Pyruvate dehydrogenase complex (
PDHC) deficiency is a disorder of energy metabolism that leads to a range of clinical manifestations. We sought to characterise clinical manifestations and biochemical, neuroimaging and molecular findings in
thiamine-responsive and nonresponsive PDHC-deficient patients and to identify potential pitfalls in the diagnosis of
PDHC deficiency. We retrospectively reviewed all medical records of all PDHC-deficient patients (n = 19; all had PDHA1 gene mutations) and one patient with severe
PDHC deficiency secondary to
3-hydroxyisobutyryl-CoA hydrolase deficiency managed at our centre between 1982 and 2012. Responsiveness to
thiamine was based on clinical parameters. Seventeen patients received
thiamine treatment: eight did not respond, four showed sustained response and the others responded temporarily/questionably. Sustained response was noted at
thiamine doses >400 mg/day. Age at presentation was 0-6 and 12-27 months in the nonresponsive (n = 8) and responsive (n = 4) patients, respectively. Corpus callosum abnormalities were noted in 4/8 nonresponsive patients. Basal ganglia involvement (consistent with
Leigh disease) was found in four patients (including 2/4
thiamine-responsive patients). Diagnosis through mutation analysis was more sensitive and specific than through enzymatic analysis. We conclude that patients presenting at age >12 months with relapsing
ataxia and possibly
Leigh syndrome are more likely to be
thiamine responsive than those presenting with neonatal
lactic acidosis and corpus callosum abnormalities. However, this distinction is equivocal and treatment with
thiamine (>400 mg/day) should be commenced on all patients suspected of having
PDHC deficiency. Mutation analysis is the preferable first-line diagnostic test to avoid missing
thiamine-responsive patients and misdiagnosing patients with secondary
PDHC deficiency.
SHORT SUMMARY:
Thiamine responsiveness is more likely in patients presenting at age >12 months with relapsing
ataxia and possibly
Leigh syndrome than in those presenting with neonatal
lactic acidosis and corpus callosum abnormalities.
Thiamine doses >400 mg/day are required for sustained response. Mutation analysis is more sensitive and specific than enzymatic analysis as a first-line diagnostic test.