Familial Prion Disease: First Indian Kindred with Gerstmann–Sträussler–Scheinker Syndrome
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.304068
Source of Support: None, Conflict of Interest: None
Keywords: Gerstmann–Sträussler–Scheinker (GSS) syndrome, M129V, position 129 polymorphism, prion, PRNP
Gerstmann–Sträussler–Scheinker (GSS) syndrome is a hereditary prion disease with progressive ataxia and dementia. It is caused by pathogenic variants in the PRNP gene leading to aggregation of misfolded prion protein resulting in neurodegeneration and death within a few years of onset., We present an Indian kindred with mutation proven GSS and highlight the impact of polymorphism at position 129 of the protein sequence. Conversion of a normal prion protein (PrPc) into a misfolded form (PrPSc) is a key feature of prion disorders. Methionine at position 129 in prion protein is an important genetic modifier.
A 44-year-old male presented with progressive difficulty in walking and slurring of speech for past three months. He also experienced imbalance and swaying in standing position. There was no history of fever, trauma or tremors. There was no history of abnormal behaviour, change in personality, difficulty in concentration, seizures or impaired memory. There was no history of stiffness in limbs, abnormal posturing or uncontrolled movements of limbs. There were no sensory, visual, auditory complaints or any episodic variation of symptoms. There was no history of slipping of foot wear or weakness in hand grip.
There was family history of similar symptoms of progressive imbalance leading to bedridden state in his sister. Seven paternal cousins/nephews had died between the ages of 35-55 years after having suffered similar illness for duration of 5-10 years [Figure 1]. Interestingly, 80-year-old father of proband was healthy, showing no symptoms of progressive gait imbalance. Thus, heterogeneity in clinical presentation is noted in the kindred with progressively severer disease, early age of onset in the newer generations.
On examination, vital parameters were stable and higher mental functions were preserved. Cranial nerve examination was unremarkable other than slurring of speech. Motor system examination showed normal bulk, tone, power and deep tendon reflexes. Gait was unsteady and there was no rebound phenomenon, nystagmus, intention tremor, dysdiadochokinesia or pendular knee jerk. Babinski sign was negative. Eye examination was normal and other systems were unremarkable. Investigations showed a normal MRI brain and motor nerve conduction studies.
Spinocerebellar ataxia panel for SCA types 1, 2, 3, 5, 7 and 12 triplet nucleotide repeat disorders was normal. In view of a strong family history of similar complaints affecting three generations, autosomal dominant hereditary ataxias were evaluated by whole exome sequencing. A missense heterozygous pathogenic variant, c. 305C>T, p.Pro102Leu in Exon 2, PRNP gene was detected. The variant has been previously reported in several families and is the most frequent mutation causing GSS., This variant is not reported in population databases gnomAD exomes and gnomAD genomes, is considered pathogenic by several in silico prediction software like MutationTaster, PROVEAN and SIFT. The variant was validated by Sanger sequencing to be present in heterozygous state in the proband [Figure 2]a and was also present in his affected sister. Stored DNA was available in one of the deceased paternal cousin [broken arrow in [Figure 1]] who had suffered similar illness more than a decade ago, and had been tested for SCA panel at our centre. After necessary consent, the stored DNA was tested for the above variant and was found to be positive for c. 305 C>T change in PRNP gene. This reasonably established the fact that this variant is responsible for the familial illness in the reported kindred. Intriguingly, the variant was also present in the proband's father who is around 80 years old and is asymptomatic. In view of the variability within family members, other factors like polymorphism at codon 129 [Figure 2]b and octapeptide repeats were evaluated [Table 1].
Prion diseases are also known as Transmissible Spongiform Encephalopathies (TSEs). They constitute a group of neurodegenerative disorders which include Creutzfeldt-Jakob disease More Details (CJD), Gerstmann–Sträussler–Scheinker Disease (GSS), Fatal Familial Insomnia (FFI); and “kuru” which was historically associated with ritualistic cannibalism. TSEs also affect animals, causing natural scrapie in sheep and goats; and Bovine Spongiform Encephalopathy (BSE) in cattle. Stanley Prusiner, introduced the term prion for a transmissible pathogen and was awarded the Nobel Prize in 1997 for his pioneering work.,
The most common presentation of prion disease is sporadic Creutzfeld-Jakob disease (sCJD) with onset in the seventh decade, rapid cognitive decline over few months and myoclonus, comprising 85% of cases. Familial cases occur due to mutations of PRNP and may have one of the three phenotypes including GSS, FFI and familial CJD (fCJD) which are allelic disorders. The distinguishing features include predominant cognitive decline and myoclonus in fCJD, insomnia in FFI and cerebellar features in GSS. There is a modified World Health Organisation (W.H.O) diagnostic criteria for sCJD, but no formal diagnostic criteria has been established for genetic prion disorders including GSS. GSS may have to be differentiated from common causes of inherited ataxias like Spinocerebellar ataxia, Huntington disease and disorders presenting with dementia such as Alzheimer disease, frontotemporal dementia and ceroid lipofuscinosis. Other differentials may include autoimmune disorders like Hashimoto's thyroiditis, CNS vasculitis, multiple sclerosis, heavy metal toxins and metabolic disorders.
We report the first Indian kindred with mutation proven GSS affecting multiple individuals over three generations. The paternal deceased cousin had been extensively evaluated for years but succumbed without a clear aetiological diagnosis. The proband, himself a doctor by profession, was aware of this family history and underwent genetic testing leading to the diagnosis of GSS. All affected individuals had onset of illness between 4th - 6th decade with ataxia, movement disorder, seizures and dementia with slow progression leading to death within 5-10 years. This is the classical presentation as first reported by three neuropathologists Gerstmann, Sträussler, and Scheinker in 1936.
GSS is caused by mutations in the prion protein (PRNP) gene on human chromosome 20, inherited in an autosomal dominant manner. Numerous insertion, missense, and point mutations in PRNP have been described though a point mutation at codon 102 occurs relatively frequently. This particular mutation is associated with heterogeneity of neurological signs and symptoms. We have also observed similar heterogeneity in this family with variation in clinical features and rate of progression with c. 305C>T (P102L) mutation on codon 102. Concomitant variations in PRNP gene exhibit two peculiar features which affect disease penetrance and severity. These include polymorphism at position 129 and octapeptide repeat variable region. In general, GSS patients with P102L mutation and methionine at position 129 on the mutated allele exhibit the typical progressive course. GSS with Valine at position 129 has been described to have a prolonged course but with early seizures., It has been proposed that homodimers with respect to position 129 may interact more readily and aid in conversion of PrPc into abnormal PrPSc conformation. The proband, affected sister, and deceased paternal cousin have the previously reported common c. 305C>T mutation on codon 102 along with p.Met129Val polymorphism at codon 129. The proband's 'asymptomatic' father who is 80 years of age tested positive for the variant c. 305C>T in PRNP as expected but was surprisingly noted to have a different polymorphism at position 129 (p.Met129Met) as depicted in [Figure 2]b. Barbanti et al. studied codon 129 polymorphism in GSS and concluded that the polymorphism probably does not constitute a reliable explanation for the pathologic and clinical heterogeneity. Clinical variability amongst family members with the same mutation and atypical presentations have been noted in genetic prion diseases. Incomplete penetrance has been described in an octagenerian with Q212P mutation whose son developed GSS at 60 yrs of age with the same mutation in PRNP.
Normal PRNP alleles have sequence for one nonapeptide followed by four octapeptide repeats in the region 51-91 amino acids, which comprises the following: Pro-(His/Gln)-Gly-Gly-Gly-(-/Trp)-Gly-Gln. One to four additional octapeptide repeats are typically associated with the familial CJD whereas five to nine extra repeats are associated with GSS., We checked the repeat region sequence and found no expansion in the three affected individuals as well as in unaffected father of proband.
The primary structure of proteins is a linear chain of amino acids and the secondary structure comprises ±-helix and β pleated sheets [Figure 3]. The normal cellular isoform of the prion protein PrPc (c for cellular) is rich in ±-helix with little β element, while PrPSc (Sc, from scrapie, a prion disease of sheep) has minimal ± component and a high amount of the β material. This “±” to “β” transition in the prion protein is the fundamental event in the pathogenesis of prion diseases which can be a sporadic event as in sCJD or due to inherited mutations in PRNP gene in familial disorders such as GSS. The abnormal PrPSc isoform leads to aggregation of prion proteins leading to progressive neurodegeneration, with characteristic neuropathologic features of amyloid plaque deposition in the cerebral cortex, cerebellar cortex, and the basal ganglia.,
The standard diagnostic tools for prion disorders such as Magnetic resonance imaging (MRI), EEG, CSF 14-3-3- protein may support the diagnosis, which may be confirmed by a brain biopsy. Real-time quaking-induced conversion (RT-QuIC) is a new technique which appears promising. Genetic testing is considered gold standard for diagnosis of familial prion disorders. Management is largely supportive and trials of Quinacrine and pentosan polysulphate did not prevent progression of illness. There is some hope with immunotherapy such as humanised antibodies against PrPSc and PrPC proteins. PRN100 is a humanized anti-PrPC monoclonal antibody which binds extremely tightly to PrP and has been effective in prion infected mice in prolonging survival and and is currently undergoing human trials.
To conclude, a few learning points in our case report are as follows.
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Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3]