Severe Mitochondrial Disease Caused by FBXL4 Gene Mutations Identified in Premature Birth

A severe case of mitochondrial disease, caused by mutations in the FBXL4 gene, was confirmed by sequencing the coding parts of the genes of an infant born more than three months premature.

The study, “Polyhydramnios and cerebellar atrophy: a prenatal presentation of mitochondrial encephalomyopathy caused by mutations in the FBXL4 gene,” published in the journal Clinical Case Reports, is the first to report a case of FBXL4-linked disease affecting a child before birth, and highlights the need for thorough examinations of signs of excess amniotic fluid during pregnancy.

Excess amniotic fluid in pregnant women can be a sign that the fetus is not developing normally. Most often, the condition is caused by pregnancy-associated diabetes or infections in the mother, but at times, such cases are caused by metabolic disorders.

A woman was referred to Leiden University Medical Centre in the Netherlands after routine tests showed signs of excess amniotic fluid and premature contractions at week 25 + 5 of her pregnancy. Except for a heart defect at birth that spontaneously healed, neither the woman nor the child’s father had any history of disease.

This was the 30-year-old woman’s first pregnancy. She received  anti-contraction medications and corticosteroids to speed up the lung maturation of the fetus. Doctors excluded the possibility that the condition was caused by an infection. After draining some of the fluid, ultrasound analyses showed that the fetus had a too-large cisterna magna — one of the ventricles, or cavities, inside the brain.

The scan also showed that the cerebellum was smaller than normal. The heart tissue was thicker than normal, and the fetus had a hole in the heart of the type the mother had as a child, called a ventricular septal defect.

Two days later the woman spontaneously gave birth to a boy weighing 835 grams or 1.84 pounds. The child had poor muscle tone and lacked fat. He had slightly abnormal facial features, long and slender arms and legs, large hands, pronounced foot arches and prominent heels.

An ultrasound found small bleeds inside and surrounding the brain ventricles. A few hours after birth he developed respiratory distress syndrome and low blood pressure. He had also developed acidosis, acidification of the blood caused by high levels of the metabolic by-products lactic and pyruvic acid, and had high levels of the amino acids proline and lysine in both urine and plasma. The child died two days after birth.

The laboratory findings, along with the clinical observations, suggested the condition might have been linked to mitochondrial dysfunction, and so the child’s DNA was analyzed with various methods. Whole exome sequencing — an analysis looking for mutations in all the regions of the DNA coding for proteins, found two mutations, one in each copy of the gene coding for FBXL4. The mutations caused the production of truncated versions of the gene transcripts. The child’s parents each carried one of the mutations.

Mutations in the FBXL4 gene have recently been linked to severe cases of mitochondrial conditions affecting the brain, but this is the first time the gene was linked to an onset of mitochondrial disease before birth. One of the mutations the child carried had been described before, in a child that died young with similar symptoms.

While the other mutation is new to scientists, it is also linked to the inability to produce the FBXL4 protein, and is likely to produce the same kind of symptoms.

Evidence that the mutations affected mitochondrial function came from analyses of skin and muscle biopsies of the child, showing dysfunctional mitochondria and loss of mitochondrial DNA. The research team believed that the hole in the heart was not linked to the mutations.

The woman got pregnant again before the genetic analyses had started. Genetic analysis of the fetus showed it was unaffected, and this time, the woman gave birth to a healthy child.