Mutations

PSEN1 S169L

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1): g.38803C>T
Genomic Mutation Name (NT1): g.55408C>T
dbSNP ID: rs63751210
Coding/Non-Coding: Coding
Genomic Region: Exon 6
Mutation Type: Point, Missense
Codon Change: TCA to TTA

Findings

This mutation was first reported in a patient, known as Perth-4, who developed progressive forgetfulness, clumsiness and speech difficulty at the age of 31 (Taddei et al., 1998). She later developed myoclonus and seizures. Her condition progressed to end-stage dementia over several years and she died at the age of 37. Her mother and sister died with dementia at the age of 36 and 42 years, respectively. The proband had a brother apparently unaffected at the age of 45. Segregation could be formally assessed, but the pattern of inheritance suggests autosomal-dominant transmission in this family.

A second family, known as family G, has been described carrying this mutation whose two affected family members experienced early-onset myoclonus, seizures and dementia. An extensive pedigree was constructed with 73 members over five generations; only the proband and his mother were affected. The proband’s maternal grandparents, who were originally from Eastern Europe, lived beyond the age of 80 and were not reported to have suffered from any neurological disorder. The proband began to experience memory loss, periods of confusion and disorientation at age 29. Family members noticed bizarre behaviors and personality changes at age 30. He developed arm twitching and seizures and died at the age of 40. His mother also experienced symptom onset at age 29, notably forgetfulness and personality changes. Seizures developed within 1 year. At age 33, a neurological examination found myoclonus, dysarthria, hyperreflexia, intention tremor, and gait ataxia. She died at age 38 with a diagnosis of progressive myoclonus epilepsy, Unverricht-Lundborg type. The proband was the only member of the family to be test genetically, therefore segregation with disease could not be assessed (Takao et al., 2001).

Neuropathology

A brain biopsy of one affected mutation carrier at the age of 33 showed abundant neurofibrillary tangles, diffuse and compact plaques, and neuritic changes. Four years later, an autopsy confirmed the presence of typical AD pathology, finding extensive plaques and tangles in the cortex and hippocampus. Marked cortical atrophy was observed as well as depigmentation of the substrantia nigra, but no Lewy bodies. Extensive neuronal loss was noted in the cortex as well as the cerebellum (Taddei et al., 1998).

A detailed neuropathological assessement is also available for an unrelated individual with this mutation, the proband from family G. Not surprisingly, he had severe brain atrophy and characteristic histopathologic lesions of AD, including severe deposition of Aβ in the cortex. Unusual features included diffuse Aβ deposits in the cerebellar cortices and subcortical white matter as well as numerous ectopic neurons, often containing tau-immunopositive neurofibrillary tangles, in the white matter of the frontal and temporal lobes. The origin of the ectopic neurons is unknown, but they have been attributed to errant migration during brain development (Takao et al., 2001).

Biological Effect

Unknown.

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References

Paper Citations

  1. . Two novel presenilin-1 mutations (Ser169Leu and Pro436Gln) associated with very early onset Alzheimer's disease. Neuroreport. 1998 Oct 5;9(14):3335-9. PubMed.
  2. . Ectopic white matter neurons, a developmental abnormality that may be caused by the PSEN1 S169L mutation in a case of familial AD with myoclonus and seizures. J Neuropathol Exp Neurol. 2001 Dec;60(12):1137-52. PubMed.

Further Reading

Papers

  1. . Genetic mutations associated with presenile dementia. Neurobiology of Aging 23 (1S): S322, 2002

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Two novel presenilin-1 mutations (Ser169Leu and Pro436Gln) associated with very early onset Alzheimer's disease. Neuroreport. 1998 Oct 5;9(14):3335-9. PubMed.

Other mutations at this position

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