2.2 Patient 2
This female patient, aged 8 years, was born to non-consanguineous, healthy Japanese parents at 41 weeks of gestation after an uneventful pregnancy. Her birth weight and OFC were 3156 g (0.1 SD) and 32.0 cm (- 1.2 SD), respectively. She had no significant family medical history. During the neonatal period, she showed hypotonia, sleep disturbance, and inconsolable crying. The developmental milestones were severely delayed with no regression; she acquired head control at 6 months, turned over at 15 months, and sat up at 2 years. Because of feeding problems due to swallowing difficulties, she was fed via a nasogastric tube from 1 year and 9 months. Her head growth was postnatally decelerated and microcephaly became evident (OFCs of 40.2, 41.0, and 43.0 cm at 7 months, 1 year, and 2 years, respectively, all below - 2 SD). At the age of 3 years, she remained incapable of standing up, acquiring speech sounds, and purposeful hand skills. She displayed prominent hyperkinetic movement disorders with hand stereotypies. Brain MRI scans showed microcephaly with hypoplasia of the frontal lobe and the corpus callosum (Figure 1c and d). She showed clinical features and brain MRI findings that were reminiscent of FOXG1 syndrome; however, she had increased lactate and pyruvate levels in blood (lactate 18.2 mg/dL, pyruvate 2.5 mg/dL) and cerebrospinal fluid (CSF) (lactate 32.6 mg/dL, pyruvate 3.3 mg/dL), although the lactate/pyruvate molar ratio was normal. Genetic testing revealed a disease-associated variant ofPDHA1 , leading to a diagnosis of PDHC deficiency. She was enrolled in a clinical trial of pyruvate therapy for mitochondrial diseases,7 which was effective in promoting motor development, but not the cognitive impairment. She was able to walk a few steps at 7 years of age, but remained unable to speak any meaningful words.