Gerstmann-Sträussler-Scheinker syndrome misdiagnosed as conversion disorder

Abstract

Gerstmann-Sträussler-Scheinker syndrome (GSS) is a rare cause of genetic prion disease. Overlapping neurological, cognitive and psychiatric symptoms make GSS difficult to diagnose based on clinical features alone. We present a 40-year-old man without relevant medical or family history who developed progressive neurocognitive and behavioural symptoms over 3 years. Initial extensive diagnostic workup of his variable motor symptoms was unrevealing and he was diagnosed with conversion disorder. This diagnosis persisted for over 2 years, despite progressive neurocognitive symptoms. He eventually developed dementia and severe neurological impairment. Repeat brain MRI revealed generalised cortical volume loss, establishing the diagnosis of a rapidly progressive neurodegenerative process. He ultimately died from aspiration pneumonia at age 43. Postmortem neuropathological examination showed widespread multicentric prion protein amyloid plaques characteristic of GSS. Ultimately, genetic testing of brain tissue revealed a heterozygous A117V variant in the PNRP gene, confirming the diagnosis.

Background

Gerstmann-Sträussler-Scheinker syndrome (GSS) is a rare genetic prion disease which typically manifests in the fourth or fifth decade of life with progressive cerebellar dysfunction and cognitive decline, often with overlapping psychiatric and behavioural symptoms, parkinsonism and other movement disorders.^1–3 Prevalence is thought to range from 1 in 10–100 million; however, the true prevalence is difficult to ascertain given the phenotypic heterogeneity.⁴

Case presentation

A 40-year-old white construction worker with a history of chronic lower back pain and sciatica developed progressive behavioural changes including irritability, paranoia and hoarding, and he became withdrawn. He had left-sided jerking limb movements and gait instability complicated by falls over a period of 5 months. He had no other medical or psychiatric history, no occupational exposure or travel history and was taking no medications. He used marijuana recreationally, and in the remote past, he used ecstasy, alcohol, amphetamines and lysergic acid diethylamide. He was of Irish and German descent and his family history included two paternal cousins with mental health disease; his mother died in her 30s due to accidental drowning.

He was hospitalised for an expedited diagnostic evaluation. Neurological examination was notable for asymmetric increased muscle tone predominantly on the left, generalised jerking movements and gait disturbance requiring use of a walker. MRI of the brain and entire spine, CT myelogram, positron emission tomography (PET) scan, cerebrospinal fluid (CSF) infectious and inflammatory diagnostic studies, anti-NMDAR antibodies, ceruloplasmin, serum protein electrophoresis and oligoclonal bands were unrevealing. Workup was notable only for mild diffuse volume loss seen on brain imaging.

The diagnosis remained unknown at his discharge, and he was referred to movement disorders clinic for further evaluation. Examination was notable for left leg rigidity, incoordination and gait disturbance with left leg dragging and he was diagnosed with corticobasal syndrome. However, at subsequent clinic visits, these neurological findings were variable and inconsistent. Additionally, during follow-up encounters, he perseverated on his lower back pain and admitted to depressive symptoms, which led to a revised diagnosis of conversion disorder. The diagnosis of a psychogenic disorder was seemingly substantiated at a subsequent hospital admission for falls, when inpatient video monitoring revealed inconsistencies in his neurological examination.

He continued to experience progressive neurocognitive decline and presented to the emergency department repeatedly for falls due to gait disturbance. However, given his diagnosis of conversion disorder, his symptoms were interpreted as psychogenic. He was later evaluated by Psychiatry and was diagnosed with major depressive disorder. He was treated with numerous antidepressants and eventually received electroconvulsive therapy, without improvement in psychiatric symptoms. His condition worsened and he transferred to a skilled nursing facility due to deterioration in gait and inability to care for himself.

Twenty months after the onset of his neurological symptoms, the patient was admitted to the hospital for agitation and combative behaviour. During this admission, Neurology was consulted and his examination was notable for dementia, dysarthric speech, dysphagia and severe akineto-rigid parkinsonism manifesting with generalised bradykinesia and rigidity, as well as diffuse myoclonus which worsened with willed action. He was confined to bed and was unable to walk. A repeat brain MRI (figure 1) showed diffuse, mild to moderate cerebral volume loss, which had progressed from the prior imaging, establishing the diagnosis of a rapidly progressive neurodegenerative disease. The differential diagnosis included prion disease or a neurodegenerative proteinopathy such as corticobasal ganglionic degeneration, despite his young age. Repeat diagnostic workup included CSF fluid analysis sent for 14-3-3 protein (ARUP Laboratories), which was negative, precluding the reflex test for prion protein (PrP) with the real-time quaking-induced conversion (RT-QuIC). CSF tau was normal (84 pg/mL). The patient suffered from multiple aspiration episodes and underwent gastrostomy-tube placement. In the setting of his rapid functional decline, his family opted for hospice care, and he ultimately died at age 43 due to aspiration pneumonia, approximately 3 years after his symptom onset.

Figure 1.

Axial MRI brain images demonstrating diffuse right greater than left cortical volume loss; top row: T1 images; bottom row: T2 images.

Outcome and follow-up

Postmortem neuropathological examination

Gross pathology

Gross neuropathological examination was notable for mild diffuse cortical atrophy including frontal and occipital lobes, with sparing of temporal lobes (figure 2). There was moderate darkening of the globus pallidus but the basal ganglia were otherwise unremarkable. The brainstem appeared normal and the cerebellum did not demonstrate atrophy.

Figure 2.

Gross pathology showing mild generalised cortical atrophy and ventriculomegaly, without midbrain atrophy.

Neuropathology microscopic description and immunohistochemistry

The neocortex had no significant neuronal loss or gliosis, but there were scattered pyknotic pyramidal neurons most frequent in the frontal, parietal and motor cortices (figure 3). There was focal neuropil microvacuolation most marked in the parietal cortex. With thioflavin S fluorescent microscopy, variable numbers of small Kuru-ike plaques and dense-cored, multicentric plaques were detected in the neocortex, basal ganglia, cerebellum and hippocampus. These plaques were strongly immunoreactive for PrP (figure 4). There were no neurofibrillary tangles or evidence of amyloid angiopathy.

Figure 3.

Microscopic pathology demonstrating neuronal loss and gliosis in striatum, globus pallidus, thalamus and substantia nigra.

Figure 4.

PrP-immunoreactive plaques in the cerebellum. PrP, prion protein.

There was also neuronal loss and gliosis in the neostriatum, thalamus, mammillary bodies and substantial nigra. The findings of multicentric, PrP-positive plaques affecting the neocortex, basal ganglia, limbic structures and cerebellum are characteristic for GSS⁵ (figure 5).⁵

Figure 5.

‘Multicentric’ plaques consistent with Gerstmann-Sträussler-Scheinker disease. PrP, prion protein.

Genetic studies

A brain tissue sample sent to the Centers for Disease Control and Prevention (CDC) Prion Surveillance Laboratory revealed a heterozygous c.350C>T; 351 A>G (p. A117V) variant in the PNRP gene, which has been previously reported as pathological in cases of genetic prion disease.^{6 7} These genetic results, along with the clinical features, imaging and characteristic neuropathological findings, confirmed the diagnosis of GSS.

Discussion

Case discussion

We present a 40-year-old man with 3 years of progressive neurocognitive decline. Our patient exhibited behavioural symptoms early in the course, including paranoia and perseveration on his chronic pain and depressive symptoms, which likely biased his treating clinicians to suspect a psychogenic aetiology. His examination initially showed left-sided rigidity and abnormal movements which were variable, distractible and inconsistent and led to the presumptive diagnosis of a functional movement disorder. This diagnosis persisted until he developed dementia and severe motor symptoms. In retrospect, it was likely that the variable nature of the abnormal movements was due to dystonia. Although sporadic prion disease was in the differential diagnosis for our patient’s presentation, genetic prion disease was not suspected. It is likely, however, that his mother carried the pathogenic PNRP variant, but given her premature death, she did not manifest any signs or symptoms.

Prion disease

PrP is a highly evolutionarily conserved cellular protein comprised of three α-helices and an antiparallel β-sheet.^{8 9} Its exact function remains unclear. Genetic prion disease is typically caused by nonsense mutations and polymorphisms in the PRNP gene which induce changes in the secondary structure of the protein; specifically, α-helices are converted to β-sheets, resulting in a protein which resists degradation by detergents and proteases.¹⁰ These abnormally folded proteins are prone to aggregation and self-propagate by inducing further misfolding of other normal PrPs.¹¹ Accumulation and aggregation of these misfolded proteins results in neuronal injury and death.

Clinical characteristics of GSS

GSS was first described in an Austrian family in 1936 and was the first human prion disease in which a specific PRNP gene variant was identified as causative.^{1 12} GSS is characterised histopathologically by the presence of multicentric PrP amyloid plaques, differentiating it microscopically from other hereditary prion diseases, which include fatal familial insomnia and familial Creutzfeld-Jakob disease (fCJD).⁴ GSS is inherited in an autosomal dominant manner. It is thought to have a prevalence of 1–10 in 100 000 000; however, the true prevalence is unknown due to the wide spectrum of clinical presentations.⁴ The symptoms of GSS can overlap with other neurodegenerative, psychiatric and movement disorders, which makes it difficult to diagnosis based on clinical features alone.2–4 13 14 Most persons with GSS present in the fourth or fifth decade of life with neurological symptoms including cerebellar dysfunction (eg, incoordination, gait impairment) and pyramidal or extrapyramidal signs, but may also present with behavioural, psychiatric and/or cognitive disturbances. Additionally, up to 30% of GSS cases may not have a reported familial history of neurodegenerative disease, although some of these may be due to incomplete family history or premature death.¹⁵

Diagnosis

Given the variable clinical features of GSS, diagnosis of this rare disease can be challenging. CSF biomarkers for prion disease, 14-3-3 and total tau protein, are elevated in less than half of the cases of genetic prion disease, and as demonstrated in our case, are often not sensitive enough to detect GSS.¹⁵ RT-QuIC is a more specific and sensitive test for genetic prion disease; in GSS, this test has shown sensitivity of up to 75% and specificity of essentially 100%.^{16 17} Given the low degree of sensitivity of 14-3-3 and total tau in genetic prion disease, CSF samples should be sent for RT-QuIC testing regardless of a negative 14-3-3 when there is a high degree of clinical suspicion for prion disease. In our case, the patient had normal 14-3-3, which did not trigger the reflex RT-QuIC, which could have established the diagnosis earlier in his clinical course. Brain MRI in GSS may show generalised atrophy of the cerebral cortices or cerebellum; however, early in the disease course, MRI may be normal.¹⁸ Amyloid PET has been found to highlight protein amyloid deposits in patients with GSS, although this is a non-specific finding.¹⁹

Management

Unfortunately, there are no disease-modifying therapies for any of the prion diseases and treatment is supportive. However, there are promising therapeutic targets. A major target of potential treatment involves inhibiting the conversion of normal PrP into the misfolded disease-causing PrP. Several small molecules, such as pentosane polysulfate, quinacrine and amphotericin B, have been tried with limited success.²⁰ Intraventricular pentosane polysulfate administered prophylactically has yielded the most potential benefit in a small trial involving seven patients with either GSS or CJD, showing a trend towards longer survival time compared with the mean survival time of natural history patients, although this study was limited by sample size.²¹ Immunotherapies focused on clearing of misfolded PrPs involving vaccines and T-lymphocyte therapies have found moderate success in animal models, showing delayed disease onset and extending the duration of disease in mice vaccinated with PrP loaded syngeneic dendritic cells.²² All of these treatments, while promising, hinge on early diagnosis of the disease prior to development of irreversible neuronal damage, further emphasising the need for early detection.²³

Learning points.

• Gerstmann-Sträussler-Scheinker syndrome can present with a myriad of symptoms including movement disorders, pyramidal signs, cognitive and behavioural disturbances and psychiatric symptoms, which can make diagnosis based on clinical features alone challenging.

• Cerebrospinal fluid protein biomarkers including 14-3-3 and tau are often not sensitive enough to detect genetic prion diseases. Real-time quaking-induced conversion testing is highly sensitive and specific for prion disease and should be explicitly requested when there is a high clinical suspicion for prion disease.

• Testing the PRNP gene can also be used to confirm the diagnosis of genetic prion disease.