Progressive encephalopathy with oedema, hypsarrhythmiaand optic atrophy (PEHO) a neurological disease that is rarely seen in general pediatric practice.Children may present with unexplained psychomotor retardation and signs ofprogressive CNS diseases. The incidence of PE is unknown but has been estimatedto be 0.
5e0.6 per 1000 live births (2,3). Importantly, the risk of PE and otherdisabilities increases in consanguineous unions or in communities with a highincidence of known consanguinity(3) It was first described in Finnish children in 1991 (4). In1993Someretal.2 defined the necessary diagnosticcriteria including: (1) infantile onset of hypotonia, (2) epileptic seizures withmyoclonic jerks or infantile spasms with hypsarrhythmia,(3) profounddevelopmental delay with absence of motor milestones and absent speech, (4) absenceor early loss of visual fixation and optic atrophy by the age of 2 years, and(5) progressive atrophy of the cerebellum and pons(6) Clinically early-infantile epileptic encephalopathies showed aphenotypic overlap with PEHO syndrome (Cross and Guerrini, 2013). Moreover,patients without either optic atrophy or cerebellar hypoplasia are frequentlytermed PEHO-like (Chitty et al.
, 1996). A novel nonsense variant was detected in homozygous statein the CCDC88A gene. This gene encodes a member of the Girdin family ofcoiled-coil domain containing proteins. The encoded protein is an actin-bindingprotein that is activated by the serine/threonine kinase Akt and plays a rolein cytoskeleton remodeling and cell migration. The encoded protein alsoenhances Akt signaling by mediating phosphoinositide 3-kinase (PI3K)-dependentactivation of Akt by growth factor receptor tyrosine kinases and Gprotein-coupled receptors.
Increased expression of this gene andphosphorylation of the encoded protein may play a role in cancer metastasis.Alternatively spliced transcript variants encoding multiple isoforms have beenobserved for this gene A single mutation in CCDC88A, more specifically a frameshift causing introduction of a premature stop codon (c.2313delT; p.Leu772X)has been identified in 3 related patients from two families, presenting with aPEHO-like syndrome. Clinical features of these patients included congenitalmicrocephaly, early-onset seizures (onset before 1 month of age), hypotonia,profound psychomotor retardation, progressive brain atrophy particularlyaffecting the cerebellum and brain stem and absence or early loss of visualfixation with atrophy of the optic disc (Nahorski et al.
, 2016). The affectedmember of the family in this study showed significant overlap with theCCDC88A-related PEHO-like syndrome regarding both microcephaly and early-onsetepilepsy.