Annals of clinical and translational neurology · 2026
Developmental and Epileptic Encephalopathy due to Biallelic Pathogenic Variants in PIGM.
СтатьяКлинический случайНазвание и аннотация: Перевод в очереди
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Sala-Coromina Júlia, Marcé-Grau Anna, Masotto Barbara, Codina Marta, BenJemaa Lamia, Elaribi Yasmina, Martinez-Gallo Mónica, Colobran Roger, Sanchez-Montañez Angel, Valenzuela Irene, Murakami Yoshiko, Macaya Alfons
Аннотация
OBJECTIVE: PIGM encodes a critical enzyme in the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway. While promoter-region mutations in PIGM have been associated with a relatively mild phenotype characterized by portal vein thrombosis and absence seizures, recent evidence suggests that coding-region mutations result in a more severe multisystemic disorder.
METHODS: Whole-exome sequencing reanalysis was performed in a patient with early-onset developmental and epileptic encephalopathy, and subsequent matchmaking identified another patient with a similar phenotype. The pathogenicity of the variant was evaluated through multiple functional assays. To further delineate the genotypic and phenotypic spectrum of PIGM, we reviewed all patients reported to date with PIGM variants.
RESULTS: We describe two unrelated patients, both carrying the same homozygous missense variant in PIGM (c.1001A > C, p.Gln334Pro), presenting with early-onset developmental and epileptic encephalopathy, profound neurodevelopmental impairment, multi-organ involvement, and distinctive neuroimaging findings including hypomyelination. Both patients died in infancy due to super-refractory status epilepticus. Treatment with sodium phenylbutyrate was attempted in one patient without clinical benefit. Flow cytometry revealed partial GPI-anchor deficiency. Comparative analysis with previously reported cases highlights a potential genotype-phenotype correlation between coding region variants and disease severity.
INTERPRETATION: Our findings establish PIGM as a causative gene of early-onset developmental and epileptic encephalopathy and expand the clinical and radiological spectrum of PIGM deficiency to include hypomyelination and prenatal onset. This study underscores the importance of including PIGM in the differential diagnosis of developmental and epileptic encephalopathy and leukoencephalopathies and provides further insight into the molecular mechanisms underlying phenotypic variability of GPI-anchor disorders.
METHODS: Whole-exome sequencing reanalysis was performed in a patient with early-onset developmental and epileptic encephalopathy, and subsequent matchmaking identified another patient with a similar phenotype. The pathogenicity of the variant was evaluated through multiple functional assays. To further delineate the genotypic and phenotypic spectrum of PIGM, we reviewed all patients reported to date with PIGM variants.
RESULTS: We describe two unrelated patients, both carrying the same homozygous missense variant in PIGM (c.1001A > C, p.Gln334Pro), presenting with early-onset developmental and epileptic encephalopathy, profound neurodevelopmental impairment, multi-organ involvement, and distinctive neuroimaging findings including hypomyelination. Both patients died in infancy due to super-refractory status epilepticus. Treatment with sodium phenylbutyrate was attempted in one patient without clinical benefit. Flow cytometry revealed partial GPI-anchor deficiency. Comparative analysis with previously reported cases highlights a potential genotype-phenotype correlation between coding region variants and disease severity.
INTERPRETATION: Our findings establish PIGM as a causative gene of early-onset developmental and epileptic encephalopathy and expand the clinical and radiological spectrum of PIGM deficiency to include hypomyelination and prenatal onset. This study underscores the importance of including PIGM in the differential diagnosis of developmental and epileptic encephalopathy and leukoencephalopathies and provides further insight into the molecular mechanisms underlying phenotypic variability of GPI-anchor disorders.