MV2 subtype of sporadic Creutzfeldt-Jakob disease presenting as corticobasal syndrome

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Movement Disorders Vol. 22, No. 6, 2007, pp. 898 –906 © 2007 Movement Disorder Society

Letters to the Editors Related to New Topics

MV2 Subtype of Sporadic Creutzfeldt-Jakob Disease Presenting as Corticobasal Syndrome Clinicopathologic correlative studies have shown that the corticobasal syndrome (CBS) is associated with various pathologies, including PSP, AD or sporadic Creutzfeldt-Jakob disease (sCJD), in addition to corticobasal degeneration (CBD).1-6 sCJD is generally distinguished from CBD by the much shorter duration of illness and the finding of either a 14-3-3 positive CSF test or periodic sharp wave complexes (PSWCs) in the EEG or a characteristic DWI-MRI signal. However, because of the existence of distinct disease subtypes,7 sCJD may show a less specific clinical course, which hampers the clinical distinction from CBD or other neurodegenerative disorders in case of overlapping clinical presentations. We observed a CBS in a subject with sCJD MV2, a disease subtype characterized by a relative long disease duration, the absence of EEG PSWCs, and a relatively high frequency of negative or inconclusive 14-3-3 CSF test.7,8 A 56-year-old right-handed man complained of difficulty in writing and using his left hand in daily activities. Neurological examination, 6 months after onset, disclosed a left hemi-parkinsonism without tremor associated with dysdiadochokinesia, hypographesthesia, mild ataxia of the left hand, severe constructive, and ideomotor apraxia prevalent in the left hand, apraxic agraphia, and mild memory and language impairment. Six months later, after an episode of space disorientation during driving, the patient underwent a brain 3T MRI scan (with FLAIR but no DWI sequences), and complete serological and CSF analyses including the 14-3-3 determination, which were all normal. The EEG showed a mild slowness. Neuropsychological examination disclosed severe worsening of cognitive functions with an associated left hemi-spatial neglect. The clinical picture continued to worsen in the following 12 months with gait disturbances, falls, dysphagia, and, late in the course, diffuse spontaneous myoclonus. He died of an aspiration pneumonia 24 months after clinical onset. Neuropathologic examination showed diffuse moderate to severe spongiform degeneration, gliosis, and neuronal loss in the cerebral cortex and several subcortical structures (Fig. 1). In addition, kuru-type amyloid plaques were seen in the cerebellum. PrP immunohistochemistry showed both a synaptic and a plaque-like pattern (Fig. 1). Molecular genetics revealed no PRNP mutation and methionine-valine (MV) heterozygosity at polymorphic codon 129. CSF total tau, only measured retro-

FIG. 1. (A) Severe spongiform degeneration and reactive gliosis in the putamen nucleus (H&E, 200⫻). (B) Plaque-like PrP immunoreactivity in the cerebellum (3F4 antibody, 1:400, 100⫻).

spectively, was 1,450 pg/mL, which is above the threshold (1,300 pg/mL) consistent with a clinical diagnosis of sCJD.8 The present case represents the second observation of a sCJD mimicking CBD with the duration of 2 years of illness or longer. Whereas a significant number of CJD patients with a typical but short clinical history of CBS3– 6 lasting from a few weeks3-5 to several months6 have been reported, we are aware of only one case of postmortem confirmed CJD

Received 21 November 2006; Revised 5 January 2007; Accepted 7 January 2007 Published online 28 March 2007 in Wiley InterScience (www. DOI: 10.1002/mds.21426


LETTERS TO THE EDITORS associated with a CBS lasting 4 years.1 Unfortunately, no information on CSF analyses or disease subtype is available for this case. Although 14-3-3 test was negative in other “CJD mimicking CBD” patients,4,6 CSF total tau determination was never performed. Recent data showed that the combined analyses of total tau and 14-3-3 protein in CSF is associated with the highest test sensitivity raising it to 89% in sCJD-MV2.8 Thus, although a sequential 14-3-3, EEG and MRI investigations during further disease course might have also yielded typical CJD findings,8 our results emphasize the clinical usefulness of CSF total tau determination in addition to 14-3-3 test for CJD differential diagnosis. In conclusion, we further stress the importance of bearing in mind sCJD, particularly the MV2-subtype, in CBS differential diagnosis. We also recommend measuring CSF total tau in addition to 14-3-3 in these cases, especially if genetic analyses reveals MV at PRNP codon 129. Anna Magherini, MD Roberta Pentore, MD Giuliana Galassi, MD Carlo M. Stucchi, MD Department of Neuroscience Neurological Clinic AUSL Modena Modena, Italy Sabina Capellari, MD Piero Parchi, MD, PhD* Department of Neurological Sciences Neurological Clinic University of Bologna Bologna, Italy *E-mail: [email protected]

References 1. Boeve BF, Maraganore DM, Parisi JE, et al. Pathological heterogeneity in clinically diagnosed corticobasal degeneration. Neurology 1999;53:795– 800. 2. Litvan I, Agid Y, Goetz C, et al. Accuracy of the clinical diagnosis of corticobasal degeneration: a clinicopathologic study. Neurology 1997;48:119 –125. 3. Fogel B, Wu M, Kremen S, Murthy K, Jackson G, Vanek Z. Creutzfeldt-Jakob disease presenting with alien limb sign. Mov Disord 2006;21:1040 –1042. 4. Moreaud O, Monavon A, Brutti-Mairesse MP, Grand S, Lebas JF. Creutzfeldt-Jakob disease mimicking corticobasal degeneration clinical and MRI data of a case. J Neurol 2005;252:1283–1284. 5. Kleiner-Fisman G, Bergeron C, Lang AE. Presentation of Creutzfeldt-Jakob disease as acute corticobasal degeneration syndrome. Mov Disord 2004;19:948 –949. 6. Anschel DJ, Simon DK, Llinas R, Joseph JT. Spongiform encephalopathy mimicking corticobasal degeneration. Mov Disord 2002; 17:606 – 607. 7. Parchi P, Giese A, Capellari S, et al. Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 1999;46:224 –233. 8. Krasnianski A, Schulz-Schaeffer WJ, Kallemberg K, et al. Clinical findings and diagnostic tests in the MV2 subtype of sporadic CJD. Brain 2006;129:2288 –2296.


Common Variants in Parkinson’s Disease Over the last two years, Lrrk2 G2019S has been established as a leading cause of both familial parkinsonism and apparent sporadic Parkinson’s disease.1 However, the frequency of Lrrk2 G2019S is dependent upon the ethnic background of the population that is studied, a crucial observation when one considers the lack of identification of common variants in Parkinson’s disease using genome-wide approaches in US patients.2 Lrrk2 G2019S is rare in Asian populations, although other Lrrk2 variants demonstrate population attributable risk. Recently, we described an amino acid substitution, glycine to arginine at position 2385 (G2385R) in the Lrrk2 WD40 domain, in one family with a history of parkinsonism.3 Lrrk2 G2385R substitution is rare in Caucasian populations yet observed at ⬃5% of the normal healthy ethnic Chinese population.4 – 6 In ethnic Chinese patients with familial parkinsonism, however, the frequency of G2385R is increased to ⬃20% and in typical sporadic late-onset Parkinson’s disease ⬃10%.4 –7 This observation was supported by a number of presentations at the recent 10th International Congress of Parkinson’s disease and Movement Disorders in Kyoto, Japan (October 28 to November 2, 2006), an appropriate venue for the confirmation of this exciting finding with results from Taiwan, Singapore, and Japan in concurrence.4 – 8 Our group’s presentation at this meeting also demonstrated that Lrrk2 G2385R carriers are genetically descended from a common ancestor over 4,800 years ago during the reign of the Yellow Emperor, ancestor of the Han Chinese. Lrrk2 G2385R is therefore the first common ‘functional risk-factor’ for Parkinson’s disease and may have a similar impact on the field of parkinsonism genetics as the identification of the Apo-E ε4 did in Alzheimer’s disease.9 Given that Asia accounts for approximately a quarter of the world’s population, Lrrk2 G2385R may be the most frequent ‘risk factor’ for Parkinson’s disease. We eagerly await results from mainland China and Asian communities outside of the continent itself to evaluate the global dispersion of this variant. Lrrk2 G2385R and G2019S may hold the key to resolving potential genetic contributions to this complex disease. Genome-wide approaches with sufficient genome coverage could identify both Lrrk2 G2385R in an ethnic Chinese sample and G2019S in either North African Arabs or Ashkenazi Jews. The ‘identical-by-descent’ nature of both Lrrk2 G2385R and G2019S carriers creates two extensive ‘pseudo-families’ in which to identify disease modifying loci and longitudinally follow asymptomatic carriers. The field of clinical genetics may once again look to excess incidence in isolates and population homogeneity to identify disease-associated variants which can then be examined in other populations with greater diversity. Owen A. Ross, PhD* Matthew J. Farrer, PhD Mayo Clinic College of Medicine Jacksonville, Florida, USA *E-mail: [email protected]

Published online 20 March 2007 in Wiley InterScience (www. DOI: 10.1002/mds.21463

Movement Disorders, Vol. 22, No. 6, 2007

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