Recessive mutations in SLC35A3 cause early onset epileptic encephalopathy with skeletal defects.
We describe the clinical and whole genome sequencing (WGS) study of a non-consanguineous Italian family in which two siblings, a boy and a girl, manifesting a severe epileptic encephalopathy (EE) with skeletal abnormalities, carried novel SLC35A3 compound heterozygous mutations. Both siblings exhibited infantile spasms, associated with focal, and tonic vibratory seizures from early infancy. EEG recordings showed a suppression-burst (SB) pattern and multifocal paroxysmal activity in both. In addition both had quadriplegia, acquired microcephaly, and severe intellectual disability. General examination showed distal arthrogryposis predominant in the hands in both siblings and severe left dorso-lumbar convex scoliosis in one. WGS of the siblings-parents quartet identified novel compound heterozygous mutations in SLC35A3 in both children. SLC35A3 encodes the major Golgi uridine diphosphate N-acetylglucosamine transporter. With this study, we add SLC35A3 to the gene list of epilepsies. Neurological symptoms and skeletal abnormalities might result from impaired glycosylation of proteins involved in normal development and function of the central nervous system and skeletal apparatus.
Neurology Unit and Neurogenetics Laboratories, Meyer Children Hospital, Florence, Italy.
Carla
C
Marini
Neurogenetics Group, VIB-Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium.|Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
Katia
K
Hardies
Neurology Unit and Neurogenetics Laboratories, Meyer Children Hospital, Florence, Italy.
Tiziana
T
Pisano
Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Luxembourg, Luxembourg.|Institute for Systems Biology (ISB), Seattle, Washington.
Patrick
P
May
Neurogenetics Group, VIB-Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium.|Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
Sarah
S
Weckhuysen
Neurology Unit and Neurogenetics Laboratories, Meyer Children Hospital, Florence, Italy.
Elena
E
Cellini
Neurogenetics Group, VIB-Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium.|Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
Arvid
A
Suls
Neurology Unit and Neurogenetics Laboratories, Meyer Children Hospital, Florence, Italy.
Davide
D
Mei
Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Luxembourg, Luxembourg.
Rudi
R
Balling
Neurogenetics Group, VIB-Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium.|Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.|Division of Neurology, Antwerp University Hospital, Antwerp, Belgium.
Peter D
PD
Jonghe
Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian-Albrechts University, Kiel, Germany.|Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Ingo
I
Helbig
CNR, Institute of Chemistry and Technology of Polymers, Section of Catania, Catania, Italy.
Domenico
D
Garozzo
Neurology Unit and Neurogenetics Laboratories, Meyer Children Hospital, Florence, Italy.|University of Florence, Florence, Italy.
Renzo
R
Guerrini
D001176:Arthrogryposis / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D001842:Bone and Bones / Q000002:abnormalities; D002648:Child; D004569:Electroencephalography; D005260:Female; D015870:Gene Expression; D006031:Glycosylation; D006579:Heterozygote; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D008297:Male; D008831:Microcephaly / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D033704:Nucleotide Transport Proteins / Q000235:genetics*; D011782:Quadriplegia / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D035781:Siblings; D013036:Spasms, Infantile / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology
D033704:Nucleotide Transport Proteins; C000621190:SLC35A4 protein, human
epileptic encephalopathy; genetics; infantile spasms; skeletal abnormalities; suppression burst