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Neurology. 2014 May 6;82(18):1587-96. doi: 10.1212/WNL.0000000000000389. Epub 2014 Apr 4.

PIGA mutations cause early-onset epileptic encephalopathies and distinctive features.

Author information

1
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.

Abstract

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.

PMID:
24706016
DOI:
10.1212/WNL.0000000000000389
[Indexed for MEDLINE]
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