Parkinsonism and Related Disorders 20 (2014) 388e393

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Expansion of the clinicopathological and mutational spectrum of Perry syndrome Eun Joo Chung a, Ji Hye Hwang b, Myung Jun Lee c, Jeong-Hoon Hong d, Ki Hwan Ji a, Woo-Kyoung Yoo e, f, Sang Jin Kim a, Hyun Kyu Song g, Chong S. Lee b, Myung-Sik Lee c, Yun Joong Kim d, f, h, * a

Department of Neurology, Busan Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea d ILSONG Institute of Life Science, Hallym University, Anyang, Republic of Korea e Department of Physical and Rehabilitation Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Republic of Korea f Hallym Institute of Translational Genomics & Bioinformatics, Hallym University Medical Center, Republic of Korea g School of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea h Department of Neurology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Republic of Korea b c

a r t i c l e i n f o

a b s t r a c t

Article history: Received 17 July 2013 Received in revised form 9 January 2014 Accepted 13 January 2014

Background: Perry syndrome (PS) caused by DCTN1 gene mutation is clinically characterized by autosomal dominant parkinsonism, depression, severe weight loss, and hypoventilation. Previous pathological studies have reported relative sparing of the cerebral cortex in this syndrome. Here, we characterize novel clinical and neuroimaging features in 3 patients with PS. Methods: 18F-fluorinated N-3-fluoropropyl-2-ß-carboxymethoxy-3-b-(4-iodophenyl) nortropane ([18F]FPCIT) PET, [18F]fluorodeoxyglucose PET, or volumetric MRI was performed in probands, and imaging data were analyzed and compared with those of control subjects. Results: We identified 2 novel mutations of DCTN1. Oculogyric crisis that presented before levodopa treatment was observed in 1 case. One patient had supranuclear gaze palsy. In 2 cases, [18F]FP-CIT showed marked loss of dopamine transporter binding with only mild parkinsonism. Areas of hypometabolism or cortical thickness change were observed in dorsolateral frontal, anterior cingulate, lateral temporal, and inferior parietal cortices. Conclusion: Oculomotor manifestations are not uncommon in PS. Neuroimaging studies suggest involvement of the frontotemporoparietal cortex, which may be the clinical correlate of apathy and depression, as well as pathological changes in subcortical structures. Ó 2014 Elsevier Ltd. All rights reserved.

Keywords: Perry syndrome DCTN1 Novel mutation MR volumetry Positron-emission tomography

1. Introduction Perry syndrome (PS; MIM: 68605) is a rapidly progressive neurodegenerative disorder characterized by parkinsonism, central hypoventilation, severe weight loss, and depression or psychiatric symptoms; this disorder is inherited in an autosomal dominant manner [1,2]. Since PS was first described in 2 unrelated Canadian families [3,4], additional families with this syndrome have been

* Corresponding author. Hallym Institute of Translational Genomics & Bioinformatics, Hallym University Medical Center, 1605-4 Gwanyang-dong, Dongan-gu, Anyang-si, Gyeonggi-do 431-061, Republic of Korea. Tel.: þ82 31 380 1666; fax: þ82 31 388 3427. E-mail address: [email protected] (Y.J. Kim). 1353-8020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.parkreldis.2014.01.010

identified in different countries (United States [5], France [6], United Kingdom [7,8], Turkey [9], and Japan [10], a Hawaiian family from Japan, and the Fukuoka-4 family [11]). All mutations (G71R, G71E, G71A, T72P, and Q74P) associated with PS are located on exon 2 of the DCTN1 gene (dynactin 1; NM_004082) encoding the p150Glued protein, the major subunit of the dynactin protein complex [2,11]. Previous clinicopathological studies have revealed severe neuronal loss and gliosis in the brainstem and basal ganglia as well as loss of serotonergic neurons in the dorsal raphe nucleus [1,11], whereas cortical regions were usually reported to be unaffected [1,10,12]. In contrast to this, autopsies of a French family [6] exhibited atrophy in the frontal and cingulate cortices, as well as in the ventral tegmental area. A recent report described a case of PS manifesting with behavioral variants of frontotemporal dementia;

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however, the authors did not report any neuroimaging changes except for diffuse cerebral atrophy [13]. Here, we describe 3 PS patients with 2 novel mutations of the DCTN1 gene who displayed degeneration of frontotemporoparietal cortex documented by 3dimensional volumetric MRIs or [18F]fluorodeoxyglucose PET ([18F]FDG-PET), accompanied by marked reduction of dopamine transporter binding.

with hypoxia. Respiratory monitoring revealed frequent spells of apnea lasting longer than 20 s, and he received a tracheostomy with respiratory supports. Findings of serial brain MRIs were unremarkable, except for diffuse brain atrophy. [18F]FP-CIT PET also showed marked loss of dopamine transporters.

2. Subjects and methods

The proband, a 51-year-old man, visited a movement disorder center because of a six month history of intermittent involuntary upward deviation of the eyes. He was on no medication when his involuntary eyeball movement first developed. He complained that an involuntary tonic upward deviation of his eyeballs occurred every 2e3 days, but he could correct his eyeball position voluntarily. He reported that the frequency of the tonic upward deviation decreased to once every 5e6 days after initiation of levodopa treatment, which had been prescribed based on a diagnosis of PD in another hospital. His father died at age 52 with an unknown neurological problem, and his mother died at the age of 59 with heart disease. His younger sister had levodopa-responsive parkinsonism with supranuclear gaze palsy and jaw openingeclosing dyskinesia. On examination, he had symmetric bradykinesia, moderate rigidity, and postural instability. There was no tremor. When walking, there was bilateral reduction of arm swing with relatively good stride and cadence. There was no postural instability. Extraocular movements in the interictal phase were unremarkable. In the ictal phase, though visual fixation restored his eyes temporarily to their primary position, his eyes had the tendency to deviate upward, which did not change with distraction or during rapid alternating movements. He could perform saccades and pursuit with full range, but his eyes showed a tendency to deviate upward while performing saccadic movements. Optokinetic nystagmus was not generated in either the vertical or horizontal directions. Frontal lobe releasing signs, including glabellar, snout, and palmomental reflexes, were positive. Muscle power and sensory examinations were normal. Deep tendon reflexes were brisk without ankle clonus. Serial brain MRIs were unremarkable. Twenty-four-hour urine copper levels were within normal range, and there were no KaysereFleischer rings. After initiation of levodopa treatment (250 mg), his hand function improved by 39.4% (right) and 36.2% (left), and his gait improved by 17.6% as assessed by the CAPSIT test.

Informed consents for genetic testing were obtained from each patient. 3. Case reports 3.1. Case #1 A 56 year-old woman who was diagnosed with Parkinson’s disease (PD) 2 years ago was transferred to a tertiary referral hospital because of respiratory failure. She had a history of depression. Both her sister and mother, who were diagnosed with PD, had neurogenic respiratory problems and were on ventilators for years before their death. Three years ago, our patient developed a masked face, slurred speech, bradykinesia, rigidity, and gait disturbances, which were resolved with 200 mg of levodopa thrice daily and 0.75 mg of, pramipexole, once daily. She lost approximately 8.5 kg over a 6-month period. Her family did not report any behavioral changes such as disinhibition, perseveration, or violence. She had a history of sudden onset episodic dyspnea that had developed 6 months prior to presentation, but she remained relatively well until she started to experience breathing difficulties while sleeping. An arterial blood gas study in the emergency room revealed marked hypercarbia (pCO2 ¼ 77 mmHg). On examination, mild bradykinesia and rigidity without tremor were observed. External ocular movements and saccadic movements were normal. OKN was normal. There was no motor weakness. Sensory examination was normal. Frontal lobe releasing signs were negative. Her MiniMental State Exam score was 23, but she had no impairment of ADL. Serial brain MRIs were unremarkable. [18F]FP-CIT PET showed marked loss of dopamine transporters. In addition, [18F]FDG-PET showed significant glucose hypometabolism in the anterior cingulate cortex, orbitofrontal cortex, pars opercularis of the inferior frontal gyrus, and inferior parietal lobule.

3.3. Case #3

3.4. DCTN1 sequence analysis 3.2. Case #2 A 51-year-old man was referred to a movement disorder clinic because of parkinsonism and apathy. His first noticeable symptoms were depressed mood, reduced fluency of speech, and insomnia, all which appeared around 43 years of age. From the age of 45 years, he developed bilateral hand tremor followed by rigidity and bradykinesia, which gradually worsened. His family noticed that he was withdrawn and had no interest in either his surroundings or socializing. He lost about 24 kg in 3 years. His family history revealed that his oldest brother died at age 58 and his and youngest sister at age 52; both had parkinsonism. On neurologic examination, he had dysphagia, shallow breath, and severe tachypnea. Both upward and downward vertical saccades were limited; vertical optokinetic nystagmus was absent, but the vertical vestibulocephalic reflex was preserved. His parkinsonian motor symptoms partially responded to levodopa where the motor scores from the Unified Parkinson’s Disease Rating Scale improved from 63 to 53 after treatment with levodopa/benserazide (200 mg/50 mg thrice daily). An arterial blood gas study and polysomnography revealed an apnea index of 6.96 (normal < 5) and central hypoventilation

After obtaining informed consent from patients and family members, genomic DNA was extracted from peripheral blood leukocytes using a standard method. Polymerase chain reaction was performed as previously described [2], and the sequence was analyzed by ABI3730 (Applied Biosystems, CA). Novel DCTN1 mutations were validated in 120 Korean healthy controls, and in the 1000 Genomes database. 3.5. MR volumetry image analysis Using a 1.5 T MR scanner (ACS-NT, Philips, Netherlands), T1weighted 3D MPRAGE images (repetition time ¼ 8.6 ms, echo time ¼ 4.0 ms, flip angle ¼ 8 , acquired matrices ¼ 252  250, slice thickness ¼ 1 mm) were obtained from an index case and from 12 age- and sex-matched controls. Image files in DICOM format were analyzed using the FreeSurfer software (v5.0, Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA). FreeSurfer is a semi-automated brain morphometry tool. The details of this postprocessing sequence have been described elsewhere [14]. Using a general linear model using age as a covariate, we estimated the

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regional difference pattern of cortical thickness at each vertex across the cortical surface between patients with PS and agematched healthy controls. Clusters of vertices with thicknessgroup and volume-group regression coefficient p values exceeding a predetermined threshold (p ¼ 0.01) were identified, and cluster-wise statistical significances were calculated via 10,000 instances of a Monte Carlo simulation.

(185 MBq). Emission PET data were acquired for 10 min in 3D mode after brain CT scanning, which was performed in spiral mode at 120 kVp with 380 reference mAs using the CARE Dose 4D (Siemens Medical, Forchheim, Germany) program. [18F]FP-CIT PET images were reconstructed using CT data for attenuation correction with the TrueX algorithm and an all-pass filter using a 336  336 matrix.

3.5.1. [18F]Fluorodeoxyglucose PET studies and image analysis [18F]FDG-PET was performed using an ECAT HR þ scanner (Siemens Medical Systems Inc., Hoffman Estate, IL, USA), which has a 50-cm transaxial field of view and an intrinsic resolution of 4.5 mm full width at half maximum. The subject had fasted for at least 6 h before the scan. A transmission scan of 5 min using a 68Ge rotating pin source and an emission scan of 15 min were acquired 40 min after intravenous injection of 370 MBq [18F]FDG in a quiet dimly lit room. The scanner simultaneously imaged 63 planes with a slice thickness 2.46 mm for a longitudinal field of view of 15.5 cm. All emission images were reconstructed with ordered subset expectation maximization using 16 subsets and 6 iterations. For the ROI analysis, all PET images were spatially normalized to a generic SPM2 PET template (Wellcome Trust Centre for NeuroImaging, London, United Kingdom) after converting the data from DICOM into Analyze format. The mean activity values in anatomically defined ROIs were automatically extracted from the spatially normalized PET images, using the Automated Anatomical Labeling template [15]. This procedure allows the automatic extraction of the mean activity value of 116 anatomically labeled brain ROIs. These 116 means were averaged to obtain the mean activity of the global cerebral cortex. Regional glucose metabolism was normalized by dividing [18F]FDG uptake of each ROI by a mean value of the primary visual cortex.

4. Results

3.5.2. [18F]FP-CIT PET studies and image analysis Tracer chemistry of 18F-fluorinated N-3-fluoropropyl-2-ßcarboxymethoxy-3-b-(4-iodophenyl) nortropane (FP-CIT) is described elsewhere [16]. [18F]FP-CIT PET was performed using a Biograph 40 TruePoint PET/CT camera (Siemens/CTI, Knoxville, TN), which provides an in-plane spatial resolution of 2.0 mm full width half maximum at the center of the field of view. Image acquisition was started 3 h following injection of [18F]FP-CIT

Three heterozygous mutations including 2 novel mutations (G67D and Y78C) were identified from 3 patients; c518G>A (p.Gly67Asp) in case #1, c.529G>A (p.Gly71Arg) in case #2, and c.551A>G (p.Tyr78Cys) in case #3 (Fig. 1). Amino acid sequences were conserved across subjects (Supplementary Fig. 1 in online). Using Polyphen-2 software, both novel mutations were predicted as having a damaging impact [17]. [18F]FP-CIT PET showed marked loss of dopamine transporters in 2 patients (Fig. 2). [18F]FDG-PET in case 1 showed significant glucose hypometabolism in the anterior cingulate cortex, orbitofrontal cortex, pars opercularis of the inferior frontal gyrus, and inferior parietal lobule. Metabolism of the caudate nuclei and midbrain on both sides was also decreased (Fig. 2). Analysis of MR volumetry in case #2 showed significant reduction in cortical thickness in some portions of the frontal, temporal, and parietal lobes, while cortical volume was reduced mostly in frontal regions (Table 1 and Supplementary Table 1 in online). Interestingly, cortical regions with reduced cortical thickness in case #2 are congruent with those of hypometabolism. 5. Discussion To date no cases of PS have been reported in the Korean population. Two patients in our series had novel mutations; the G67D mutation is located within and the Y78C mutation is adjacent to the CAP-Gly “GKNDG” binding motif of p150glued (Supplementary Fig. 2). The characteristic structure of the “GKNDG” binding region is critical for interaction with microtubule plus-end-tracking proteins [18]. Mutation G71R found in case #2 and the novel mutation G67D in case #1 lead to defective binding to EB1 proteins because these glycine residues cannot adopt into the correct

Fig. 1. Electropherogram showing mutations in DCTN1. Heterozygous point mutations are marked with arrows.

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Fig. 2. Functional brain imaging findings in Perry syndrome. A. [18F]FP-CIT PET of case 1 shows near complete loss of ligand binding in the striatum. This marked reduction was also noted in case 2. B. [18F]FDG-PET of case 1 demonstrated abnormal hypometabolism in certain subcortical and cortical areas. C. Regional uptake of [18F]FDG in the cerebral cortex of case 1. Significant glucose hypometabolism was observed in the inferior parietal lobule, pars opercularis of the inferior frontal gyrus, and anterior cingulate cortex.

conformation. Another novel mutation Y78C identified in case #3 causes a similar defect, but via a different mechanism. The hydrophobic cluster near Tyr78 is destroyed by the introduction of smaller, polar cysteine residues (Supplementary Fig. 2). Therefore, the identified mutations G67D, G71R, and Y78C in CAP-Gly domain of p150glued may cause a severe problem in binding with microtubule cargo proteins and subsequently, dysregulating microtubule dynamics, which is a known causative factor of PS [11]. Supranuclear gaze palsy in PS, which was first described by Newsway et al. [13] may not be a rare feature since one of our cases also had supranuclear gaze palsy. Oculogyric crisis has not been reported in PS. Oculogyric crisis is most frequently reported as a complication of short- or long-term treatment with neuroleptics or other drugs. Oculogyric crisis also can develop secondary to focal lesions in the basal ganglia or thalamus, which was excluded by MRI in our case. Tonic upward deviation of the eyes has been observed in patients with ChediakeHigashi syndrome, Rett syndrome, Tourette’s syndrome, and Wilson’s disease [19e22]. A patient with a mutation in the PARK9 gene showed both oculogyric dystonic spasm and

Table 1 Reduction of vertex cortical thickness in a patient with Perry syndrome compared to that in controls, after controlling for age. Vertex cluster-wise statistics determined by Monte Carlo simulation. Cortex Left hemisphere Rostral middle frontal Superior frontal Medial orbitofrontal Inferior parietal Superior temporal Right hemisphere Superior frontal Rostral middle frontal Caudal middle frontal Supramarginal Middle temporal a b

TalX

TalY

TalZ

Area (mm2)a

CWPb

36.0 7.8 7.0 30.0 36.7

42.8 40.3 30.2 74.0 33.8

12.3 25.8 20.9 17.6 11.2

3095.7 1890.6 1203.5 598.0 524.7

0.0001 0.0001 0.0001 0.0016 0.0040

20.8 24.6 39.3 53.9 58.5

13.9 55.2 6.1 19.6 17.8

53.2 12.8 42.0 18.5 12.0

3995.9 1485.9 541.6 507.5 2758.7

0.0001 0.0001 0.0032 0.0057 0.0001

Surface area of cluster in standardized cortical surface. Cluster-wise p-value.

supranuclear gaze palsy in which involuntary eyeball movements were reported to respond to levodopa [23]. The mechanisms underlying concurrent oculogyric crisis OGC and supranuclear gaze palsy in people with PARK9 mutations are unclear. In our case, given that there was no optokinetic nystagmus, the eyeball movements might be under supranuclear control because, we were able exclude the possibility that it might have been caused by oculogyric crisis. We suggest that neural circuits responsible for supranuclear control of eyeball movements are involved in PS. Most previous pathological data came from autopsy studies emphasizing changes in subcortical and brainstem structures rather than cortex [3e7,10]. We were able to review clinicpathological correlation by functional imaging or volumetric MRI in 2 patients with PS. PS is a form of TDP-43 proteinopathy where clinical syndromes include frontotemporal dementia and/or amyotrophic lateral sclerosis. Most autopsy studies, apart from those of a French family with atrophy in frontal and cingulate cortices, did not report cortical atrophy or TDP-43 inclusions in the cortex [11,12]. Conversely, in previous studies of [18F]FDG-PET, lateral prefrontal and temporal hypometabolism was reported [11,24], which is consistent with our findings. This discrepancy between autopsy findings and [18F]FDG-PET results is probably due to differential sensitivities of the assessments that were used. Interestingly, changes of MR volumetry in our case #2 are strikingly congruent with areas of hypometabolism shown by [18F]FDG-PET in case 1. In both cases, the orbitofrontal, dorsolateral frontal, superior and middle temporal, and inferior parietal cortices were involved. Pathological changes in the pars opercularis of the inferior frontal gyrus are probably reflected by reduced verbal fluency in case #1. We did not identify clinical correlates of change in the inferior parietal cortex because neuropsychological tests were not performed in any of our cases. Apathy and depression are known to be early symptoms of PS. Apathy in case #2 is reflected by marked hypometabolism in the anterior cingulate cortex, although it could not be demonstrated in case #3 by MR volumetry because of technical limitations. Previous reports have explained depression in PS by changes in subcortical structures, such as loss of dopaminergic projections from the ventral tegmental areas to the frontal

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cortex [1,12] and the loss of serotonergic neurons in the dorsal raphe nucleus, rather than pathological changes in the cortex [1,10,12]. A recent neuroimaging study suggests that dysfunction in the ventromedial and dorsolateral prefrontal cortex is associated with depression in a number of neurodegenerative disorders [25]. In PD, morphological and functional neuroimaging studies suggest that depression is associated with reduced activity in the prefrontal cortex (especially medial and inferior), thalamus, anterior and posterior cingulate cortex, as well as biochemical changes in subcortical structures [26]. We speculate that volumetric or metabolic changes in the frontal cortex and caudate nucleus may be associated with depression in our patients. Pathological studies have reported a marked loss of dopaminergic neurons and dopamine content in the substantia nigra and striatum [1,11]. Only 1 [18F]fluorodopa PET report has shown mild reduction of uptake rate constant in the striatum [4]. It is intriguing that our patients with PS revealed near complete loss of [18F]FP-CIT binding all over the striatum while patients showed only mild to moderate motor parkinsonism. Such a discrepancy between clinical severity of parkinsonism and striatal binding of dopaminergic ligands has been described in other disorders such as pure akinesia with gait freezing [27], POLG encephalopathy [28], and spinocerebellar ataxia type 2 [29]. Relatively mild parkinsonism in these cases could be accounted for by compensatory changes arising from postsynaptic neural circuits although the exact mechanism remains uncertain. Weight loss and respiratory failure are characteristic features of PS. However, why people with this disease lose weight and become hypoxic remains unclear from our studies and those of others. Our findings of [18F]FDG-PET with significant hypometabolism in the orbitofrontal and anterior cingulate cortex are consistent with the pattern of cortical atrophy in frontotemporal lobar degeneration, characteristically affecting the paralimbic frontaleinsularestriatal network, of which the anterior cingulate is a part [30]. In summary, we report 3 Korean cases of PS. Our findings indicate that oculomotor manifestations may not be uncommon in this disorder. As in previous pathological studies, our study shows marked degeneration of dopaminergic neurons in PS as assessed by [18F]FP-CIT PET. Contrary to previous autopsy reports, neuroimaging studies suggest that the frontotemporoparietal cortex is involved in PS. Author roles EJ Chung; Manuscript preparation, and writing of the first draft. JH Hwang; Collection of data, and drafting manuscript. MJ Lee; Collection of data, drafting manuscript. JH Hong; Analysis of DCTN1 sequence, and drafting manuscript. JK Hwan; Collection of data, and data analysis. WK Yoo; MR data analysis, and critical review of manuscript. SJ Kim; Collection of data, and critical review of manuscript. HK Song; Analysis of data, and critical review of manuscript. CS Lee; Collection of data, analysis of PET, and critical review of manuscript. MS Lee; Collection of data, and critical review of manuscript. YJ Kim; Design of this study, analysis of data, and writing the manuscript. Full financial disclosures EJ Chung; nothing to disclose. JH Hwang; nothing to disclose. MJ Lee; nothing to disclose. JH Hong; nothing to disclose. JK Hwan; nothing to disclose.

WK Yoo; nothing to disclose. SJ Kim; nothing to disclose. HK Song; nothing to disclose. CS Lee; nothing to disclose. MS Lee; nothing to disclose. YJ Kim; nothing to disclose. Acknowledgment This research was supported by basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2-10011158). And the Hallym University Research Fund, 2012 (HRF-G2012-6). Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.parkreldis.2014.01.010. References [1] Wider C, Wszolek ZK. Rapidly progressive familial parkinsonism with central hypoventilation, depression and weight loss (Perry syndrome) e a literature review. Parkinsonism Relat Disord 2008;14:1e7. [2] Farrer MJ, Hulihan MM, Kachergus JM, Dächsel JC, Stoessl AJ, Grantier LL, et al. DCTN1 mutations in Perry syndrome. Nat Genet 2009;41:163e5. [3] Perry TL, Bratty PJ, Hansen S, Kennedy J, Urquhart N, Dolman CL. Hereditary mental depression and parkinsonism with taurine deficiency. Arch Neurol 1975;32:108e13. [4] Perry TL, Wright JM, Berry K, Hansen S, Perry Jr TL. Dominantly inherited apathy, central hypoventilation, and Parkinson’s syndrome: clinical, biochemical, and neuropathologic studies of 2 new cases. Neurology 1990;40: 1882e7. [5] Roy 3rd EP, Riggs JE, Martin JD, Ringel RA, Gutmann L. Familial parkinsonism, apathy, weight loss, and central hypoventilation: successful long-term management. Neurology 1988;38:637e9. [6] Lechevalier B, Schupp C, Fallet-Bianco C, Viader F, Eustache F, Chapon F, et al. Familial parkinsonian syndrome with athymhormia and hypoventilation. Rev Neurol (Paris) 1992;148:39e46. [7] Bhatia KP, Daniel SE, Marsden CD. Familial parkinsonism with depression: a clinicopathological study. Ann Neurol 1993;34:842e7. [8] Vilarino-Guell C, Wider C, Soto-Ortolaza AI, Cobb SA, Kachergus JM, Keeling BH, et al. Characterization of DCTN1 genetic variability in neurodegeneration. Neurology 2009;72:2024e8. [9] Saka E, Topcuoglu MA, Demir AU, Elibol B. Transcranial sonography in Perry syndrome. Parkinsonism Relat Disord 2010;16:68e70. [10] Tsuboi Y, Wszolek ZK, Kusuhara T, Doh-ura K, Yamada T. Japanese family with parkinsonism, depression, weight loss, and central hypoventilation. Neurology 2002;58:1025e30. [11] Wider C, Dachsel JC, Farrer MJ, Dickson DW, Tsuboi Y, Wszolek ZK. Elucidating the genetics and pathology of Perry syndrome. J Neurol Sci 2010;289:149e54. [12] Wider C, Dickson DW, Stoessl AJ, Tsuboi Y, Chapon F, Gutmann L, et al. Pallidonigral TDP-43 pathology in Perry syndrome. Parkinsonism Relat Disord 2009;15:281e6. [13] Newsway V, Fish M, Rohrer JD, Majounie E, Williams N, Hack M, et al. Perry syndrome due to the DCTN1 G71R mutation: a distinctive levodopa responsive disorder with behavioral syndrome, vertical gaze palsy, and respiratory failure. Mov Disord 2010;25:767e70. [14] Fischl B, Dale AM. Measuring the thickness of the human cerebral cortex from magnetic resonance images. Proc Natl Acad Sci U S A 2000;97:11050e5. [15] Tzourio-Mazoyer N, Tran GT, Schwarzlmuller T, Specht K, Haugarvoll K, Balafkan N, et al. Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. NeuroImage 2002;15:273e89. [16] Oh M, Kim JS, Kim JY, Shin KH, Park SH, Kim HO, et al. Subregional pattern of preferential striatal dopamine transporter loss differs among Parkinson’s disease, progressive supranuclear palsy and multiple system atrophy. J Nucl Med 2012;53:399e406. [17] Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, et al. A method and server for predicting damaging missense mutations. Nat Methods 2010;7:248e9. [18] Bjelic S, De Groot CO, Scharer MA, Jaussi R, Bargsten K, Salzmann M, et al. Interaction of mammalian end binding proteins with CAP-Gly domains of CLIP-170 and p150(glued). J Struct Biol 2012;177:160e7. [19] Uyama E, Hirano T, Ito K, Nakashima H, Sugimoto M, Naito M, et al. Adult Chediak-Higashi syndrome presenting as parkinsonism and dementia. Acta Neurol Scand 1994;89:175e83.

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Expansion of the clinicopathological and mutational spectrum of Perry syndrome.

Perry syndrome (PS) caused by DCTN1 gene mutation is clinically characterized by autosomal dominant parkinsonism, depression, severe weight loss, and ...
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