Very Early Onset Familial Alzheimer’s Disease Due to Mutation in PSEN1 I143T – First Case Report from South Asia

Sir, Alzheimer’s disease (AD) is the most common cause of degenerative dementia first described by Alois Alzheimer in a 51-year-old female, Auguste Deter. Familial AD represents 5–10% of AD. Early onset familial AD (Age <60 or 65 years) (EOFAD) accounts for 1–6% of all AD cases. Three main genes are involved in EOFAD. APP (Chromosome 21), PSEN1(Chromosome 14), and PSEN2(Chromosome 1) encoding amyloid precursor protein, presenilin-1 and presenilin-2, respectively. Mutations in PSEN1 are the most common cause of EOFAD and account for 18% to 50% of autosomal dominant EOFAD. Mutations within APP account for 10% to 15% of early-onset familial AD (EOFAD) and mutation in PSEN2 gene is rare. PSEN1 gene is located on chromosome 14q24.3 and is involved in cleavage of APP into Aβ fragments. Presenilin 1 is a part of the gamma-secretase complex with several interacting substrates, including amyloid precursor protein (APP), Notch, adhesion proteins, and beta-catenin.[1] Here we report a case of very early onset autosomal dominant familial AD in a 32-year-old girl from Kerala with a mutation in Exon 5 of Presenilin 1 gene at codon 428 T > C causing substitution of Threonine for Isoleucine in Presenilin 1 protein. This specific mutation (PSEN1 I143T) has so far not reported in the Medgenome database and is the first case from South Asia. A 32-year-old B Com graduate girl from Central Kerala, India presented to the emergency department with 1 episode of a generalized tonic-clonic seizure lasting 2–3 minutes during sleep, which was followed by postictal confusion. There was a tongue bite. There was a history of one episode of generalized tonic-clonic seizure during the postpartum period 5 years back and was treated as postpartum eclampsia at an outside hospital as she had hypertension at that period. She was on levetiracetam and stopped medications a few months back. For the last 3 years, relatives have noted progressive memory impairment. She often forgets her appointments and tasks told her to do. She had to be reminded multiple times to do her household work. She completes her tasks slowly. She is less concerned about her child and other family members. There is no history of visuospatial disorientation or difficulty in identifying relatives. There is no history of language difficulties. There is no history of weakness, ataxia, sensory symptoms, slowness of activities, or incontinence. There was no history of myoclonus. Her father had a progressive dementing illness which started at the age of 39. He became bedridden and died at the age of 42. He had a history of seizures during the late stages of his illness [Figure 3]. Her higher mental examination showed moderate cognitive impairment. She had a Mini-Mental State Examination (MMSE) score of 16/30 and a Montreal Cognitive Assessment (MOCA) score of 12/30. She mainly lost points in delayed recall, construction, orientation, and attention. Detailed neuropsychological evaluation showed bilateral medial temporal, right parietal, and mild frontal dysfunction. Her predominant mesial temporal and parietal dysfunction was suggestive of AD. Her routine investigations were normal. CT and MRI brain showed diffuse cerebral atrophy [Figures 1 and 2] and EEG showed diffuse nonspecific slowing. In view of a strong family history, blood was sent for genetic analysis at Medgenome Labs. She was found to be heterozygous for Presenilin 1 gene mutation in exon5, c428T > C (pIle143Thr) which is classified as pathogenic. She was put on levetiracetam and a Donepezil/memantine combination and there were no further seizures. At 3 months follow up her cognitive functions remain same.Figure 1: CT Head axial image showing cerebral atrophyFigure 2: MRI Brain Coronal FLAIR image showing hippocampal atrophyFigure 3: Pedigree chartMutations in the PSEN1 gene, encoding presenilin-1 (PS1), are the most common cause of familial Alzheimer’s disease (FAD). Mutations in PSEN1 account for up to 50% of EOAD, with complete penetrance and early age of onset. Mutant γ-secretase increases Aβ42 level while it decreases Aβ40 level, leading to an increase in the Aβ 42/40 To date, more than 300 pathogenic mutations have been identified in PSEN1, of which 70% mutations occur in exons 5, 6, 7, and 8. In addition to the classical early onset Alzheimer’s disease (EOAD) phenotypes, PSEN1 mutations were discovered in several atypical AD or non-AD phenotypes, such as frontotemporal dementia, Parkinson’s disease, dementia with Lewy bodies or spastic paraparesis. The majority of patients present with disease phenotypes in their 40s or 50s, but disease onset at a young age (in their 20s and 30s) is also possible. PSEN1 mutations also have non-neurodegenerative phenotypes, including acne inversa or dilated cardiomyopathy.[2] PSEN1 I143T was first identified by linkage analysis in a large Belgian family affected by early onset AD with a mean age at onset of 35 years.[3] Family AD/A (PSEN1 I143T) of the Belgian family currently includes ≥240 documented individuals, of whom 51 with probable (n = 39) or definite (n = 18) AD. Most patients have a predominant amnestic presentation with a mean onset age of 33.6 ± 4.7 years. Progression is rapid with a mean disease duration of 4.0 ± 1.9 years, and an age at death of 40.1 ± 3.6 years. Two Japanese sisters with early onset AD also carried this mutation[4] and this mutation has been reported also from China.[5] In a Swedish family with this mutation, five family members across three generations were affected with pre-senile dementia with the age of onset 35.6 ± 2.1 years. The mean age of death was 42.4 ± 1.3 years and the duration of the disease from onset to death was 6.8 ± 2.4 years. Initial symptoms were typical for AD and included memory impairment, visuospatial difficulties, disorientation, apraxia, and aphasia. Additional early findings were coordination difficulties associated with gradually increasing myoclonic jerks, multiple falls, and in some cases, epileptic seizures.[6] Other mutations at this site are I143V, I143F, I143M, and I143N and all are associated with EOAD but with different ages at onset.[7] Presenilin 1 (PSEN1) gene mutations with AD are associated with marked heterogeneity in clinical phenotype, with behavioral and psychiatric features, parkinsonism, myoclonus, epileptic seizures, spastic paraparesis, frontal behavioral changes, aphasia, cerebellar ataxia as well as cognitive decline. Age at onset differed by mutation, with a younger onset for individuals with PSEN1 mutations than for those with APP mutations. Myoclonus and seizures were the most common additional neurological features. Myoclonus occurs in 47% of patients with PSEN1 mutations and 33% of patients with APP mutations. They were significantly more likely to develop seizures. A number of patients with PSEN1 mutations had pyramidal (25%), extrapyramidal (14%), or cerebellar (4%) signs.[8] PSEN1 mutations have the earliest age at onset and were more frequently affected by atypical clinical features along the clinical course; PSEN2 mutations have a delayed age at onset with the longest disease duration and presented more frequently with disorientation; APP mutations presented more frequently with aggression and APP duplication presented more frequently with apraxia.[9] Mutation position in PSEN1 can also result in differences in clinical manifestations. Patients with mutations before codon 200 are more likely to suffer from seizures and myoclonus along the clinical course, whereas the reverse is true for visuospatial impairment and spastic paraparesis. PSEN1 mutations beyond codon 200 have been associated with a later onset, more severe amyloid angiopathy, and a greater burden of white matter hyperintensities on MRI than mutations before codon 200.[10] Around 20% of recorded PSEN1 mutations have been reported to be associated with epileptic seizures, sometimes occurring as an early feature of the disease, sometimes late. The epilepsy-associated PSEN1 mutations are spread throughout the PSEN1 gene. PSEN1 AD is to be proposed, using the new International League Against Epilepsy nomenclature, as a genetic epilepsy syndrome.[11] Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

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