New mutations affecting the NDUFA6 gene were identified as the cause of early-onset severe mitochondrial disorder in four unrelated children, a report shows.
The study, “Bi-allelic Mutations in NDUFA6 Establish Its Role in Early-Onset Isolated Mitochondrial Complex I Deficiency,” is the first report implicating this gene in mitochondrial disease. It was published in The American Journal of Human Genetics.
Mitochondria are responsible for production of the energy that sustains cells’ normal functions. This process is carried out by the oxidative phosphorylation system (OXPHOS), which is encoded by specific mitochondrial genes.
The NDUFA6 is one of the genes that encodes one of the essential parts of this process, the OXPHOS complex I subunit protein, and is critical for energy production.
A team led by researchers from the Wellcome Centre for Mitochondrial Research at Newcastle (England) University presented the cases of four unrelated children who showed symptoms and clinical manifestations highly suggestive of an underlying mitochondrial disorder.
The first patient, a female infant, was born at term with enlarged brain ventricles (fluid-filled structures), mildly underdeveloped cerebellum, and very low weight.
Less than an hour after birth she was shown to have some metabolic alterations, with blood analysis showing that she was in metabolic acidosis with reduced blood levels. She received treatment with 10% dextrose infusion and antibiotics, but although the metabolic acidosis improved, sugar levels did not show significant alterations.
Additional blood analysis revealed that her lactic acid levels were still increased despite the improvement in metabolic acidosis. She also was found to have clotting abnormalities and high levels of ammonia in the blood.
Around 24 hours after birth she began to experience breathing difficulties, requiring artificial ventilation.
Further clinical examination revealed that she had severe generalized low muscle tone and no primitive reflexes. Cerebral function monitoring and brain magnetic resonance imaging (MRI) revealed that she had several alterations that were not within the normal parameters for her age.
The clinical team tried to re-establish a healthy metabolic state, but her condition continued to worsen and she died at approximately 51 hours of age.
The second case reported was a boy who had normal overall development until age 2.
At this point, his parents noted that he had general weakness and his gait deteriorated after an unexplained fever. This was followed by further motor regression and rapid onset of continuous muscle contraction affecting all four limbs.
His condition rapidly progressed and he developed swallowing difficulties. By age 2 1/2, he was bedridden and unable to walk, grasp, or speak. In subsequent months he showed some signs of recovery, regaining several words, and by age 3 he was walking with assistance. He developed vision problems due to optic atrophy.
“Although there have been no further episodes of rapid regression, he has slowly deteriorated and has displayed [slurred] speech and wheelchair dependency from 7 years of age,” researchers stated.
For more than two years he has been treated with baclofen (sold under the names Kemstro and Lioresal) and Botox injections to manage the muscle contractions in the limbs.
Clinical and biochemical evaluations revealed that he had elevated lactate in multiple areas of the brain, although his lactate blood levels were normal. He also had several progressive lesions in various areas of the brain.
The third patient, a male infant, was born at 36 weeks after a complicated pregnancy. At birth, he was small for his gestational age and presented some physical alterations, including an accessory nipple, mildly displaced opening of the urethra, and sparse, fine scalp hair.
He developed within normal parameters until 3 months, when he experienced what researchers called an “explosive” onset of seizures. At 5 months old, he had lost all the developmental skills he had acquired, and was showing low muscle tone with limb and facial repetitive muscle contractions.
After several evaluations, he was found to have about twice the normal level of lactate in cerebral spinal fluid, and showed alterations in the brain on MRI scans.
His seizures did not respond to treatment and remained a problem. He also suffered significant gastroesophageal reflux, which led to the development of bronchiectasis (enlargement of the airways) by age 2 1/2.
Despite some improvement, his development remained markedly delayed. He is now 10 and can sit independently, but is unable to stand or walk. He is mute but responds positively to familiar voices; his vision is significantly impaired.
The last case reported was that of a female infant, born after an uneventful pregnancy, who at birth did not require special care.
At 7 weeks, she started to experience unusual movements suggestive of a seizure disorder. Upon admission to a hospital, she was found to have high blood gas lactate. Her condition progressively deteriorated, with seizures, episodes of apnea, and persistent lactic acidosis.
Despite intensive-care management, her lactate levels continued to increase until her death at 13 weeks old. At this point she had about five times the normal level of lactate in cerebral spinal fluid and about 13 times higher in her blood.
The symptoms and clinical manifestations of all four children were consistent with diagnosis of mitochondrial disease.
Genetic analysis revealed that they all had different mutations in the NDUFA6 gene sequence. However, this gene had not previously been linked to mitochondrial disorders.
To further test the association between NDUFA6 mutations and mitochondrial disease, researchers conducted experiments in cells collected from the patients. These confirmed that the children’s genetic mutations had the potential to promote OXPHOS dysfunction due to impaired complex I assembly, leading to mitochondrial deficiency.
“This study therefore establishes NDUFA6 as the 29th structural subunit of complex I to be associated with human pathology,” researchers stated.
Tests to evaluate NDUFA6 gene status are now available within routine practice to patients of the United Kingdom’s National Health Service (NHS).
“For our patients, it is important to pursue this because it gives parents an answer to why their child was poorly. It also offers them some choices for the future — if we know what disease-causing spelling mistakes run in the family, we can test their next children at an early stage of pregnancy to see if they will be healthy. Hopefully we can prevent them having to suffer the loss of any more children to this devastating and incurable disease,” Charlotte Alston, PhD, lead author of the study, said in a news release.