Multiple phenotypes in phosphoglucomutase 1 deficiency.
BACKGROUND
Congenital disorders of glycosylation are genetic syndromes that result in impaired glycoprotein production. We evaluated patients who had a novel recessive disorder of glycosylation, with a range of clinical manifestations that included hepatopathy, bifid uvula, malignant hyperthermia, hypogonadotropic hypogonadism, growth retardation, hypoglycemia, myopathy, dilated cardiomyopathy, and cardiac arrest.


METHODS
Homozygosity mapping followed by whole-exome sequencing was used to identify a mutation in the gene for phosphoglucomutase 1 (PGM1) in two siblings. Sequencing identified additional mutations in 15 other families. Phosphoglucomutase 1 enzyme activity was assayed on cell extracts. Analyses of glycosylation efficiency and quantitative studies of sugar metabolites were performed. Galactose supplementation in fibroblast cultures and dietary supplementation in the patients were studied to determine the effect on glycosylation.


RESULTS
Phosphoglucomutase 1 enzyme activity was markedly diminished in all patients. Mass spectrometry of transferrin showed a loss of complete N-glycans and the presence of truncated glycans lacking galactose. Fibroblasts supplemented with galactose showed restoration of protein glycosylation and no evidence of glycogen accumulation. Dietary supplementation with galactose in six patients resulted in changes suggestive of clinical improvement. A new screening test showed good discrimination between patients and controls.


CONCLUSIONS
Phosphoglucomutase 1 deficiency, previously identified as a glycogenosis, is also a congenital disorder of glycosylation. Supplementation with galactose leads to biochemical improvement in indexes of glycosylation in cells and patients, and supplementation with complex carbohydrates stabilizes blood glucose. A new screening test has been developed but has not yet been validated. (Funded by the Netherlands Organization for Scientific Research and others.).
The authors' affiliations are listed in the Appendix.
Laura C
LC
Tegtmeyer
Stephan
S
Rust
Monique
M
van Scherpenzeel
Bobby G
BG
Ng
Marie-Estelle
ME
Losfeld
Sharita
S
Timal
Kimiyo
K
Raymond
Ping
P
He
Mie
M
Ichikawa
Joris
J
Veltman
Karin
K
Huijben
Yoon S
YS
Shin
Vandana
V
Sharma
Maciej
M
Adamowicz
Martin
M
Lammens
Janine
J
Reunert
Anika
A
Witten
Esther
E
Schrapers
Gert
G
Matthijs
Jaak
J
Jaeken
Daisy
D
Rymen
Tanya
T
Stojkovic
Pascal
P
Laforêt
François
F
Petit
Olivier
O
Aumaître
Elzbieta
E
Czarnowska
Monique
M
Piraud
Teodor
T
Podskarbi
Charles A
CA
Stanley
Reuben
R
Matalon
Patricie
P
Burda
Soraya
S
Seyyedi
Volker
V
Debus
Piotr
P
Socha
Jolanta
J
Sykut-Cegielska
Francjan
F
van Spronsen
Linda
L
de Meirleir
Pietro
P
Vajro
Terry
T
DeClue
Can
C
Ficicioglu
Yoshinao
Y
Wada
Ron A
RA
Wevers
Dieter
D
Vanderschaeghe
Nico
N
Callewaert
Ralph
R
Fingerhut
Emile
E
van Schaftingen
Hudson H
HH
Freeze
Eva
E
Morava
Dirk J
DJ
Lefeber
Thorsten
T
Marquardt
D005690:Galactose / Q000627:therapeutic use; D005808:Genes, Recessive; D005947:Glucose / Q000378:metabolism; D005958:Glucosephosphates / Q000235:genetics* / Q000378:metabolism; D006008:Glycogen Storage Disease / Q000178:diet therapy / Q000235:genetics* / Q000378:metabolism; D006023:Glycoproteins / Q000096:biosynthesis; D006031:Glycosylation; D006801:Humans; D008297:Male; D009154:Mutation; D010641:Phenotype; D010733:Phosphoglucomutase / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis
D005958:Glucosephosphates; D006023:Glycoproteins; D012333:RNA, Messenger; C031590:glucose-1-phosphate; C488050:PGM1 protein, human; D010733:Phosphoglucomutase; D005947:Glucose; D005690:Galactose