The affected individual, a male, was the fourth child born to an Arab Muslim family of Palestinian origin.
Parents are first cousins.
One sibling, a girl died at the age of 1 month due to SIDS according to parents, without any investigation.
Informed consent for muscle, skin biopsy and exome sequencing was obtained from the parents, and the study was approved by the local institutional review board.
During pregnancy, the patient was suspected to have IUGR and was delivered by Cesarian section at 36+2 gestational weeks with Apgar scores 9 and 10.
Birth weight was 2.3 kg (10th percentile) and head circumference 32 cm (10th percentile).
Physical exam after birth, detected a systolic murmur 3/6.
On the first day of life, the patient developed metabolic acidosis with lactate level of 27 mm (normal range 0.5–2.4 mm) and elevated ammonia levels 277 μm (normal range 10–60 μm).
Metabolic work up showed normal acylcarnitines, elevated alanine level 1400 μm (normal <700 μm), and urine organic acids showed increased lactic acidosis and ketones.
Chest X-ray revealed cardiomegaly, and cardiac Echo revealed symmetrical left ventricular hypertrophy tricuspid regurge and pulmonary hypertension.
The patient was transported to the NICU and treated with bicarbonate, acetate and diuretics.
At the age of 4 days, quadriceps muscle biopsy was performed.
Pathology showed decreased cytochrome c oxidase stain.
Brain ultrasound performed at age 5 days was normal.
Subsequently, head circumference grew rapidly adding 13 centimeters by age 35 days, repeated brain US revealed dilated ventricles confirmed by head CT, which also showed subcortical and white matter cortical hemorrhage in the occipital region.
At 15 weeks, a ventriculoperitoneal (VP) shunt was inserted.
Head CT performed at age 2 years showed prominent dilatation of the ventricles (Figure 1).
Due to hypotonia with feeding difficulties and recurrent aspirations, a percutaneous endoscopic gastrostomy (PEG) feeding tube was inserted at age 10 weeks.
Eye examination at the age of 15 weeks revealed cortical blindness.
Hearing test ABR was normal.
Repeated cardiac Echo continued to show mild tricuspid regurge, mild left ventricular hypertrophy (LVH) and pulmonary hypertension (PHTN) in the first months of life.
At the age of 4 months, he started developing hypertrophic obstructive cardiomyopathy, he was started on diuretics and beta blockers and later calcium channel blockers were added; follow-up Echo at the age of 2 years revealed improvement in the LVH and no PHTN.
Coenzyme Q10 supplementation (60 mg twice daily) was initiated at 4 months but discontinued by the parents.
In the following months, the patient was admitted several times to the hospital mainly due to chest infections, shunt malfunctioning and fevers.
He died at the age of 30 months due to severe hypoxemia after a febrile illness with chest infection and pulmonary edema; parents refused mechanical ventilation and refused reanimation.