PEHO Syndrome May Represent Phenotypic Expansion at the Severe End of the Early-Onset Encephalopathies

Abstract

BACKGROUND Progressive encephalopathy with edema, hypsarrhythmia and optic atrophy (PEHO) syndrome is a distinct neurodevelopmental disorder. Patients without optic nerve atrophy and brain imaging abnormalities but fulfilling other PEHO criteria are often described as a PEHO-like syndrome. The molecular bases of both clinically defined conditions remain unknown in spite of the widespread application of genome analyses in both clinic and research. METHODS We enrolled two patients with a prior diagnosis of PEHO and two individuals with PEHO-like syndrome. All four individuals subsequently underwent whole-exome sequencing and comprehensive genomic analysis. RESULTS We identified disease-causing mutations in known genes associated with neurodevelopmental disorders including GNAO1 and CDKL5 in two of four individuals. One patient with PEHO syndrome and a de novo GNAO1 mutation was found to have an additional de novo mutation in HESX1 that is associated with optic atrophy. CONCLUSIONS We hypothesize that PEHO and PEHO-like syndrome may represent a severe end of the spectrum of the early-onset encephalopathies and, in some instances, its complex phenotype may result from an aggregated effect of mutations at two loci.

Spectrum of neurodevelopmental disease associated with the GNAO1 guanosine triphosphate–binding region

“…[2][3][4][5]8,10,12,[14][15][16]26 MRI studies have not shown major structural abnormalities in patients with GNAO1 variants. Developmental delay and hypotonia occur in nearly all cases, although they led less frequently to medical attention.…”

“…All 14 individuals had GNAO1 variants identified through clinical testing, either by whole exome sequencing (WES; 8,9,13,and 14) or by targeted next generation sequencing epilepsy panels (Patients 7 and 10-12). Parental testing was completed for all but one patient.…”

“…[2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] GNAO1 encodes a G-protein α subunit that, along with dimerized β and γ subunits, forms a heterotrimeric G-protein complex. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] GNAO1 encodes a G-protein α subunit that, along with dimerized β and γ subunits, forms a heterotrimeric G-protein complex.…”

“…GNAO1, or guanosine nucleotide-binding protein G(o) subunit α, is a gene that has been associated with neurodevelopmental disorders, including early onset developmental and epileptic encephalopathy (DEE), 1 developmental delay without epilepsy, and a range of movement disorders. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] GNAO1 encodes a G-protein α subunit that, along with dimerized β and γ subunits, forms a heterotrimeric G-protein complex. G-protein α subunits contain guanosine triphosphate (GTP)-binding sites and dissociate from both the G-protein-coupled receptor and the β-γ dimer of the complex when activated.…”

PRUNE is crucial for normal brain development and mutated in microcephaly with neurodevelopmental impairment

“…Since the original clinical description of this condition in 1991, a number of different genes and modes of inheritance have been associated with clinical presentations said to be consistent with PEHO, or thought to be PEHO-like in nature, including de novo dominant variants in CDKL5 and KIF1A and biallelic mutations in CCDC8A (Gawlinski et al , 2016; Langlois et al , 2016; Nahorski et al , 2016) . The phenotype in the Italian family, as well as consistent overlapping clinical aspects present in the other families described here, provides cause to consider that PRUNE1 should now also be added to the list of genes in which mutations may present in children with epileptic encephalopathy and PEHO-like features.…”