A newborn boy of healthy nonconsanguineous parents was delivered at 37 weeks’ gestation by cesarean section.
His mother (primipara, 32 years old) had been admitted to our hospital 2 weeks previously because of reduced fetal intrauterine movements and polyhydramnios.
The child’s birthweight was 2,330 g (<10th percentile), length 47 cm, and head circumference 33.2 cm (25th percentile).
He had low-set ears and bilateral clubfoot.
Apgar scores were 2, 6, and 7 at 1, 5, and 10 minutes.
The child presented with severe hypotonia and generalized muscle weakness, requiring ventilatory assistance and total parenteral nutrition.
Weaning failed because of inadequate pulmonary ventilation and respiratory acidosis.
Hearing loss was detected by auditory evoked potentials, while cranial MRI showed mildly enlarged ventricles and liquor spaces.
Two days after birth, the infant presented with severe abdominal distension with a hypoactive bowel.
MRI revealed marked intestinal dilation without mechanical obstruction.
Laboratory investigations showed hypoglycemia (27 mg/dL), hypomagnesemia (0.58 mmol/L), and hypokalemia (2.4 mmol/L).
Blood lactate was normal (1.3 mmol/L, normal range 0.5–2.2 mmol/L) and liver enzymes were unremarkable.
A skeletal muscle biopsy was performed and showed scattered, hypertrophic cytochrome c oxidase (COX)-deficient and succinate dehydrogenase–positive muscle fibers (figure), suggesting a mitochondrial disorder.
Molecular genetic studies revealed marked mtDNA depletion in muscle (93% decrease as compared to age-matched controls), while a screen for mtDNA rearrangements within individual COX-positive and COX-deficient fibers4 was negative.
We sequenced the entire coding region and intron-exon boundaries of the POLG1 gene, identifying two reported heterozygous missense mutations in compound c.679C>T predicting p.R227W and c.2542G>A predicting p.G848S.
Sequencing of parental samples confirmed recessive inheritance.
The infant died at 20 days of respiratory failure.
At autopsy, the brain did not show remarkable changes on gross examination.
Histology was not informative due to poor preservation of tissue; there was no evidence of neuronal damage in the spinal cord.
The liver showed diffuse cholestasis, consistent with total parenteral nutrition; hepatocyte steatosis, necrosis, or liver fibrosis were not observed.
The testicles were undescended, while remaining visceral organs were normal except for a marked dilation and thinning of the bowel wall.
Despite normal histology, analysis of stomach, ileum, and colon homogenates revealed severe mtDNA depletion (up to 94% decrease; table e-1 on the Neurology® Web site at www.neurology.org).
Laser capture microdissection analysis5 revealed that the mtDNA depletion was confined to the muscularis propria, being most prominent in its external layer (figure).
Ganglion cells from the myenteric plexus showed milder mtDNA depletion, restricted to the small intestine (figure).
There was no mtDNA depletion in liver (not shown).