Progressive other disabilities increases in consanguineous unions or

Progressive encephalopathy with oedema, hypsarrhythmia
and optic atrophy (PEHO) a neurological disease that  is rarely seen in general pediatric practice.
Children may present with unexplained psychomotor retardation and signs of
progressive CNS diseases. The incidence of PE is unknown but has been estimated
to be 0.5e0.6 per 1000 live births (2,3). Importantly, the risk of PE and other
disabilities increases in consanguineous unions or in communities with a high
incidence of known consanguinity(3) It was first described in Finnish children in 1991 (4). In1993Someretal.2 defined the necessary diagnostic
criteria including: (1) infantile onset of hypotonia, (2) epileptic seizures with
myoclonic jerks or infantile spasms with hypsarrhythmia,(3) profound
developmental delay with absence of motor milestones and absent speech, (4) absence
or 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 a
phenotypic overlap with PEHO syndrome (Cross and Guerrini, 2013). Moreover,
patients without either optic atrophy or cerebellar hypoplasia are frequently
termed PEHO-like (Chitty et al., 1996).

A novel nonsense variant was detected in homozygous state
in the CCDC88A gene. This gene encodes a member of the Girdin family of
coiled-coil domain containing proteins. The encoded protein is an actin-binding
protein that is activated by the serine/threonine kinase Akt and plays a role
in cytoskeleton remodeling and cell migration. The encoded protein also
enhances Akt signaling by mediating phosphoinositide 3-kinase (PI3K)-dependent
activation of Akt by growth factor receptor tyrosine kinases and G
protein-coupled receptors. Increased expression of this gene and
phosphorylation of the encoded protein may play a role in cancer metastasis.
Alternatively spliced transcript variants encoding multiple isoforms have been
observed for this gene

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A single mutation in CCDC88A, more specifically a frame
shift causing introduction of a premature stop codon (c.2313delT; p.Leu772X)
has been identified in 3 related patients from two families, presenting with a
PEHO-like syndrome. Clinical features of these patients included congenital
microcephaly, early-onset seizures (onset before 1 month of age), hypotonia,
profound psychomotor retardation, progressive brain atrophy particularly
affecting the cerebellum and brain stem and absence or early loss of visual
fixation with atrophy of the optic disc (Nahorski et al., 2016). The affected
member of the family in this study showed significant overlap with the
CCDC88A-related PEHO-like syndrome regarding both microcephaly and early-onset


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