Variants p.Q1236H and p.E1143G in mitochondrial DNA polymerase gamma POLG 1 are not associated with increased risk for valproate‐induced hepatotoxicity or pancreatic toxicity: A retrospective cohort study of patients with epilepsy
Summary Objective Previous studies have suggested that heterozygous variants p.Q1236H and p.E1143G in mitochondrial DNA polymerase gamma ( POLG 1 ) increase the risk for liver injury for patients on valproate ( VPA ) therapy. We assessed the prevalence of these common variants and seven other pathog...
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Published in | Epilepsia (Copenhagen) Vol. 59; no. 11; pp. 2125 - 2136 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
01.11.2018
|
Online Access | Get full text |
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Summary: | Summary
Objective
Previous studies have suggested that heterozygous variants p.Q1236H and p.E1143G in mitochondrial
DNA
polymerase gamma (
POLG
1
) increase the risk for liver injury for patients on valproate (
VPA
) therapy. We assessed the prevalence of these common variants and seven other pathogenic mutations in
POLG
1
and determined the occurrence of
VPA
‐induced hepatotoxicity (
VHT
) or pancreatic toxicity in a cohort of patients with epilepsy.
Methods
Patients with epilepsy (N = 367) were retrospectively identified from medical record files and screened for mutations in
POLG
1
. Patients who had received
VPA
monotherapy and carried either of the two variants, p.Q1236H or p.E1143G, without other pathogenic mutations in
POLG
1
(n = 33, variant group) and patients without these variants (n = 28, nonvariant group) were included in the study. Clinical data on epilepsy, characteristics of
VPA
treatment, risk factors for
VHT
, laboratory data on liver and pancreas functions, and adverse effects were collected.
Results
A total of 122 patients had either the
POLG
1
p.Q1236H (n = 99) or p.E1143G (n = 24) variant in the heterozygous or homozygous state. Transient liver dysfunction was identified in three (n = 33, 9.1%) variant group patients and in one (n = 28, 3.6%) nonvariant group patient (
P
= 0.62). Mild to moderate elevations in liver enzymes were encountered in both groups. Furthermore, two patients on
VPA
polytherapy developed acute pancreatitis, and two pediatric patients with heterozygous p.Q1236H variants and mutations in
IQSEC
2
and
GLDC
, respectively, had elevated levels of
VPA
metabolites in urine, elevated plasma glycine, and/or increased acylglycine excretion.
Significance
POLG
1
p.Q1236H and p.E1143G variants could not be identified as statistically significant risk factors for
VHT
or pancreatic toxicity. We suggest that
VPA
treatment could be suitable for patients who harbor these common variants in the absence of other pathogenic mutations in
POLG
1
. |
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ISSN: | 0013-9580 1528-1167 |
DOI: | 10.1111/epi.14568 |