neurodevelopmental and metabolic disorders.

What is FOXRED1?

FOXRED1 is a nuclear gene that encodes a mitochondrial protein critical for energy production. 

It acts as a chaperone for Complex I, the first and largest enzyme complex in the mitochondrial electron transport chain. This complex is essential for ATP generation through oxidative phosphorylation.

Located at chromosome 11q24.2, the FOXRED1 protein belongs to the FAD-dependent oxidoreductase family. It supports the mid-to-late stages of Complex I assembly, helping to ensure the correct formation and stabilization of the functional enzyme complex within the inner mitochondrial membrane.

Clinical Implications of FOXRED1 Mutations

Mutations in the FOXRED1 gene are associated with mitochondrial dysfunction, primarily affecting energy production in high-demand tissues such as the brain, muscles, and heart. The key clinical condition linked to FOXRED1 mutations is mitochondrial complex I deficiency, with phenotypes that may overlap with Leigh syndrome and other early-onset neurodevelopmental disorders.

Mitochondrial Complex I Deficiency, Nuclear Type 19 (MC1DN19)

This is the primary condition caused by FOXRED1 mutations. It is inherited in an autosomal recessive manner, resulting in an isolated deficiency of mitochondrial complex I—critical for oxidative phosphorylation and ATP production.

Key features include:

• Early-onset encephalopathy
• Congenital lactic acidosis
• Developmental delay and loss of motor skills
• Hypotonia
• Cerebellar atrophy
• Seizures
• Visual impairment (e.g., cortical blindness)
• Progressive neurological decline
• Hypertrophic cardiomyopathy in some patients

Leigh Syndrome (Phenotypic Presentation)

Several patients with FOXRED1-related complex I deficiency have met clinical criteria for Leigh syndrome—a severe neurometabolic disorder characterized by symmetric brain lesions, particularly in the basal ganglia and brainstem.

Associated findings include:

• Athetoid movements
• Microcephaly
• Irritability
• Feeding difficulties
• Failure to thrive
• Respiratory abnormalities (noted in other Leigh variants)

Isolated Encephalomyopathy

Some patients may present with predominantly neurological symptoms without meeting full Leigh syndrome criteria, including:

• Acquired microcephaly
• No voluntary movement
• Profound developmental delay
• Normal hearing despite cortical blindness

When is FOXRED1 Genetic Testing Relevant?

FOXRED1 testing may be relevant in the following scenarios:

Individuals with Suspected Mitochondrial Complex I Deficiency

Genetic testing is appropriate for patients—especially infants and children—presenting with symptoms such as:

• Lactic acidosis
• Hypotonia or muscle weakness
• Neurological features (seizures, developmental delay, encephalopathy)
• Cardiomyopathy

Individuals with Biochemical Evidence of Complex I Deficiency

Genetic testing for FOXRED1 mutations may be indicated if the initial workup shows isolated complex I deficiency, with normal activity in other mitochondrial complexes.

Patients with a Family History of Mitochondrial Disease

All FOXRED1 mutations lead to mitochondrial disease; FOXRED1 testing may help identify carriers or guide reproductive planning in families with known mitochondrial disorders, especially in consanguineous backgrounds.

Determining a Differential Diagnosis

Because it’s known to cause complex 1 deficiency, FOXRED1 testing can help distinguish complex I deficiency from other mitochondrial disorders caused by nuclear or mitochondrial DNA mutations.

Genetic Counseling

Because FOXRED1-related disease follows an autosomal recessive inheritance pattern, both parents must be carriers for a child to be affected. Genetic counseling is recommended before and after testing to interpret results and understand implications.

Test Procedure and Interpretation

Testing for FOXRED1 is performed as a genetic test to look for mutations in the gene that would alter functional protein availability. The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for FOXRED1 genetic testing are considered to be without mutations that can alter the activity of the FOXRED1 proteins.

Clinical Implications of Positive FOXRED1 Mutations

The clinical implications of a positive FOXRED1 mutation test result will vary by individual, although FOXRED1 mutations in symptomatic patients may signal a need for further assessment and possibly treatment, especially in the setting of symptoms of impaired metabolism, cardiovascular or neurological symptoms, especially in infants or young children.

Patients or practitioners with questions about the clinical implications of FOXRED1 mutations should seek further assessment with a genetic counselor or expert. 

What Does the Absence of Pathogenic FOXRED1 Mutations Mean?

A negative result for FOXRED1 mutations does not rule out complex I deficiency or other mitochondrial disorders. Over 50 genes are involved in complex I biogenesis, and others in mitochondrial function more broadly.

If clinical suspicion remains high, clinicians should consider comprehensive mitochondrial gene panels or whole exome/genome sequencing, including both nuclear and mitochondrial DNA.

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