2.1 Patient 1
This 31-year-old female patient was born to non-consanguineous, healthy Japanese parents at 40 weeks of gestation after an uneventful pregnancy. Her birth weight and length were 2650 g (- 1.1 SD) and 44.2 cm (- 2.8 SD), respectively. Her occipitofrontal circumference (OFC) was 32 cm (- 1.1 SD). She had no significant family medical history. Because of floppiness and inability to suck, she was fed through a nasogastric tube from the first day of life. At the age of 3 months, psychomotor delay, hypotonia, and strabismus were noted, and myoclonic seizures from the age of 11 months. The seizures were eventually controlled with phenytoin and phenobarbital. Developmental milestones were severely delayed; she acquired head control and turned over at 3 years, and was never able to walk unaided and never acquired speech sounds. She displayed hand stereotypies with hand-to-mouth movements. Her OFC was 43.5 cm (- 6.6 SD) at 8 years, indicating that microcephaly had become more evident with time. Magnetic resonance imaging (MRI) scans of the brain showed ventricular dilatation and hypoplasia of the frontal lobe and the corpus callosum (Figure 1a and b). Based on the clinical and brain MRI features, FOXG1 syndrome was initially suspected. However, genetic testing identified a disease-associated variant in PDHA1 but not in FOXG1 . Metabolic investigations revealed increased levels of lactate (25.1 mg/dL) and pyruvate (1.93 mg/dL) in blood, leading to a definite diagnosis of PDHC deficiency. Lactate and pyruvate accumulation were reduced to 12.9 and 1.06 mg/dL respectively, by administration of thiamine at a dose of 150 mg a day; however, her neurological condition did not improve.