Thymidine phosphorylase gene mutations in patients with mitochondrial neurogastrointestinal encephalomyopathy syndrome.
The mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndrome is characterized by the association of gastrointestinal and neurological symptoms. It is a rare autosomal recessive mitochondrial disorder with multiple mitochondrial DNA deletions and/or depletion. It is caused by thymidine phosphorylase (TP) gene mutations resulting in a complete abolition of TP activity. We tested 31 unrelated patients presenting either with a complete MNGIE syndrome (8 patients), a severe intestinal pseudo-obstruction (10 patients), and multiple deletions and/or depletion of mitochondrial DNA (13 patients). All the tested patients presenting with a complete MNGIE had increased thymidine levels in plasma and urine, and no TP activity. The group with pseudo-obstruction syndrome had normal or partial reduction of TP activity. We found pathogenic mutations on TP gene only in the MNGIE syndrome group: all the MNGIE patients were compound heterozygous or homozygous for mutations in the TP gene. Eight of these mutations are yet unreported, confirming the lack of genotype/phenotype correlation in this syndrome. Enzymatic activity and thymidine level are thus rapid diagnosis tests to detect MNGIE affected patients prior to genetic testing for patients with gastrointestinal symptoms.
Slama
A
A
Laboratoire de Biochimie 1, AP-HP Hôpital Bicêtre, France. abdel.slama@bct.ap-hop-paris.fr
Lacroix
C
C
Plante-Bordeneuve
V
V
Lombès
A
A
Conti
M
M
Reimund
J M
JM
Auxenfants
E
E
Crenn
P
P
Laforêt
P
P
Joannard
A
A
Seguy
D
D
Pillant
H
H
Joly
P
P
Haut
S
S
Messing
B
B
Said
G
G
Legrand
A
A
Guiochon-Mantel
A
A
D000328:Adult; D002648:Child; D004272:DNA, Mitochondrial / Q000235:genetics; D006801:Humans; D007418:Intestinal Pseudo-Obstruction / Q000235:genetics; D017237:Mitochondrial Encephalomyopathies / Q000235:genetics*; D009154:Mutation; D017384:Sequence Deletion; D013577:Syndrome; D013936:Thymidine / Q000097:blood / Q000652:urine; D013939:Thymidine Phosphorylase / Q000235:genetics* / Q000378:metabolism
D004272:DNA, Mitochondrial; D013939:Thymidine Phosphorylase; D013936:Thymidine