Molecular Genetics & Genomic Medicine · 5 authors, 4 centres
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This case report describes a 2-year-old boy with EIEE1 (Ohtahara syndrome) caused by a novel homozygous stop-gained mutation (c.84C>A; p.Cys28Ter) in the ARX gene. The patient presented with microcephaly, cataracts, nystagmus, seizures, hypsarrhythmia on EEG, and decreased 3-PHGDH enzyme activity, a finding not previously associated with EIEE1. Genetic testing is essential for diagnosing EIEE1 and guiding management.
**Background** Type 1 early infantile epileptic encephalopathy (EIEE1), also known as Ohtahara syndrome, is a severe X-linked recessive epileptic encephalopathy with onset in the first three months of life. It is characterized by refractory seizures, a burst-suppression pattern on EEG, and profound psychomotor retardation. EIEE1 is caused by hemizygous mutations in the Aristaless-related homeobox (ARX) gene, which encodes a transcription factor critical for brain development. The incidence is estimated between 1 in 50,000 and 1 in 100,000. Prognosis is poor, with nearly 50% of patients dying before age 2. This paper presents a case of EIEE1 with a novel ARX mutation and reviews the literature.
**Methods** The study was approved by the Ethics Committee of Shahid Sadoughi University of Medical Sciences (IR.SSU.SPH.REC.1400.005). The proband was a 2-year-old boy born to consanguineous Iranian parents. He had a family history of a similarly affected older brother who died. Clinical evaluation included physical examination, EEG, MRI, hematologic tests, plasma amino acid analysis, and cerebrospinal fluid (CSF) analysis. Genetic analysis was performed on peripheral blood samples from the patient and his parents using autozygosity mapping, Sanger sequencing, and whole-exome sequencing.
**Key Results** The patient presented with intrauterine growth retardation, microcephaly, cataracts, nystagmus, adduction of the thumbs, and small testes. At 2 years old, he had dysmyelination, spastic quadriplegia, and seizures. EEG showed a hypsarrhythmia pattern or severe multifocal epileptic abnormalities. Hematologic tests revealed megaloblastic anemia and thrombocytopenia. Plasma amino acid analysis showed low fasting concentrations of serine and glycine, and CSF analysis showed decreased levels of serine and glycine. Enzymatic analysis of 3-PHGDH activity in cultured skin fibroblasts was decreased. Autozygosity mapping identified two homozygous regions on chromosomes 8 and 1, but Sanger sequencing of candidate genes (including PHGDH) did not find mutations. Whole-exome sequencing identified a homozygous stop-gained mutation in the ARX gene: NM_139058.3:c.84C>A; p.(Cys28Ter). Both parents were carriers, confirming X-linked recessive inheritance.
**Clinical Implications** This case expands the phenotypic spectrum of EIEE1 by reporting a novel ARX mutation (p.Cys28Ter) and the novel finding of decreased 3-PHGDH activity, which may represent a secondary metabolic abnormality or a coexisting condition. The findings underscore the importance of comprehensive genetic testing, including whole-exome sequencing, in early-onset epileptic encephalopathies. Early diagnosis can inform genetic counseling and prenatal testing. Management remains symptomatic, with antiepileptic drugs, ketogenic diet, and surgical options, but prognosis is poor. The decreased 3-PHGDH activity raises questions about potential metabolic contributions to the phenotype and warrants further investigation.