To report 2 additional cases of pyruvate dehydrogenase complex deficiency with reversible deep gray matter lesions following initiation of ketogenic diet and to perform a literature review of serial imaging in patients with pyruvate dehydrogenase complex.
Methods:
Clinical data on 3 previously unpublished cases of patients with pyruvate dehydrogenase complex deficiency and with serial magnetic resonance imagings (MRIs) before and after institution of ketogenic diet were reported. A systematic literature review was performed to search for published cases of patients with confirmed pyruvate dehydrogenase complex deficiency who underwent serial MRIs.
Results:
The 3 subjects in this series demonstrated clinical improvement on ketogenic diet. Two subjects showed reversal of some brain lesions on repeat MRI following initiation of ketogenic diet. Of the 21 published cases with serial MRIs, 13 patients underwent some form of treatment, and of this smaller subset 4 patients had repeat MRIs that showed definitive improvement. In both our described cases and those published in the literature, improvement occurred in lesions in the basal ganglia.
Conclusions:
In patients with pyruvate dehydrogenase complex deficiency, basal ganglia lesions on MRI are reversible with treatment in some cases and could serve as a biomarker for measuring response to treatment.
BarneriasCSaudubrayJ-MTouatiG, et al.Pyruvate dehydrogenase complex deficiency: four neurological phenotypes with differing pathogenesis. Dev Med Child Neurol. 2010;52:e1–e9.
2.
PatelKPO’BrienTWSubramonySHShusterJStacpoolePW. The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients. Mol Genet Metab. 2012;105:34–43.
3.
DeBrosseSDOkajimaKZhangS, et al.Spectrum of neurological and survival outcomes in pyruvate dehydrogenase complex (PDC) deficiency: lack of correlation with genotype. Mol Genet Metab. 2012;107:394–402.
4.
PatelMSNemeriaNSFureyWJordanF. The pyruvate dehydrogenase complexes: structure-based function and regulation. J Biol Chem. 2014;289:16615–16623.
5.
NaitoEItoMTakedaEYokotaIYoshijimaSKurodaY. Molecular analysis of abnormal pyruvate dehydrogenase in a patient with thiamine-responsive congenital lactic acidemia. Pediatr Res. 1994;36:340–346.
6.
BakerPR2ndFriederichMWSwansonMA, et al.Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5. Brain. 2014;137(pt 2):366–379.
WickHSchweizerKBaumgartnerR. Thiamine dependency in a patient with congenital lacticacidaemia due to pyruvate dehydrogenase deficiency. Agents Actions. 1977;3:405–410.
9.
WexlerIDHemalathaSGMcConnellJ, et al.Outcome of pyruvate dehydrogenase deficiency treated with ketogenic diets. Studies in patients with identical mutations. Neurology. 1997;49:1655–1661.
10.
FalkRECederbaumSDBlassJPGibsonGEKarkRACarrelRE. Ketonic diet in the management of pyruvate dehydrogenase deficiency. Pediatrics. 1976;58:713–721.
11.
SofuKDahlinMHallbookTLindefeldtMViggedalGDarinN. Ketogenic diet in pyruvate dehydrogenase complex deficiency: short- and long-term outcomes. J Inherit Metab Disease. 2012;40:237–245.
12.
GiribaldiGDoria-LambaLBiancheriR, et al.Intermittent-relapsing pyruvate dehydrogenase complex deficiency: a case with clinical, biochemical, and neuroradiological reversibility. Dev Med Child Neurol. 2012;54:472–476.
13.
KimuraSOsakaHSaitouKOhtukiNKobayashiTNezuA. Improvement of lesions shown on MRI and CT scan by administration of dichloroacetate in patients with Leigh syndrome. J Neurol Sci. 1995;134:103–107.
14.
NaitoEItoMYokotaI, et al.Thiamine responsive pyruvate dehydrogenase deficiency in two patients caused by a point mutation (F205 L and L216F) within the thiamine pyrophosphate binding region. Biochimica et Biophysica Acta. 2002;1588:79–84.
15.
van DongenSBrownRMBrownGKThorburnDRBonehA. Thiamine-responsive and non-responsive patients with PDHC-E1 deficiency: a retrospective assessment. JIMD Rep. 2015;15:13–27.
16.
WijburgFABarthPGBindoffLA, et al.Leigh syndrome associated with a deficiency of the pyruvate dehydrogenase complex: results of treatment with a ketogenic diet. Neuropediatrics. 1992;23:147–152.
17.
Di RoccoMLambaLDMinnitiGCarusoUNaitoE. Outcome of thiamine treatment in a child with Leigh disease due to thiamine-responsive pyruvate dehydrogenase deficiency. Eur J Paediatr Neurol. 2000;4:115–117.
18.
El-GharbawyAHBoneyAYoungSPKishnaniPS. Follow-up of a child with pyruvate dehydrogenase deficiency on a less restrictive ketogenic diet. Mol Genet Metab. 2011;102:214–215.
19.
RamadanDGHeadRAAl-TawariAHabeebY. Lactic acidosis and developmental delay due to deficiency of E3 binding protein (protein X) of the pyruvate dehydrogenase complex. J Inherit Metab Dis. 2004;27:477–485.
20.
SchiffMMinéMBrivetM, et al.Leigh’s disease due to a new mutation in the PDHX gene. Ann Neurol. 2006;59:709–714.
21.
SmallJEGonzalezGENagaoKEWaltonDSCarusoPA. Optic neuropathy in a patient with pyruvate dehydrogenase deficiency. Pediatr Radiol. 2009;39:1114–1117.
22.
SinghiPDe MeirleirLLissensWSinghiSSainiAG. Pyruvate dehydrogenase-e1α deficiency presenting as recurrent demyelination: an unusual presentation and a novel mutation. JIMD Rep. 2013;10:107–111.
23.
HeadRABrownRMZolkipliZ, et al.Clinical and genetic spectrum of pyruvate dehydrogenase deficiency: dihydrolipoamide acetyltransferase (E2) deficiency. Ann Neurol. 2005;58:234–241.
24.
StrassburgHMKochJMayrJSperlWBoltshauserE. Acute flaccid paralysis as initial symptom in 4 patients with novel E1alpha mutations of the pyruvate dehydrogenase complex. Neuropediatrics. 2006;37:137–141.
25.
MellickGPriceLBoyleR. Late-onset presentation of pyruvate dehydrogenase deficiency. Mov Disord. 2004;19:727–729.
26.
Soares-FernandesJPTeixeira-GomesRCruzR, et al.Neonatal pyruvate dehydrogenase deficiency due to a R302 H mutation in the PDHA1 gene: MRI findings. Pediatr Radiol. 2008;38:559–562.
27.
TuliniusMDarinNWiklundL-M, et al.A family with pyruvate dehydrogenase complex deficiency due to a novel C>T substitution at nucleotide position 407 in exon 4 of the X-linked Epsilon1alpha gene. Eur J Pediatr. 2005;164:99–103.
28.
BrownRMHeadRABrownGK. Pyruvate dehydrogenase E3 binding protein deficiency. Hum Genet. 2002;110:187–191.
29.
LissensWDe MeirleirLSenecaS, et al.Mutations in the X-linked pyruvate dehydrogenase (E1) α subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency. Hum Mutat. 2000;15:209.
30.
JohnsonMTMahmoodSHyattSL, et al.Inactivation of the murine pyruvate dehydrogenase (Pdha1) gene and its effect on early embryonic development. Mol Genet Metab. 2001;74: 293–302.
