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.