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.