2 New Mutations in Mitochondrial Genes Linked to Complex I Deficiency

New mutations in two mitochondrial genes, found through biopsies taken after years of complaints, led to mitochondrial complex I deficiency — with widely differing symptoms — being diagnosed in two patients, a case study reported.

These findings highlight the importance of muscle biopsies taken to identify a disease, and to confirm the disease-causing consequences of previously unknown mitochondrial DNA (mtDNA) mutations, the researchers said.

The case study, “Novel MT-ND Gene Variants Causing Adult-Onset Mitochondrial Disease and Isolated Complex I Deficiency,” was published in the journal Frontiers in Genetics.

Complex I is a group of proteins found in mitochondria — the cell compartments responsible for the production of energy. It is the largest complex of the so-called mitochondrial respiratory chain, which generates the energy necessary for cells to work as expected. Seven of the proteins making up complex I are encoded by mitochondrial DNA, while the rest are encoded by the DNA found in the cells’ nucleus.

Complex I deficiency is the most common biochemical defect associated with mitochondrial disease, and it can lead to a wide range of clinical presentations. While some deficiencies lead to tissue-specific manifestations, like Leber hereditary optic neuropathy (LHON), others result in more severe disorders like Leigh syndrome and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome.

“Pathogenic variants [disease-causing  mutations] have been identified in all seven mtDNA-encoded subunits of complex I; however, there is no clear genotype-phenotype [gene profile and symptoms] correlation,” the researchers wrote.

Investigators in the U.K. and Germany describe two adults with complex I deficiency and different clinical presentations.

The first patient, a 27-year-old man, had a 10-year history of intolerance to exercise and mild muscle weakness, which was confirmed in a neurology examination.

He also had drooping eyelids and double vision, poorer muscle mass in his arms, and an inward curvature in his lower back (lumbar lordosis). Laboratory analysis detected high levels of serum creatine kinase, a marker of muscle injury.

Electromyography (EMG) studies showed the patient had muscle disease; further testing revealed he also had excessive protein in his urine (proteinuria). He underwent a muscle biopsy a year later, when he was 28.

The second patient was a 35-year-old pregnant woman with complaints of continuous vision problems over four months. She had been diagnosed with endometriosis and gestational diabetes, and had hearing problems similar to those experienced by her mother and grandmother since she was in her 20s.

Her vision gradually improved, but three years later she developed severe headaches. A magnetic resonance imaging (MRI) scan detected some spots on her brain, but further tests found no abnormalities.

In her 40s, the woman came to the hospital with symptoms that included left arm weakness, vertigo, poor balance, and fatigue. A second MRI scan revealed white matter lesions, but further tests were again negative. (White matter refers to regions of the brain made up of myelinated nerve segments (axons) responsible for the transmission of nerve signals.)

Mitochondrial disease was suspected and she underwent a muscle biopsy.

In both patients, muscle biopsy results were consistent with isolated complex I deficiency. After sequencing the entire mitochondrial genome (all genes found in mitochondrial DNA) in the tissues, researchers identified a new mutation (m.14512_14513del) in the MT-ND6 gene in the man. A different mutation (m.3761C > A ), also never before associated with the disease, was found in the MT-ND1 gene for the woman.

“In conclusion, isolated complex I deficiency is associated with an increasingly diverse phenotypic [symptom] expression of mitochondrial disease. We highlight two novel mutations causing isolated complex I deficiency and diverse clinical features,” they wrote.

“Our findings also serve to highlight the importance of diagnostic muscle biopsy in proving the pathogenicity [disease-causing] of novel mtDNA variants, particularly in cases with non-syndromic presentations,” they added.