ALG6-CDG: a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioral and limb anomalies.
Alpha-1,3-glucosyltransferase congenital disorder of glycosylation (ALG6-CDG) is a congenital disorder of glycosylation. The original patients were described with hypotonia, developmental disability, epilepsy, and increased bleeding tendency.



Based on Euroglycan database registration, we approached referring clinicians and collected comprehensive data on 41 patients.



We found hypotonia and developmental delay in all ALG6-CDG patients and epilepsy, ataxia, proximal muscle weakness, and, in the majority of cases, failure to thrive. Nine patients developed intractable seizures. Coagulation anomalies were present in <50 % of cases, without spontaneous bleedings. Facial dysmorphism was rare, but seven patients showed missing phalanges and brachydactyly. Cyclic behavioral change, with autistic features and depressive episodes, was one of the most significant complaints. Eleven children died before the age of 4 years due to protein losing enteropathy (PLE), sepsis, or seizures. The oldest patient was a 40 year-old Dutch woman. The most common pathogenic protein alterations were p.A333V and p.I299Del, without any clear genotype-phenotype correlation.



ALG6-CDG has been now described in 89 patients, making it the second most common type of CDG. It has a recognizable phenotype and a primary neurologic presentation.
Center for Metabolic Diseases, Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium. eva.morava@uzleuven.be.|Tulane University Medical School, Hayward Genetics Center, New Orleans, LA, USA. eva.morava@uzleuven.be.
Eva
E
Morava
Department of Pediatrics, Radboud University Medical Center, Nijmegen, The Netherlands.|Translational Metabolic Laboratory, Department Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
Vera
V
Tiemes
Center for Child and Adolescent Medicine, Kinderheilkunde I, University of Heidelberg, Heidelberg, Germany.
Christian
C
Thiel
Biochimie Métabolique Hôpital Bichat-Claude Bernard, Paris, France.
Nathalie
N
Seta
Reference Center of Metabolism, Necker-Enfants Malades Hospital, APHP, Imagine Institute, University Paris-Descartes, Paris, France.
Pascale
P
de Lonlay
Department of Pediatrics, Erasmus MC - University Medical Center Rotterdam, Emma Hospital, Rotterdam, The Netherlands.
Hans
H
de Klerk
Department of Pediatrics, Free University Amsterdam, Amsterdam, The Netherlands.
Margot
M
Mulder
Department of Pediatrics and Laboratory Genetic Metabolic Diseases, University of Maastricht, Maastricht, The Netherlands.
Estela
E
Rubio-Gozalbo
Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
Gepke
G
Visser
Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
Peter
P
van Hasselt
Medical Genetics Service, Porto Alegre, RS, Brazil.
Dafne D G
DDG
Horovitz
Medical Genetics Service, Porto Alegre, RS, Brazil.
Carolina Fischinger Moura
CFM
de Souza
Medical Genetics Service, Porto Alegre, RS, Brazil.
Ida V D
IVD
Schwartz
National Centre for Medical Genetics, Dublin, Ireland.
Andrew
A
Green
Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Mohammed
M
Al-Owain
University of Milan, Institute of Neurology, Milan, Italy.
Graciella
G
Uziel
Département de Génétique Médicale, Hôpital Timone Enfant, Marseille, France.
Sabine
S
Sigaudy
Neuropediatrics Unit, Childrens Hospital CHU Timone, Marseille, France.
Brigitte
B
Chabrol
Division of Metabolic Diseases, Beatrix Children's Hospital, University Medical Center of Groningen, University of Groningen, Groningen, The Netherlands.
Franc-Jan
FJ
van Spronsen
Sozialpädiatrisches Zentrum, Neuropädiatrie, Klinik für Kinder- und Jugendmedizin, Dortmund, Germany.
Martin
M
Steinert
Kinderklinik Villingen, Schwarzwald-Baar-Klinikum, Villingen, Germany.
Eleni
E
Komini
Department of Pediatrics, Klinikum Saarbrücken, Saarbrücken, Germany.
Donald
D
Wurm
Department of Pediatric Neurology and Developmental Medicine, Universal Children's Hospital Tübingen, Tübingen, Germany.
Andrea
A
Bevot
Biochimie Métabolique Hôpital Bichat-Claude Bernard, Paris, France.
Addelkarim
A
Ayadi
Translational Metabolic Laboratory, Department Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
Karin
K
Huijben
Centre for Human Metabolomics, North-West University, Potchefstroom, South Africa.
Marli
M
Dercksen
Center for Metabolic Diseases, Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium.
Peter
P
Witters
Center for Metabolic Diseases, Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium.
Jaak
J
Jaeken
Laboratory for Molecular Diagnosis, Center for Human Genetics, University of Leuven, Leuven, Belgium.
Gert
G
Matthijs
Translational Metabolic Laboratory, Department Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Neurology, Radboud University Medical Center, Nijmegen, The Netherlands.
Dirk J
DJ
Lefeber
Translational Metabolic Laboratory, Department Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. ron.wevers@radboudumc.nl.
Ron A
RA
Wevers
D000293:Adolescent; D000328:Adult; D001259:Ataxia / Q000235:genetics / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D018981:Congenital Disorders of Glycosylation / Q000235:genetics / Q000473:pathology*; D004827:Epilepsy / Q000235:genetics / Q000473:pathology*; D005260:Female; D056726:Genetic Association Studies / Q000379:methods; D005964:Glucosyltransferases / Q000235:genetics*; D006031:Glycosylation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D017880:Limb Deformities, Congenital / Q000235:genetics / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D001523:Mental Disorders / Q000235:genetics / Q000473:pathology*; D009123:Muscle Hypotonia / Q000235:genetics / Q000473:pathology; D018908:Muscle Weakness / Q000235:genetics / Q000473:pathology*; D010641:Phenotype; D012189:Retrospective Studies; D012640:Seizures / Q000235:genetics / Q000473:pathology; D055815:Young Adult
D008565:Membrane Proteins; C498467:ALG6 protein, human; D005964:Glucosyltransferases