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Severe child form of primary hyperoxaluria type 2 - a case report revealing
consequence of GRHPR deficiency on metabolism
#MMPMID28569194
Konko?ová J
; Chandoga J
; Ková?ik J
; Repiský M
; Kramarová V
; Pau?inová I
; Böhmer D
BMC Med Genet
2017[May]; 18
(1
): 59
PMID28569194
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BACKGROUND: Primary hyperoxaluria type 2 is a rare monogenic disorder inherited
in an autosomal recessive pattern. It results from the absence of the enzyme
glyoxylate reductase/hydroxypyruvate reductase (GRHPR). As a consequence of
deficient enzyme activity, excessive amounts of oxalate and L-glycerate are
excreted in the urine, and are a source for the formation of calcium oxalate
stones that result in recurrent nephrolithiasis and less frequently
nephrocalcinosis. CASE PRESENTATION: We report a case of a 10-month-old patient
diagnosed with urolithiasis. Screening of inborn errors of metabolism, including
the performance of GC/MS urine organic acid profiling and HPLC amino acid
profiling, showed abnormalities, which suggested deficiency of GRHPR enzyme.
Additional metabolic disturbances observed in the patient led us to seek other
genetic determinants and the elucidation of these findings. Besides the elevated
excretion of 3-OH-butyrate, adipic acid, which are typical marks of ketosis,
other metabolites such as 3-aminoisobutyric acid, 3-hydroxyisobutyric acid,
3-hydroxypropionic acid and 2-ethyl-3-hydroxypropionic acids were observed in
increased amounts in the urine. Direct sequencing of the GRHPR gene revealed
novel mutation, described for the first time in this article c.454dup
(p.Thr152Asnfs*39) in homozygous form. The frequent nucleotide variants were
found in AGXT2 gene. CONCLUSIONS: The study presents metabolomic and
molecular-genetic findings in a patient with PH2. Mutation analysis broadens the
allelic spectrum of the GRHPR gene to include a novel c.454dup mutation that
causes the truncation of the GRHPR protein and loss of its two functional
domains. We also evaluated whether nucleotide variants in the AGXT2 gene could
influence the biochemical profile in PH2 and the overproduction of metabolites,
especially in ketosis. We suppose that some metabolomic changes might be
explained by the inhibition of the MMSADH enzyme by metabolites that increase as
a consequence of GRHPR and AGXT2 enzyme deficiency. Several facts support an
assumption that catabolic conditions in our patient could worsen the degree of
hyperoxaluria and glyceric aciduria as a consequence of the elevated production
of free amino acids and their intermediary products.
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