Rare case of atypical parkinsonism: why family history is important

Case description

A 41-year-old male, high achieving in his professional life, attended cardiology outpatients with a history of two transient episodes of loss of consciousness suggesting syncope. No abnormality was detected on clinical examination, and electrocardiography was normal. There was no recurrence of the syncopal episodes nor were there any other autonomic symptoms over the next two years. He was then referred to neurology services with gradual onset progressive right-hand tremor, right leg dragging, slurred speech, poor balance, forgetfulness and episodic confusion over several months. He had become socially withdrawn and reported deterioration in short-term memory with noticeable effects on his work. On examination, he was dysarthric, had a right pronator drift, cogwheel rigidity in the right more than left arm, with reduced stride length and foot clearance from the ground while walking. Deep tendon reflexes were brisk bilaterally and plantar responses extensor. He was tearful when asked about his mood. Investigations including routine blood tests (full blood count, urea and electrolytes, liver function tests, C-reactive protein, ESR), thyroid function tests, vitamin B12, folate, angiotensin converting enzyme, coeliac serology, autoantibodies (antinuclear, parietal cell, thyroglobulin, microsomal, smooth muscle, reticulin and mitochondrial), paraneoplastic antibodies (neuronal and purkinje cell), plasma immunoglobulins, serum protein electrophoresis, plasma cortisol, syphilis and lyme serology, arterial blood gases, magnetic resonance imaging (MRI) brain scan, electroencephalography and cerebrospinal fluid (CSF) (including cytology, oligoclonal bands and protein 14-3-3) were negative or normal. S-100b was marginally elevated at 0.55 ng/ml (reference < 0.38). S100b-like protein 14-3-3 is higher in the CSF of patients with Creutzfeld Jakob disease (CJD) compared to normal controls and serves as a marker of neuronal cell damage.

Genetic testing for spinocerebellar ataxia 1, 2, 3, 6, 7 and 8 was negative. A ¹²³I-n-fluoropropyl-2b-carbomethoxy-3b-(4-iodophenyl) nortropane single photon emission computed tomography (¹²³I FP-CIT SPECT) scan showed reduced uptake in putamen and caudate nuclei (Figure 1). OPEN IN VIEWER

Neuroimaging

Ropinirole was introduced for symptoms of parkinsonism and titrated to 15 mg daily by four months, but speech, mobility and memory problems worsened. On referral to the movement disorder clinic, bilateral parkinsonism with tremor, rigidity, bradykinesia, postural instability, stooped posture and reduced right arm swing were noted. There was no rest tremor, but there was postural and kinetic tremor in both arms, worse on the right side. Neuropsychology assessment found slowed processing speed with mild memory and attention problems. Levodopa-based treatment was added, and titrated to 800 mg daily over next 15 months, again without clinical response. Over the next year, he remained low in mood, his mobility progressively declined and he developed myoclonus and ataxia. Levetiracetam was added for myoclonus and fluoxetine for depression.

His parkinsonism was diagnosed as atypical owing to the poor response to dopaminergic medication. A family history emerged from a relative, indicating that the index case’s maternal first cousin (male) had a similar neurological presentation and had a mutation in the hereditary prion gene (PRNP). A previously undeclared family history of a corticobasal syndrome in the index case’s mother, encephalitis lethargica in his maternal grandfather and clinically diagnosed multiple sclerosis in his sister who died in her 40 s was obtained. This was in the days before genetic testing was commonly available.

Genetic testing entailed sequencing of the complete open reading frame of the prion protein gene. He was positive for A117V mutation and heterozygous (methionine, valine) at codon 129.

His cognitive problems, ability to self care, gait and mobility progressively worsened. Two years from the onset of parkinsonism, his mini-mental state examination score was 17/30 and he was mobilising with a stick. By four years into the illness, he was mute and wheelchair bound but was able to comprehend and obey verbal commands. Eye movements showed saccadic pursuit and limitation of both upgaze and downgaze at this stage. There was extrapyramidal rigidity in all four limbs, and deep tendon reflexes were now brisk in the upper limbs and absent in the lower limbs. He required nutritional support with percutaneous endoscopic gastrostomy, and in the final year of life, he was severely rigid in all four limbs, bed bound and had florid myoclonus. He died seven years after initial presentation.

Discussion

Our patient presented at a young age due to familial Creutzfeld Jakob disease (fCJD) with degenerative parkinsonism. He presented with bilateral parkinsonian (although slightly asymmetric) signs, early cognitive impairment and behavioural problems. These features, plus a negligible response to anti-parkinsonian therapy, indicated atypical parkinsonism. There were no specific pointers to a definitive diagnosis, until the emergence of a dominant family history of movement disorders which led to the specific gene test that established the diagnosis. In later stages, he developed vertical gaze paresis, which together with the cognitive problems superficially resembled progressive supranuclear palsy (PSP). However, more typical CJD features emerged later, in particular florid myoclonus.

More than 90 mutations are described in the PRNP gene (including missense, nonsense, insertions and deletions), ¹ and parkinsonism at presentation has been reported in cases of fCJD, ² although this case is one of the few to report the A117V PRNP mutation for such a presentation. It is notable that parkinsonism at presentation is more likely with fCJD than sporadic CJD (sCJD) or variant CJD (vCJD). ³ Recognition of fCJD is not only important for accurate case diagnosis but also because of inheritance risks. Accordingly, we now review these issues, considering both the A117V mutation and other types of fCJD.

Previously described presentations with the A117V mutation include ataxia, hemiparesis, behavioural and memory problems in three members of a single family; ⁴ early dementia, behavioural disturbances, gait difficulty and ataxia in 2 British-Irish kindreds ⁵ and a single case of Gerstmann-Straussler-Sheinker disease (GSS), in a French man. ⁶ GSS is an autosomal-dominant prion disease with a wide spectrum of clinical presentations including ataxia, spastic paraparesis, extrapyramidal signs and dementia. In 43 consecutive fCJD patients, features at presentation included limb or gait ataxia in 86%, rigidity in 51%, myoclonus in 49%, bradykinesia in 35%, dystonia in 15% and tremor in 13%. Twelve patients (28%) had at least two of the four cardinal parkinsonian signs at presentation. ²

Our patient, aged 41 years at presentation, was close to the age range of 43 to 77 years for the other reports of fCJD. ² His clinical features were dominated initially by parkinsonism, and the family history spanning two preceding generations also, according to diagnostic labelling, appeared to exhibit a movement disorder presentation, although we could not locate more detailed records. An autosomal dominant inheritance pattern was clearly present in this family, as has been reported in other patients with fCJD. ⁷

Besides the well-recognised motor phenotypes of CJD, GSS, fatal familial insomnia and Huntington disease-like 1 resulting from mutations in the PRNP gene, there have been case reports of fCJD presenting with PSP ⁸ syndrome and epilepsia partialis continua. ⁹ It is helpful to contrast the presenting and evolving movement disorder features of fCJD with those seen in sCJD, which is much more common. In sCJD, ataxia and myoclonus are often early features, and parkinsonism emerges later; movement disorder features increase with disease duration and occur in 90% of patients during the disease course. ¹⁰ In a Swedish sCJD cohort, ataxia was present in 48 of 122 patients (39%), being second to dementia as a presenting feature. While the initial parkinsonian presentation of our case was unusual, the development of myoclonus by three years is consistent with observations in other fCJD cases, as well as sCJD.^11,12

Our patient presented to cardiology with syncopal episodes and later developed absent deep tendon reflexes at an advanced stage of the illness suggestive of a peripheral neuropathy, although confirmatory electrodiagnostic tests and/or peripheral nerve biopsy were not performed as he was in a hospice by this stage. It is possible that one or both of these were manifestations of prion disease, but lack of family consent did not allow an autopsy to prove this. Accumulation of prion protein in the peripheral nervous system including autonomic ganglia and peripheral nerves is reported in CJD. ¹³

Survival was longer (seven years from initial syncopal symptoms) in this patient compared to patients with sCJD and vCJD, but within expected ranges for fCJD. Median survival in the United Kingdom for vCJD is about 14 months (range: 6 to 84), 4 months (range: 1 to 74) for sCJD, while mean survival with the E200K mutation in PRNP is 96 months. ¹⁴

FP-CIT SPECT abnormalities are reported in patients with sCJD relating to parkinsonian features. ¹⁵ Post-synaptic D2 receptor dysfunction in the striatum may explain the lack of response to dopaminergic therapy, but confirmation of this with functional imaging such as with [123] iodobenzamide SPECT is not reported in such patients.

Our case is one of the 5% of cases of CJD, the commonest human spongiform encephalopathy, who have one of the inherited variants. The possibility of such cases remaining unrecognised is exemplified in this case, which is understandable given clinical phenotypes mimicking specific neurological syndromes, and their rarity (incidence of 1 per million annually). Recognition of these cases, however, is important, as there is a familial risk of passing the disease causing gene to offspring.

Conclusions

CJD is generally recognised as a rapidly progressive dementia with myoclonus and/or ataxia but other presentations have been described. This case emphasises the importance of attention to detail of elucidating a family history in movement disorder cases with an atypical presentation.