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BRIEF REPORT
Year : 2020  |  Volume : 68  |  Issue : 6  |  Page : 1431-1434

Familial Prion Disease: First Indian Kindred with Gerstmann–Sträussler–Scheinker Syndrome


1 Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India
2 Department of Neurophysiology, Sir Ganga Ram Hospital, New Delhi, India

Date of Web Publication19-Dec-2020

Correspondence Address:
Dr. Sunita Bijarnia-Mahay
Senior Consultant, Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi - 110 060
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.304068

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 » Abstract 


Gerstmann–Sträussler–Scheinker (GSS) syndrome is a devastating hereditary prion disease, presenting in 4th–5th decade with progressive ataxia and dementia. Pathogenic variants in the PRNP gene lead to aggregation of misfolded prion protein which results in neurodegeneration and death within a few years of onset. A key feature of prion disorders is conversion of normal prion protein (PrPc) into its misfolded form (PrPSc). Genetic modifiers include methionine at position 129 in prion protein and octapeptide repeats. We present an Indian kindred with c. 305C > T, p.Pro102Leu mutation in PRNP gene causing GSS in multiple members and discuss the impact of the polymorphism at position 129 on the severity of illness.


Keywords: Gerstmann–Sträussler–Scheinker (GSS) syndrome, M129V, position 129 polymorphism, prion, PRNP
Key Messages: Familial prion disease is a rare dominantly inherited genetic disorder with no treatment and devastating consequences. There is hope in the near future with innovative immunotherapies like PRN100, a humanised anti- prion protein (PrP) antibody.


How to cite this article:
Bhatia S, Bijarnia-Mahay S, Dubey S, Gourie-Devi M. Familial Prion Disease: First Indian Kindred with Gerstmann–Sträussler–Scheinker Syndrome. Neurol India 2020;68:1431-4

How to cite this URL:
Bhatia S, Bijarnia-Mahay S, Dubey S, Gourie-Devi M. Familial Prion Disease: First Indian Kindred with Gerstmann–Sträussler–Scheinker Syndrome. Neurol India [serial online] 2020 [cited 2021 Jan 16];68:1431-4. Available from: https://www.neurologyindia.com/text.asp?2020/68/6/1431/304068




Gerstmann–Sträussler–Scheinker (GSS) syndrome is a hereditary prion disease with progressive ataxia and dementia.[1] 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.[2],[3] 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.


 » Case History Top


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.


 » Family History Top


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.
Figure 1: Pedigree showing four generations of kindred with Gerstmann–Sträussler–Scheinker syndrome. Long thick arrow – proband; short arrow- affected sister; broken arrow - affected and deceased cousin; Thin arrow - unaffected father

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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.

Genetic testing

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.[3],[4] 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].
Figure 2: Chromatogram of exon 2 of PRNP gene showing heterozygous variant, c.305C>T (a) and polymorphism c.385A>G; p.M129V (b)

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Table 1: Effect of position 129 polymorphism on clinical manifestation

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 » Discussion Top


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.[5] Stanley Prusiner, introduced the term prion for a transmissible pathogen and was awarded the Nobel Prize in 1997 for his pioneering work.[5],[6]

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.[7] 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.[5]

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.[3]

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.[3] 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.[3],[8] 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.[9] 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.[10] 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.[3] 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.[11]

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.[12],[13] 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.[2],[14]
Figure 3: Diagramatic representation of alpha and beta helix structure of protein

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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.[7] 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.[15] 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.[15]

To conclude, a few learning points in our case report are as follows.

  1. Prion disease should be considered in patients with familial and progressive ataxia, dementia or seizures, even though it is less common compared to inherited ataxia or dementia like SCA, Huntington's disease and Alzheimer's disease.
  2. The precise genetic diagnosis helps to provide accurate genetic counseling to understand the nature of illness, natural course, current therapeutic options available and a hope of a definitive therapy in near future.


Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Collins S, McLean CA, Masters CL. Gerstmann-Sträussler-Scheinker syndrome, fatal familial insomnia, and kuru: A review of these less common human transmissible spongiform encephalopathies. J Clin Neurosci 2001;8:387-97.  Back to cited text no. 1
    
2.
Hughes D, Halliday M. What is our current understanding of PrPSc-associated neurotoxicity and its molecular underpinnings? Pathogens 2017;6:63.  Back to cited text no. 2
    
3.
Liberski PP, Surewicz WK. Molecular genetics of Gerstmann-Sträussler-Scheinker disease and Creutzfeldt-Jakob disease. Genetics 2013;2. doi: 10.4172/2161-1041.1000117.  Back to cited text no. 3
    
4.
Pirisinu L, Di Bari MA, D'Agostino C, Marcon S, Riccardi G, Poleggi A, et al. Gerstmann-Sträussler-Scheinker disease subtypes efficiently transmit in bank voles as genuine prion diseases. Sci Rep 2016;6:20443.  Back to cited text no. 4
    
5.
Mastrianni JA, Roos RP. The prion diseases. Semin Neurol 2000;20:337-52.  Back to cited text no. 5
    
6.
Prusiner SB. Prions. Proc Natl Acad Sci U S A 1998;95:13363-83.  Back to cited text no. 6
    
7.
Manix M, Kalakoti P, Henry M, Thakur J, Menger R, Guthikonda B, et al. Creutzfeldt-Jakob disease: Updated diagnostic criteria, treatment algorithm, and the utility of brain biopsy. Neurosurg Focus 2015;39:E2.  Back to cited text no. 7
    
8.
Young K, Clark HB, Piccardo P, Dlouhy SR, & Ghetti B. Gerstmann-Sträussler-Scheinker disease with the PRNP P102L mutation and valine at codon 129. Brain Res Mol Brain Res 1997;44:147-50.  Back to cited text no. 8
    
9.
Young K, Jones CK, Piccardo P, Lazzarini A, Golbe LI, Zimmerman TR Jr, et al. Gerstmann-Sträussler-Scheinker disease with mutation at codon 102 and methionine at codon 129 of PRNP in previously unreported patients. Neurology 1995;45:1127-34.  Back to cited text no. 9
    
10.
Barbanti P, Fabbrini G, Salvatore M, Petraroli R, Cardone F, Maras B, et al. Polymorphism at codon 129 or codon 219 of PRNP and clinical heterogeneity in a previously unreported family with Gerstmann-Sträussler-Scheinker disease (PrP-P102L mutation). Neurology 1996;47:734-41.  Back to cited text no. 10
    
11.
Young K, Piccardo P, Kish SJ, Ang LC, Dlouhy S, Ghetti B. Gerstmann-Sträussler-Scheinker disease (GSS) with a mutation at prion protein (PrP) residue 212. J Neuropathol Exp Neurol 1998;57:518.  Back to cited text no. 11
    
12.
Schmitz M, Dittmar K, Llorens F, Gelpi E, Ferrer I, Schulz-Schaeffer WJ, et al. Hereditary human prion diseases: An update. Mol Neurobiol 2017;54:4138-49.  Back to cited text no. 12
    
13.
Piazza M, Prior TW, Khalsa PS, Appleby B. A case report of genetic prion disease with two different PRNP variants. Mol Genet Genomic Med 2020;8:e1134.  Back to cited text no. 13
    
14.
Zhao MM, Feng LS, Hou S, Shen PP, Cui L, Feng JC. Gerstmann-Sträussler-Scheinker disease: A case report. World J Clin Cases 2019;7:389-95.  Back to cited text no. 14
    
15.
Ma Y, Ma J. Immunotherapy against prion disease. Pathogens 2020;9:216.  Back to cited text no. 15
    


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