PIGA mutations cause early-onset epileptic encephalopathies and distinctive features.
OBJECTIVE
To investigate the clinical spectrum caused by mutations in PIGA at Xp22.2, which is involved in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor, among patients with early-onset epileptic encephalopathies (EOEEs).


METHODS
Whole-exome sequencing was performed as a comprehensive genetic analysis for a cohort of 172 patients with EOEEs including early myoclonic encephalopathy, Ohtahara syndrome, and West syndrome, and PIGA mutations were carefully investigated.


RESULTS
We identified 4 PIGA mutations in probands showing early myoclonic encephalopathy, West syndrome, or unclassified EOEE. Flow cytometry of blood granulocytes from patients demonstrated reduced expression of GPI-anchored proteins. Expression of GPI-anchored proteins in PIGA-deficient JY5 cells was only partially or hardly restored by transient expression of PIGA mutants with a weak TATA box promoter, indicating a variable loss of PIGA activity. The phenotypic consequences of PIGA mutations can be classified into 2 types, severe and less severe, which correlate with the degree of PIGA activity reduction caused by the mutations. Severe forms involved myoclonus and asymmetrical suppression bursts on EEG, multiple anomalies with a dysmorphic face, and delayed myelination with restricted diffusion patterns in specific areas. The less severe form presented with intellectual disability and treatable seizures without facial dysmorphism.


CONCLUSIONS
Our study confirmed that PIGA mutations are one genetic cause of EOEE, suggesting that GPI-anchor deficiencies may be an underlying cause of EOEE.
From the Department of Pediatrics (M.K., K.H.), Yamagata University Faculty of Medicine, Yamagata; Department of Human Genetics (H.S., C.O., M.N., Y.T., N. Miyake, N. Matsumoto), Yokohama City University Graduate School of Medicine, Yokohama; Department of Immunoregulation (Y.M., T.K.), Research Institute for Microbial Diseases, and WPI Immunology Frontier Research Center, Osaka University, Suita; Division of Neurology (K.K., R.M., S.-i.H.), Saitama Children's Medical Center, Saitama; Division of Neurology (S.W.), Miyagi Children's Hospital, Sendai; Division of Neurology (M.I., H.O.), Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama; Department of Pediatrics (K.M.), Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama; Department of Pediatrics (R.T.), Aomori Prefectural Central Hospital, Aomori; and Department of Pediatrics (H.O.), Jichi Medical School, Tochigi, Japan.
Mitsuhiro
M
Kato
Hirotomo
H
Saitsu
Yoshiko
Y
Murakami
Kenjiro
K
Kikuchi
Shuei
S
Watanabe
Mizue
M
Iai
Kazushi
K
Miya
Ryuki
R
Matsuura
Rumiko
R
Takayama
Chihiro
C
Ohba
Mitsuko
M
Nakashima
Yoshinori
Y
Tsurusaki
Noriko
N
Miyake
Shin-Ichiro
S
Hamano
Hitoshi
H
Osaka
Kiyoshi
K
Hayasaka
Taroh
T
Kinoshita
Naomichi
N
Matsumoto
D015703:Antigens, CD / Q000378:metabolism; D001921:Brain / Q000473:pathology; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004569:Electroencephalography; D005260:Female; D005434:Flow Cytometry; D006098:Granulocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007223:Infant; D007564:Japan; D008279:Magnetic Resonance Imaging; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D013036:Spasms, Infantile / Q000145:classification / Q000235:genetics* / Q000503:physiopathology*
D015703:Antigens, CD; D008565:Membrane Proteins; C080086:phosphatidylinositol glycan-class A protein