SNP Shot: Genomic Insights

Mitochondrial complex I deficiency arises when the complex I protein, a crucial component within mitochondria, is either deficient or malfunctioning. Mitochondria are cellular structures responsible for converting energy from food into a usable form for cells. Complex I is the first of five complexes involved in oxidative phosphorylation, a multi-step process that generates the majority of a cell's energy.

This deficiency can manifest in a wide range of symptoms affecting various organs and systems, particularly the nervous system, heart, and skeletal muscles. The onset of these symptoms can occur at any age, from infancy to adulthood.

Common neurological issues associated with mitochondrial complex I deficiency include encephalopathy (abnormal brain function), recurrent seizures (epilepsy), intellectual disability, ataxia (difficulty with coordination), and dystonia (involuntary movements). Affected individuals may also experience hypotonia (low muscle tone), myalgia (muscle pain), and exercise intolerance (extreme fatigue after physical activity). Lactic acidosis, characterized by elevated lactic acid levels in the blood, is frequently observed and can cause nausea, vomiting, weakness, and rapid breathing. Severe cases of lactic acidosis can be life-threatening.

In some instances, individuals with mitochondrial complex I deficiency may develop heart, liver, or kidney complications. Vision impairments, stemming from abnormal eye movements or the degeneration of optic nerves (which transmit signals from the eyes to the brain), can also occur.

Certain individuals with mitochondrial complex I deficiency exhibit specific symptom clusters that align with recognized syndromes. Leigh syndrome, often linked to complex I deficiency, is characterized by a progressive decline in mental and motor skills (developmental or psychomotor regression) and typically leads to death within 2-3 years of symptom onset. Leber hereditary optic neuropathy (LHON), another condition potentially caused by complex I deficiency, primarily affects vision due to optic nerve degeneration. It's important to note that these syndromes can have other underlying causes as well.

Inheritance:

The inheritance pattern of mitochondrial complex I deficiency varies depending on the specific gene affected. When the deficiency is caused by a mutation in a nuclear DNA gene, it follows either an autosomal recessive or X-linked inheritance pattern. Autosomal recessive inheritance means that both copies of the gene in each cell must carry the mutation for the condition to develop. Individuals with autosomal recessive conditions inherit one mutated gene copy from each parent, who are typically carriers without showing symptoms themselves because they possess one normal gene copy. X-linked inheritance occurs when the mutated gene resides on the X chromosome, one of the two sex chromosomes. Males, with only one X chromosome, will develop the condition if their single X chromosome carries the mutation. Females, with two X chromosomes, may exhibit milder symptoms or no symptoms at all if only one X chromosome carries the mutated gene. Notably, fathers cannot transmit X-linked traits to their sons. When mitochondrial complex I deficiency is caused by a mutation in a gene found in mitochondrial DNA (mtDNA), it follows a mitochondrial inheritance pattern, also known as maternal inheritance. Since mitochondria are exclusively inherited from the mother's egg cell, only mothers can pass on disorders resulting from mtDNA mutations to their children. These disorders can appear in every generation and affect both males and females, but fathers cannot pass on traits associated with changes in mtDNA to their children.