Alternative titles; symbols
SNOMEDCT: 442511009; ORPHA: 2836; DO: 0080539;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q12 | PEHO syndrome | 260565 | Autosomal recessive | 3 | ZNHIT3 | 604500 |
A number sign (#) is used with this entry because of evidence that progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) is caused by homozygous mutation in the ZNHIT3 gene (604500) on chromosome 17q12.
PEHO is a severe autosomal recessive neurodevelopmental disorder characterized by extreme cerebellar atrophy due to almost total loss of granule neurons. Affected individuals present in early infancy with hypotonia, profoundly delayed psychomotor development, optic atrophy, progressive atrophy of the cerebellum and brainstem, and dysmyelination. Most patients also develop infantile seizures that are often associated with hypsarrhythmia on EEG, and many have peripheral edema (summary by Anttonen et al., 2017).
Salonen et al. (1991) identified a new form of infantile progressive encephalopathy in 14 patients, 8 of whom were female, from 11 families. The clinical signs included severe hypotonia, convulsions with hypsarrhythmia, profound mental retardation, hyperreflexia, transient or persistent edema, and optic atrophy. Other features included microcephaly and atrophy of the brain, especially in the cerebellar and brainstem areas. Salonen et al. (1991) pictured edema of the hands and tapering of the fingers resembling somewhat the hands in the Coffin-Lowry syndrome (303600). Facial anomalies included a 'pear-shaped' face, protruding lower parts of the earlobes, short nose, and open mouth with curved upper lip. No metabolic abnormality was found.
Haltia and Somer (1993) reported the neuropathologic findings in 8 cases: 3 patients in the original group described by Salonen et al. (1991) and 5 others collected from medical records. Two of the 8 patients were sibs. In addition, 1 patient had 1 sib, and another patient had 2 similarly affected sibs. Macroscopically, cerebral and pronounced cerebellar atrophy was seen, the essential histopathologically lesions being confined to the cerebellar cortex and the optic nerve. There was a severe neuronal loss in the inner granular layer of the cerebellum. The Purkinje cells were relatively preserved in number but were small, deformed, and slightly disaligned. Haltia and Somer (1993) found some similarities to congenital cerebellar granular cell hypoplasia and mental retardation (213200); however, mental retardation was less severe, and no epilepsy or optic atrophy was reported.
In a combined neuroradiologic and ophthalmologic study, Somer (1993) found that 10 of 21 possible patients had the true PEHO syndrome according to clinical criteria suggested by the authors. All were abnormal at birth, showing hypotonia, drowsiness, or poor feeding. Head circumference was normal at birth, but usually dropped to 2 SD below average during the first year of life. Visual fixation was either absent from birth or lost during the first months of life. Nine patients had peripheral edema in early childhood. The mean age of onset of infantile spasms was 4.9 months, no motor milestones were ever reached, and patellar reflexes were brisk. Brainstem and somatosensory evoked potentials were abnormal in each case studied, cortical responses of somatosensory evoked potentials could not be elicited, and motor conduction velocities became delayed with age. A total of 19 PEHO patients were found in 14 Finnish families in a pattern consistent with autosomal recessive inheritance. Somer (1993) indicated that cerebellar hypoplasia is a cardinal diagnostic feature of PEHO syndrome and suggested that a PEHO-like syndrome (the same clinical manifestations with only mild supratentorial atrophy) may occur.
Fujimoto et al. (1995) reported 2 affected sibs, a male and a female, born to healthy parents of Japanese descent who fulfilled the necessary diagnostic criteria for the PEHO syndrome established by Somer (1993) but who lacked supportive criteria of peripheral edema. In the female, there was mild elevation of the plasma lactate level only during the first year of life without an accompanying elevation of lactate in the cerebrospinal fluid.
Chitty et al. (1996) described 2 female sibs and 2 unrelated infants (a boy and a girl) with progressive encephalopathy, seizures, which started between 3 days and 13 months of age, characteristic facies, edema of the hands and feet, tapering fingers, and optic atrophy. All 4 patients died between 10 weeks and 34 months of age. Autopsies were declined. MRI, which was performed in 3 cases, showed delay in myelinization but no cerebellar atrophy. The patients reported by Chitty et al. (1996) fit the criteria of PEHO-like syndrome, but noted that the distinction between PEHO and PEHO-like cases remained unclear.
Longman et al. (2003) described 2 sisters with a PEHO-like syndrome. The older sister had early epileptic spasms with hypsarrhythmia, visual inattention with optic atrophy, progressive microcephaly, and absence of development. Cranial MRI revealed periventricular white matter changes. Cerebellar hypoplasia, characteristic of true PEHO syndrome, was absent. The MRI changes were interpreted as periventricular leukomalacia due to prenatal ischemia, and a low recurrence risk was suggested. The younger sister was born similarly affected. Longman et al. (2003) noted that the diagnosis of PEHO syndrome is clinical, but cerebellar hypoplasia on neuroimaging is regarded as an additional necessary criterion. A heterogeneous group of PEHO-like patients, who lacked cerebellar hypoplasia but had varying supratentorial abnormalities, had been reported (Somer, 1993; Chitty et al., 1996). The family reported by Longman et al. (2003) was the second report of sibs with a PEHO-like syndrome, and it supported the existence of a distinct, autosomal recessive condition in which neuroimaging abnormalities may be misinterpreted.
Field et al. (2003) noted that few patients fulfilling the diagnostic criteria for PEHO syndrome had been reported outside Finland. Field et al. (2003) reported 5 Australian patients, the first with classic features of PEHO syndrome, and 4 who had a PEHO-like disorder. They suggested that the disorder may be more frequent than would be suggested based on the original diagnostic criteria.
Anttonen et al. (2017) reported 27 patients of Finnish descent with PEHO syndrome. All patients had neonatal/infantile hypotonia; profound motor and intellectual disability, usually with absent speech; absence or early loss of visual fixation, often with atrophy of the optic discs; progressive brain atrophy, mainly of the cerebellum and brainstem; and dysmyelination. More variable features included edema, dysmorphic features, and hyperreflexia. Dysmorphic features, described in 1 patient in detail, included narrow forehead, epicanthal folds, outward-turning ear lobules, open mouth, and tapering fingers. Infantile spasms with hypsarrhythmia were found in 89% of patients, and Anttonen et al. (2017) suggested that these features be removed from the essential clinical criteria.
The transmission pattern of PEHO in the families reported by Anttonen et al. (2017) was consistent with autosomal recessive inheritance.
In 24 patients of Finnish descent with PEHO syndrome, Anttonen et al. (2017) identified a homozygous missense mutation in the ZNHIT3 gene (S31L; 604500.0001). The mutation in the first 3 patients was found by a combination of homozygosity mapping and Sanger sequencing of candidate genes; the mutation in 1 patient was found by whole-exome sequencing. The mutation segregated with the disorder in all families. It was found in heterozygous state at a low frequency in the ExAC database (0.07%), and at a slightly higher frequency (0.92%) among Finnish individuals. The mutant protein was unstable and underwent more rapid proteasomal degradation compared to wildtype. Cellular expression studies showed that it also tended to form large nuclear aggregates, suggesting impaired folding with subsequent degradation. Injection of the S31L mutant was unable to rescue the microcephaly, cerebellar atrophy, and pericardiac edema of zebrafish embryos with morpholino knockdown of the znhit3 gene, suggesting that the mutation results in a loss of function. Cellular knockdown of Znhit3 in mouse cerebellar granule cells sensitized the neurons to death and impaired their migration.
PEHO syndrome is enriched in the Finnish population, with an estimated incidence of 1 in 74,000 (Somer, 1993).
Anttonen et al. (2017) found that morpholino knockdown of the znhit3 gene in zebrafish embryos resulted in microcephaly, cerebellar atrophy, and pericardiac edema. Morphant animals and CRISPR mutants had depletion of neuronal axons across the cerebellar midline as well as the caudolateral portion of the cerebellum, which represented an aberrant granule cell phenotype. These defects could be rescued by expression of human wildtype ZNHIT3.
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]
Chitty, L. S., Robb, S., Berry, C., Silver, D., Baraitser, M. PEHO or PEHO-like syndrome? Clin. Dysmorph. 5: 143-152, 1996. [PubMed: 8723564] [Full Text: https://doi.org/10.1097/00019605-199604000-00006]
Field, M. J., Grattan-Smith, P., Piper, S. M., Thompson, E. M., Haan, E. A., Edwards, M., James, S., Wilkinson, I., Ades, L. C. PEHO and PEHO-like syndromes: report of 5 Australian cases. Am. J. Med. Genet. 122A: 6-12, 2003. [PubMed: 12949965] [Full Text: https://doi.org/10.1002/ajmg.a.20216]
Fujimoto, S., Yokochi, F., Nakano, M., Wada, Y. Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO syndrome) in two Japanese siblings. Neuropediatrics 26: 270-272, 1995. [PubMed: 8552220] [Full Text: https://doi.org/10.1055/s-2007-979771]
Haltia, M., Somer, M. Infantile cerebello-optic atrophy: neuropathology of the progressive encephalopathy syndrome with edema, hypsarrhythmia and optic atrophy (the PEHO syndrome). Acta Neuropath. 85: 241-247, 1993. [PubMed: 8460530] [Full Text: https://doi.org/10.1007/BF00227717]
Longman, C., Tolmie, J., McWilliam, R., MacLennan, A. Cranial magnetic resonance imaging mistakenly suggests prenatal ischaemia in PEHO-like syndrome. Clin. Dysmorph. 12: 133-136, 2003. [PubMed: 12868478] [Full Text: https://doi.org/10.1097/00019605-200304000-00012]
Salonen, R., Somer, M., Haltia, M., Lorentz, M., Norio, R. Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO syndrome). Clin. Genet. 39: 287-293, 1991. [PubMed: 2070547] [Full Text: https://doi.org/10.1111/j.1399-0004.1991.tb03027.x]
Somer, M. Diagnostic criteria and genetics of the PEHO syndrome. J. Med. Genet. 30: 932-936, 1993. [PubMed: 8301648] [Full Text: https://doi.org/10.1136/jmg.30.11.932]