3. Discussion
PDHC catalyzes the oxidative decarboxylation of pyruvate to acetyl-CoA, a critical step in energy production. The clinical spectrum of PDHC deficiency ranges from episodic ataxia to severe fatal neonatal lactic acidosis.9 We identified a disease-associated variant in the X-linked PDHA1 in two female patients who were clinically suspected to have FOXG1 syndrome. Both had the same heterozygous deletion of a 7-bp repeat sequence in exon 10 of PDHA1. This mutation was already reported in female patients with PDHC deficiency who exhibited variations in clinical severity, most probably due to different patterns of X-chromosome inactivation.10 Our patients exhibited similar clinical features, including microcephaly, hypotonia, feeding difficulties, abnormal involuntary movements, stereotypic hand movements, and a profound delay in psychomotor development. Brain MRI scans revealed cerebral atrophy, ventriculomegaly, and hypoplasia of the corpus callosum. These features have been reported in patients with FOXG1 syndrome,11-13 suggesting a phenotypic overlap between PDHC deficiency and FOXG1 syndrome (Table 1).
Although patients with PDHC deficiency shared clinical features with FOXG1 syndrome, specific brain MRI findings may distinguish PDHC deficiency from FOXG1 syndrome. Corpus callosum hypogenesis was observed in both diseases. However, the corpus callosum in FOXG1 syndrome was affected mostly the anterior parts,14 whereas in PDHC deficiency, the posterior body and splenium were preferentially affected.15 Moreover, patients with PDHC deficiency had dilated ventricles with ventricular septations and/or subependymal cysts (Figure 1), probably due to a destructive process secondary to a metabolic defect, which were absent in FOXG1 syndrome. Subependymal cysts were also described in other metabolic disorders that cause primary lactic acidosis.16 Intraventricular septations probably reflect the evolution of subependymal cysts. Thus, none of the MRI findings described here is unique to PDHC deficiency. The detection of these MRI findings should prompt further investigation, including metabolic analysis and genetic testing for PDHA1 variants.
Most importantly, PDHC deficiency is commonly associated with lactic acidosis.9 Specific structural brain abnormalities, with the characteristic clinical features may allow distinction of PDHC deficiency from FOXG1 syndrome if the lactate and pyruvate levels are elevated in the blood and/or CSF. Therefore, this study further reinforces the necessity of measuring the lactate and pyruvate levels in blood and/or CSF even in the cases of clinically suspected FOXG1 syndrome.