Familial Creutzfeldt–Jakob Disease (CJD) Kindred – An Unusual Case Report from India

Dear Editor, Here, we report a case of 47-year-old male with no prior comorbidity, who presented with a 9-month history of difficulty in navigating familiar routes. Initially, this occurred outside the house, but later progressed to difficulties navigating inside the house. This was accompanied by a 6-month history of unfamiliarity of known buildings. Over the subsequent 3 months, his wife noticed emotional lability, apathy, anhedonia, and slowness in performing daily activities, along with tremulousness in both hands. Notably, his paternal family members pedgree, as described in Figure 1 also had a history of similar illness, which typically began around the same age as that of the patient, as detailed in Table 1.Figure 1: Pedigree chart of the reported kindredTable 1: Summary of the family members showing history of similar illnessHis higher mental function examination revealed impaired complex attention, delayed recall, visuospatial disorientation, and dyscalculia, along with dorsal simultagnosia. The frontal assessment battery score was 15/18, with points lost in lexical fluency and motor Luria. His Montreal Cognitive Assessment (MoCA) score was 22/30, with points lost in clock drawing, language, and delayed recall. Neurologic examination revealed abulia, hypomimia, bradykinesia, cogwheel rigidity, and brisk deep tendon reflexes. These findings were associated with resting as well as action tremors involving both upper limbs. Therefore, the differentials for rapidly progressive dementia with neuropsychiatric and extrapyramidal features, along with positive family history were considered. Magnetic resonance imaging (MRI) of the brain [Figure 2] revealed symmetric cortical ribbon-like hyperintensity affecting the bilateral precuneus, cuneus, and angular gyrus. There was also asymmetric hyperintensity involving the right putamen and the right insular cortex. These signal alterations were more prominent in diffusion-weighted sequences compared to T2/fluid attenuated inversion recovery sequences and exhibited no contrast enhancement.Figure 2: MRI of the brain axial and coronal diffusion weighted images (a and b) showing cortical ribboning in precuneus, cuneus, angular gyrus, right insula, and right putamen, with a gradient between T2/FLAIR sequence (c) and diffusion sequences (a and b)FLAIR: fluid attenuated inversion recovery, MRI: magnetic resonance imagingCerebrospinal fluid (CSF) analysis indicated the presence of less than five white blood cells, with no red blood cells, a protein level of 36 mg/dl, and a sugar level of 67 mg/dl. Comprehensive infectious evaluations, including cerebro spinal fluid (CSF) tests for Reverse transcriptase –polymerase test for various viruses including Herpes Zoster, Cytomegalovirus, Varicella Zoster and Ebstein virus, fungal analysis including india ink, cartridge-based nucleic acid amplification test for tuberculosis, gram stain and culture, yielded negative results. Serum tests for human immunodeficiency virus (HIV) and venereal disease research laboratory (VDRL) also returned negative. Autoimmune workup (encompassing serum antinuclear antibody, extractable nuclear antigen antibody, and anti-thyroid peroxidase antibody) was negative. The autoimmune encephalitis panel in CSF yielded negative results. Further workup including contast enhanced computed tomograpgy (CECT) chest and abdomen was unremarkable. Electroencephalogram (EEG) revealed diffuse background slowing with no discharges. CSF 14-3-3 protein gamma quantitation was done and level was-16091.45AU/ml. Notably, whole exome sequencing was performed, which revealed positive result for a heterozygous mutation in D178N in the PRNP gene on chromosome 20. Given the clinical presentation, positive family history, typical MRI and EEG findings, and a positive test for PRNP gene mutation, a diagnosis of familial Creutzfeldt–Jakob disease (fCJD) was made. fCJD is a group of genetic prion diseases that includes fCJD, fatal familial insomnia (FFI), and Gerstmann–Straussler–Scheinker syndrome. fCJD is defined as a case must have definite or probable CJD and definite or probable CJD in a first-degree relative and/or neuropsychiatric disorder plus disease-specific Prion protein (PrP) gene mutation.[1] fCJD often presents with initial signs of cognitive impairment, particularly memory loss, which is often accompanied by neuropsychiatric symptoms such as depression, irritability, and abnormal behavior. This is typically followed by ataxia, dysarthria, aphasia, tremors, and myoclonus. The age of onset is usually in the third or fourth decade with slow progression compared to sporadic CJD.[2] The D178N mutation is one of the many known mutations in fCJD and involves a point mutation (GAC to AAC) at the first nucleotide of codon 178. This mutation was first reported in 1991 in a Finnish family.[3] Few kindred of fCJD have been reported from India with the same mutation in D178N, which are summarized in Table 2.Table 2: Summary of reported kindred of familial CJD from IndiaIn all these cases, the age of onset was in the fourth to fifth decade, with variable progression ranging from 3 months to over 3 years. Forgetfulness was the most common initial symptom in majority of them, including ours. As the disease progresses, extrapyramidal symptoms develop along with ataxia, ultimately leading to akinetic rigidity and myoclonus. Notably, all cases reported form India had similarities in disease manifestation. A typical EEG in patients with this mutation consists of generalized slowing. This is in contrast to the typical periodic sharp wave complex usually seen in patients with sporadic CJD. However, our reported kindred had some variations. The duration of disease progression was slow in our kindred, with most of its members surviving for 2–4 years. Anticipation was also noted in our kindred, with the mean age of disease presentation in subsequent generations shifting approximately a decade earlier compared to previous generation. In our index case, CSF showed mild elevation of 14-3-3 levels. Typical myoclonic jerks were uncommonly seen in our kindred, manifesting in just two of the reported members. Often, a polymorphism at the PRNP codon 129 leads to the protein containing either methionine or valine. This polymorphism may affect the phenotype of many PRNP gene. When codon 129 codes for methionine, the phenotype is often that of FFI, and when it codes for valine, the phenotype is that of fCJD.[8] The major limitation of our study was that the genetic polymorphism at codon 129 was not available in our case. Therefore, it can be concluded that in a case of rapidly progressive dementia with extrapyramidal symptoms and strong family history of similar illness, the possibility of fCJD should always be considered. Despite its rarity, CJD can have a significant genetic component, as highlighted by the positive genetic test for a heterozygous D178N mutation in the PRNP gene in our patient. This case not only emphasizes the need for increased awareness among clinicians to facilitate early diagnosis and prognosis, but also offers the opportunity for genetic counseling and family planning for the affected kindred, as well as potential insights into the variability of disease manifestation across different regions. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patients understands that his names and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

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