Alternative titles; symbols
SNOMEDCT: 770678005; ORPHA: 99807;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2p16.1 | ?PEHO syndrome-like | 617507 | Autosomal recessive | 3 | CCDC88A | 609736 |
A number sign (#) is used with this entry because of evidence that progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO)-like syndrome (PEHOL) is caused by homozygous mutation in the CCDC88A gene (609736) on chromosome 2p16. One such family has been reported.
Nahorski et al. (2016) reported 3 children from a large consanguineous Caucasian family with a severe encephalopathy, progressive microcephaly, and hypotonia beginning at birth. All developed seizures at birth or within the first month of life, which progressed to hypsarrhythmia on electroencephalogram. The seizures persisted and were difficult to control. The infants had edema of the face, hands, and feet that was present since birth and persisted. Over the first 6 months, poor visual attention, fixing, and following were noted, and all had moderate optic atrophy. They had profound cognitive delay, severe motor delay, central hypotonia, peripheral hypertonia with spasticity, and kyphoscoliosis. Microcephaly progressed to -6 SD by age 3 years. Brain imaging showed coarse pachygyria, polymicrogyria, dilated ventricles due to brain atrophy, hypoplastic corpus callosum, and hypoplastic pons. One of the 3 had a small cerebellum. The patients also had subtle dysmorphic features consistent with PEHO syndrome, including narrow forehead, epicanthal folds, short nose, open mouth, receding chin, and tapering fingers. Anttonen et al. (2017) suggested that the polymicrogyria and pachygyria observed in the individuals reported by Nahorski et al. (2016) argued against a diagnosis of PEHO syndrome (260565).
The transmission pattern of PEHO-like syndrome in the family reported by Nahorski et al. (2016) was consistent with autosomal recessive inheritance.
In 3 patients from a consanguineous Caucasian family with PEHO-like syndrome, Nahorski et al. (2016) identified a homozygous truncating mutation in the CCDC88A gene (609736.0001). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient cells showed presence of the mutant transcript, indicating that it is not subject to nonsense-mediated mRNA decay. However, Nahorski et al. (2016) suggested that even if the protein were produced, it would be highly disrupted due to absence of C-terminal functions.
Nahorski et al. (2016) found that Ccdc88a-null mice developed mesial temporal lobe epilepsy and showed postnatal growth retardation and postnatal lethality. Neuropathologic examination of mutant mice showed a developmental defect in the caudal end of the corpus callosum and cerebral atrophy. There was no evidence of polymicrogyria, optic nerve atrophy, or cerebellar atrophy.
Anttonen, A.-K., Laari, A., Kousi, M., Yang, Y. J., Jaaskelainen, T., Somer, M., Siintola, E., Jakkula, E., Muona, M., Tegelberg, S., Lonnqvist, T., Pihko, H., and 10 others. ZNHIT3 is defective in PEHO syndrome, a severe encephalopathy with cerebellar granule neuron loss. Brain 140: 1267-1279, 2017. [PubMed: 28335020] [Full Text: https://doi.org/10.1093/brain/awx040]
Nahorski, M. S., Asai, M., Wakeling, E., Parker, A., Asai, N., Canham, N., Holder, S. E., Chen, Y.-C., Dyer, J., Brady, A. F., Takahashi, M., Woods, C. G. CCDC88A mutations cause PEHO-like syndrome in humans and mouse. Brain 139: 1036-1044, 2016. [PubMed: 26917597] [Full Text: https://doi.org/10.1093/brain/aww014]