Mutations

PSEN1 N135S

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1): g.25607A>G
Genomic Mutation Name (NT1): g.42161A>G
dbSNP ID: rs63751278
Coding/Non-Coding: Coding
Genomic Region: Exon 5
Mutation Type: Point, Missense
Codon Change: AAT to AGT

Findings

This mutation was reported in a Greek family with a history of Alzheimer’s disease in which two cousins were found to carry the mutation. One of the mutation carriers, p.42, presented at age 33 with a mild deficit in short-term memory. Two years later, she had severe dementia, myoclonic jerks, and epilepsy. Her brother experienced symptom onset at age 36 and a biopsy of his frontal cortex three years later showed signs of advanced AD. Their 40 year-old cousin (p.41), also carried the N135S mutation and presented with mild memory deficits at age 35, gait disorder at age 36, and limb spasticity and ataxia at age 39. Three siblings in the previous generation and the common grandfather were also affected and died between the ages of 40 and 42 years (Finckh et al., 2005).

Similar clinical features, including limb spasticity and seizures, were noted in members of a second family with the N135S mutation (Rudzinski et al., 2006). The family had three affected members, a mother and her two children, all of whom developed dementia beginning in their thirties. Both children had an unusual phenotype for AD, with prominent spastic dysarthria and limb spasticity, although these symptoms were not documented in their mother. The mother first developed signs of cognitive impairment in her early thirties, and later developed seizures. After 8 years of illness she died at age 40.

The daughter presented with memory problems at age 32. By age 37 she had problems producing speech, specifically dysarthria, gait unsteadiness and agitation. Like her mother, she also developed seizures. She died around age 38. She carried the mutation.

The son presented with memory difficulties at age 33. At age 40 he reported increasing difficulty at work due to impairments in executive functions and short term memory. He later developed dysarthria, balance difficulties, and gait unsteadiness. Like his sister, he was a mutation carrier.

Neuropathology

Autopsy of the mother and daughter confirmed the diagnosis of AD, with widespread neurofibrillary tangles and neuritic plaques. Mild amyloid angiopathy was also noted. Some “cotton wool plaques” were observed, but most of the plaques were neuritic and had dense amyloid cores. Corticospinal tract pathology was detected in both cases, but was more pronounced in the mother, contrasting with her lack of documented motor symptoms (Rudzinski et al., 2006).

Biological Effect

Unknown.

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References

Paper Citations

  1. . Novel mutations and repeated findings of mutations in familial Alzheimer disease. Neurogenetics. 2005 May;6(2):85-9. Epub 2005 Mar 18 PubMed.
  2. . Early onset familial Alzheimer Disease with spastic paraparesis, dysarthria, and seizures and N135S mutation in PSEN1. Alzheimer Dis Assoc Disord. 2008 Jul-Sep;22(3):299-307. PubMed.

Further Reading

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Novel mutations and repeated findings of mutations in familial Alzheimer disease. Neurogenetics. 2005 May;6(2):85-9. Epub 2005 Mar 18 PubMed.

Other mutations at this position

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