O.R.I.A. Osservatorio Ricerca e Innovazione Aziendale

A NEW CASE OF GERSTMANN-STRÄUSSLER-SCHEINKER SYNDROME
ASSOCIATED WITH THE 202 ASPARTIC TO ASPARAGINE MUTATION
COUPLED WITH VALINE AT CODON 129 (D202N-129V)
*Romana Rizzi, *Enrico Ghidoni, ^Sabina Capellari, *Riccardo Zucco, *Norina Marcello, ^Piero Parchi
*Department of Neurology, Arcispedale Santa Maria Nuova, IRCCS, Reggio Emilia, Italy - Dipartimento di Scienze
Biomediche e Neuromotorie, Università di Bologna, Italy^ IRCCS, Istituto delle Scienze Neurologiche, Bologna, Italy
SUMMARY
PURPOSE: Genetic prion diseases (gPrD) are linked to mutations in the prion protein gene (PRNP), and are classified based on type of mutation, clinical
phenotype, and neuropathological features. We describe a new clinical case of Gerstmann-Sträussler-Scheinker syndrome associated with the 202 aspartic
to asparagine mutation linked to valine at the polymorphic codon 129 (D202N-129V)
METHODS: A 60-year-old male with a 34 month history of progressive cerebellar ataxia, extrapyramidal signs and spastic paraparesis was investigated
using EEG, ENG/EMG, evoked potentials, brain MRI, DAT scan, neuropsychological evaluation, cerebrospinal fluid assays (14-3-3 protein, T-Tau, P-Tau,
beta-amyloid 1-42 peptide) and sequencing of PRNP open reading frame.
RESULTS: EEG showed irregular generalized, triphasic, slow-wave complexes, brain MRI only showed some signs of vascular encephalopathy, while DAT
scan showed a bilateral reduction of uptake in the putamen nuclei and in the right caudate. Neuropsychological examination revealed impairment of
attention, praxis, constructive abilities, and phonemic fluency as well as a reduced verbal span associated with dysarthria. The 14-3-3 protein test was
weakly positive, T-tau and P-Tau concentrations were abnormally elevated, whereas the CSF levels of the beta-amyloid 1-42 peptide were normal. Genetic
analysis demonstrated a codon 202 aspartic to asparagine mutation coupled with valine at codon 129 (D202N-129V).
DISCUSSION: Our patient did not have a positive family history for neurodegenerative diseases as reported in many other genetic cases of prion disease.
CONCLUSIONS: Despite the rarity of Gerstmann-Sträussler-Scheinker syndrome, our observation underlines the importance of considering this syndrome
in the differential diagnosis of patients with parkinsonism associated with cerebellar and pyramidal signs
Introduction
Gerstmann-Straussler-Scheinker syndrome (1) is a familial form of Prion Disease (2,3) with a phenotype originally descripted in a large Austrian family with
affected members manifesting slowly progressive cerebellar ataxia and/or spastic paraparesis with cognitive decline transmitted with autosomal dominant
inheritance. This type of TSE (transmissible spongiform encephalopathy) can be caused by a range of mutations within the open reading frame of PRNP
(prion protein gene) on chromosome 20 including D202N-129V (202 aspartic acid to asparagine with either valine at codon 129). We describe a new
clinical case of Gerstmann-Straussler-Scheinker associated with the 202 aspartic to asparagine mutation linked to valine at the polymorphic codon 129
(D202-129V).
Clinical Case
A 57-year-old male, without a positive history for neurodegenerative diseases, graduate in geology, married without children, smoker, hypertensive, right
handed, legally disabled because of an accident at work when he was 47-year-old in 2003, showed at the beginning of 2011 slowing of the speech
(dysarthria) and gait imbalance (unsteadiness). The symptoms of the patient progressively worsen over time causing impairment of gait and frequent
falls. Since the beginning of his symptoms He also lost about 14 Kg. On July 17th, 2013 the patient was admitted to our Department and underwent an
extensive neurological work up including: - brain and spine NMRI (Nuclear Magnetic Resonance Imaging), - NPS (Neuropsychological) evaluation, - awake
and sleep EEG (Electroencephalogram), - Carotid and transcranial Doppler sonography, - brain parenchymal sonography- DaTscan (Ioflupane I123
a
injection)- ENG and EMG (Electroneurography and Electromyography), - PESS
(SomatoSensory Evoked Potentials) and MEP (Motor Evoked Potentials), CSF (Cerebrospinal Fluid) analysis and Serological tests (cerebrospinal fluid and serum). The patient was also investigated using gastroscopy, colonscopy,
chest and abdomen computed tomography (CT) scanning.
Neurological examination
bradykinesia, dysarthria, slowed horizontal and vertical eyes saccades, bilateral tremor of the arms, mixed plastic and elastic hypertonus of the limbs
especially of the legs, hyperactive deep tendon reflexes in all 4 extremities, gait paraparetic and ataxic, left >right arm dysmetria, bilateral Babinski
Clinical Investigations:
Brain NMRI: signs of chronic vascular lacunar encephalopathy - Spine NMRI: no significative alterations
NPS examination: impairment of attention, praxis, constructive abilities and phonemic fluency as well as reduced verbal span associated with dysarthria
Awake and sleep EEG: irregular generalized, triphasic, slow-wave complexes
DaTscan: bilateral reduction of uptake in the putamen nuclei and in the right caudate
Carotid and transcranial Doppler sonography: no alterations - Brain parenchymal sonography: no alterations
ENG and EMG: no alterations - PESS: bilateral delayed somatosensory evoked potentials -PEM: reduced amplitude of the motor evoked potential from the
right leg with normal central latencies
CSF analysis: protein level mild elevated (70 mg/dl) with normal glucose level (49 mg/dl) and normal cell (1uL), mirror pattern at the
ISOELECTROFOCUSING with similar oligoclonal bands in the CSF and in the serum, medium damage of the hematoencephalic barrier, negative the search
for DNA of neurotropic virus (Herpes and Enterovirus), negative the search for anti NMDRAr , anti GAD, anti VGKC (voltage-gate potassium channels),
anti GB autoantibodies, T-tau (> 1300 pg/mi) and P-tau (337 mg/ml ) concentrations abnormally elevated, normal level of the beta-amyloid 1-42
peptide (982 pg/ml), 14-3-3 protein test weakly positive
Serological tests (cerebrospinal fluid and serum): Paraneoplastic autoantibody evaluation (serum): normal findings - Autoantibodies vs Purkinje cells, vs
neuronal cells, vs gabaergic synapsies, anti-Ri (cerebellum), anti-Hu (cerebellum), anti-Yo (cerebellum), anti amfifisina, anti cerebellum anti CV2, anti
cerebellum Ma: normal findings
Gastroscopy: hiatal ernia with signs of previous duodenal ulcer - Colonoscopy: no alterations - Chest and abdomen CT: no alterations
genetic analysis of the prion mutations: detection of codon 202 aspartic to asparagine mutation coupled with valine at codon 129 (D202N-129V)
Commentary and clinical evolution
a
b
d
c
In the beginning, we made a descriptive diagnosis of “ Dysarthria and progressive ataxia in a patient with extrapyramidal, cerebellar and pyramidal signs”
suspecting a form of “Multiple System atrophy (MSA)”, but detection of the T-tau and P-tau concentrations abnormally elevated together with the
positivity of the 14-3-3 protein test led us to a diagnosis of Prion disease probably genetic (gPr), taking into account of the long history of symptoms. So
we made the genetic analysis of the prion mutations and we found the codon 202 aspartic to asparagine mutation coupled with valine at codon 129
(D202N-129V): it is one of the mutations described as associated to the Gerstmann-Straussler-Scheinker Syndrome.
The patient is now 60-year-old with a 42 month history of disease; he showed marked dysarthria and cannot be able to walk without help. He can read and
tape to write using the PC to communicate. Another major problem is the dysphagia because he can’t swallow solid food but he has some problems to
accept a semisolid diet. He lived home with 24/24 h assistance from his wife.
Conclusions and Discussion
Despite the rarity of Gerstmann-Sträussler-Scheinker syndrome, our observation underlines the importance of considering this syndrome in the differential
diagnosis of patients with parkinsonism associated with cerebellar and pyramidal signs. Our patient did not have a positive family history for
neurodegenerative diseases as reported in many other genetic cases of prion disease. A genetic study of the unaffected mother and brothers of the
patient would be controversial for ethical concerns. We think it is better to study only the affected patient eventually by the autopsy in order to confirm
the diagnosis.
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