Overview

Pathogenicity: Retinitis Pigmentosa : Not Classified
Clinical Phenotype: Acute Encephalopathy, Retinitis Pigmentosa
Position: (GRCh38/hg38):Chr14:73206398 G>A
Position: (GRCh37/hg19):Chr14:73673106 G>A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Nonsense
Codon Change: TGG to TAG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 9

Findings

Unlike most PSEN1 mutations which result in missense substitutions, this point mutation creates a termination codon (You et al., 2020). It was identified by whole-exome sequencing in a Chinese family spanning three generations, with three living mutation carriers suffering from retinitis pigmentosa and acute symptoms resembling viral meningoencephalitis.

The proband suffered from progressive vision loss starting at age 13, and was hospitalized due to fever, headache, vomiting, and losing consciousness, at age 20. He also had spasticity, paralysis of the left limbs, and abnormal reflexes. The primary diagnosis was “suspected viral meningoencephalitis.” As expected for an infection, his peripheral white blood count was elevated, but no evidence of infection was detected in the cerebrospinal fluid (CSF), although total protein levels were increased. The condition worsened, including convulsions, severe pulmonary infection, and upper gastrointestinal bleeding, before improving after several days in the hospital. After being released, the proband’s vision continued to deteriorate.

The proband’s two female siblings also carried the mutation and had similar symptoms, including poor vision due to retinitis pigmentosa, as well as signs of pyramidal tract damage and meningeal irritation that appeared acutely in their late teens. All affected individuals had increased protein in their CSF and suffered from seizures at different stages of disease. Moreover, the proband’s mother and maternal grandfather, who were deceased and not genotyped, had progressive bilateral vision loss at a young age, and the mother was hospitalized with signs of meningeal irritation and elevated CSF proteins at age 38. 

Consistent with the mutation being associated with these phenotypes, six noncarrier family members were asymptomatic. The variant was absent from the gnomAD database.

Neuropathology
Neuropathological data are unavailable, but MRI of the brains of two mutation carriers revealed extensive lesions in the white matter and subcortex of both hemispheres. Electroencephalography showed that one of these carriers had abnormal brain delta waves, while the other had an unusual sharp, slow-wave complex. A third mutation carrier had lesions in the occipital and parietal lobes as revealed by MRI, and disrupted brain theta waves.

Biological effect
The biological effect of this mutation is unknown, but three-dimensional in silico modeling predicted pronounced structural effects, which the authors considered are likely pathogenic.

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References

Paper Citations

1. You C, Zeng W, Deng L, Lei Z, Gao X, Zhang VW, Wang Y. Identification and Clinical Analysis of the First Nonsense Mutation in the PSEN1 Gene in a Family With Acute Encephalopathy and Retinitis Pigmentosa. Front Neurol. 2020;11:319. Epub 2020 May 5 PubMed.

Further Reading

No Available Further Reading