Case Report Details Fatal Neonatal Encephalopathy and Lactic Acidosis Caused by COQ9 Deficiency

In a recent study published in the journal European Journal of Human Genetics, a team of researchers from Germany provide additional insights into the clinical and cellular consequences of COQ9 deficiency in prenatal development.

Coenzyme Q10 (CoQ10) is a lipid-soluble, naturally occurring enzyme that is a key part of the mitochondrial respiratory chain, shuttling electrons and creating a kind of cycle between the oxidized and the reduced form of mitochondria. CoQ10 also links mitochondrial fatty acid β-oxidation into this respiratory chain and plays other key roles in keeping the “cellular powerhouses” of cells functional.

When CoQ10 exists in it reduced form, it also serves as a potent antioxidant, and people acquire it through both biosynthesis and what they eat. While CoQ10 can be ingested from food, however, biosynthesis is the major source of CoQ10, which involves a complex coordination of at least 13 genes (PDSS1, PDSS2, COQ2, COQ3, COQ4, COQ5, COQ6, COQ7, ADCK3, ADCK4, COQ9, COQ10A and COQ10B). When a person fails to produce ample CoQ10 through biosynthesis, it is important to identify the deficiency so that physicians can prescribe CoQ10 supplementation in certain conditions.

While there are several different means by which CoQ10 biosynthesis can be disrupted, to date, there has been only one report of a patient with CoQ10 deficiency caused by an issue with the COQ9 gene. However, the case study is significant, since this genetic dysfunction led to neonatal lactic acidosis, intractable seizures and global developmental delay.

In the study titled “Fatal neonatal encephalopathy and lactic acidosis caused by a homozygous loss-of-function variant in COQ9,” Katharina Danhauser from the Department of General Pediatrics at University Children’s Hospital in Düsseldorf, Germany along with her colleagues used exome sequencing to identify a new variant affecting function in COQ9 associated with neonatal encephalopathy and early death.

The boy reported in the study was the second child of healthy, first-grade consanguineous Turkish parents. His 13-year-old brother is healthy as well. Pregnancy was normal until the 27th gestational week when Oligohydramnios (low levels of amniotic fluid) was noticed. APGAR scores used to assess newborns’ health were 5/4/6, respectively. In the APGAR test, scores between 4 to 6 are considered “fairly low,” but not critically dangerous. However, the immediate postnatal period, the patient showed poor respiratory efforts, muscular hypotonia, bradycardia and generalized cyanosis.

Laboratory investigations revealed lactic acidosis (up to 22 mmol/l; norm: o1.8 mmol/l), requiring continuous buffering therapy with sodium bicarbonate. Cranial ultrasound demonstrated multiple choroid plexus cysts and symmetrical hyperechoic signal alterations in the basal ganglia, suggesting neonatal Leigh-like syndrome. The infant was also found to have elevated blood alanine (1088 μmol/l, norm o414 μmol/l) and massive lactic-acid excretion in urine.

On the fifth day of life, slow improvement in acidosis was noticed with minimal lactate levels of 5 mmol/l. Respiratory efforts improved and the boy was extubated with adequate spontaneous breathing on the eighth day of life. However, the child showed reduced spontaneous movements with intermittent opisthotonus and muscle stiffness in the extremities.

On the tenth day of life the child suffered from seizures and recurrent episodes of apnea and bradycardia. The boy’s clinical condition further deteriorated and he died due to cardio-respiratory failure at 18 days of age. Because of a suspected mitochondrial disease, a skin biopsy was performed. Activity measurements of the oxidative phosphorylation enzymes in cultured fibroblasts showed a strongly reduced activity of respiratory chain succinate-cytochrome c oxidoreductase (complex II+III: 62 mU/ UCOX, norm4160), pointing to a CoQ10 metabolism defect.

The case report could be valuable to researchers, as it expands the clinical spectrum associated with COQ9 variants and indicates a severe pre-/neonatal-onset phenotype. As a result of this report, COQ9-deficient patient fibroblasts were characterized in detail and the functional consequences of the genetic defect are shown.

Based on the case reported, the researchers suggest that a critical function of COQ9 is already present during prenatal development. The researchers concluded that COQ9 deficiency is among the most severe forms of CoQ10 metabolism disorders, comparable to descriptions in patients with defects in COQ2 or COQ4.