Clinical features, with video documentation, of the original familial lewy body parkinsonism caused by α‐synuclein triplication (Iowa kindred)
2011; Wiley; Volume: 26; Issue: 11 Linguagem: Inglês
10.1002/mds.23776
ISSN1531-8257
AutoresKatrina Gwinn, Michael J. Devine, Lee‐Way Jin, Janel Johnson, Thomas D. Bird, Manfred D. Muenter, Cheryl Waters, Charles H. Adler, Richard J. Caselli, Henry Houlden, Grisel Lopez, Amanda Singleton, John Hardy, Andrew Singleton,
Tópico(s)Genetic Neurodegenerative Diseases
ResumoMovement DisordersVolume 26, Issue 11 p. 2134-2136 Letters: New ObservationFull Access Clinical features, with video documentation, of the original familial lewy body parkinsonism caused by α-synuclein triplication (Iowa kindred)†‡ Katrina Gwinn MD, Katrina Gwinn MD National Institutes of Neurological Disorders and Stroke, Bethesda, Maryland, USA Katrina Gwinn and Michael J. Devine contributed equally to this work.Search for more papers by this authorMichael J. Devine, Corresponding Author Michael J. Devine m.devine@ion.ucl.ac.uk Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, United Kingdom Katrina Gwinn and Michael J. Devine contributed equally to this work.Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, United KingdomSearch for more papers by this authorLee-Way Jin MD, PhD, Lee-Way Jin MD, PhD University of Washington, Seattle, Washington, USASearch for more papers by this authorJanel Johnson BA, Janel Johnson BA National Institutes of Neurological Disorders and Stroke, Bethesda, Maryland, USASearch for more papers by this authorThomas Bird MD, Thomas Bird MD University of Washington, Seattle, Washington, USASearch for more papers by this authorManfred Muenter MD, Manfred Muenter MD Mayo Clinic, Scottsdale, Arizona, USASearch for more papers by this authorCheryl Waters MD, Cheryl Waters MD Columbia University College of Physicians and Surgeons, New York, New York, USASearch for more papers by this authorCharles H. Adler MD, PhD, Charles H. Adler MD, PhD Mayo Clinic, Scottsdale, Arizona, USASearch for more papers by this authorRichard Caselli MD, Richard Caselli MD Mayo Clinic, Scottsdale, Arizona, USASearch for more papers by this authorHenry Houlden MD, PhD, Henry Houlden MD, PhD Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, United KingdomSearch for more papers by this authorGrisel Lopez MD, Grisel Lopez MD National Human Genome Research Institute, Bethesda, Maryland, USASearch for more papers by this authorAmanda Singleton BS, Amanda Singleton BS National Institutes of Neurological Disorders and Stroke, Bethesda, Maryland, USASearch for more papers by this authorJohn Hardy PhD, John Hardy PhD Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, United KingdomSearch for more papers by this authorAndrew Singleton PhD, Andrew Singleton PhD National Institute for Aging, Bethesda Marylandd, USASearch for more papers by this author Katrina Gwinn MD, Katrina Gwinn MD National Institutes of Neurological Disorders and Stroke, Bethesda, Maryland, USA Katrina Gwinn and Michael J. Devine contributed equally to this work.Search for more papers by this authorMichael J. Devine, Corresponding Author Michael J. Devine m.devine@ion.ucl.ac.uk Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, United Kingdom Katrina Gwinn and Michael J. Devine contributed equally to this work.Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, United KingdomSearch for more papers by this authorLee-Way Jin MD, PhD, Lee-Way Jin MD, PhD University of Washington, Seattle, Washington, USASearch for more papers by this authorJanel Johnson BA, Janel Johnson BA National Institutes of Neurological Disorders and Stroke, Bethesda, Maryland, USASearch for more papers by this authorThomas Bird MD, Thomas Bird MD University of Washington, Seattle, Washington, USASearch for more papers by this authorManfred Muenter MD, Manfred Muenter MD Mayo Clinic, Scottsdale, Arizona, USASearch for more papers by this authorCheryl Waters MD, Cheryl Waters MD Columbia University College of Physicians and Surgeons, New York, New York, USASearch for more papers by this author … See all authors First published: 08 June 2011 https://doi.org/10.1002/mds.23776Citations: 27 † Relevant conflicts of interest/financial disclosures: Nothing to report. ‡ Full financial disclosures and author roles may be found in the online version of this article. AboutFiguresReferencesRelatedInformationPDFSections Case 9-77 (Video Segment 1) Case 9-60 (Video Segment 2) Case 9-70 (Video Segment 3) Case 9-246 (Video Segment 4) Summary Legends to the Video Acknowledgements Author Roles:Supporting InformationReferencesCiting LiteraturePDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessClose modalShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL We previously reported triplication of α-synuclein in a large kindred with autosomal dominant parkinsonism.1-5 Here we share videotapes of selected cases (see abbreviated pedigree in Fig. 1A). Figure 1Open in figure viewerPowerPoint A: Abridged pedigree. Affected individuals are shown in solid black. B: Progressive worsening of case 9-60′s constructional apraxia over a 3-year period. Case 9-77 (Video Segment 1) This woman noted insidious, progressive right upper extremity (RUE) resting and activation tremor and stiffness at age 30. She noted parasomnias suggesting REM behavior disorder (RBD) and depression several years prior to motor symptoms. Handwriting became small and tremulous. She also experienced urinary urgency. Examination (age 32) revealed RUE resting and activation tremor and cogwheel rigidity. She was diagnosed with Parkinson's disease (PD) and treated with carbidopa/levodopa with good response, although dyskinesias occurred within 3 years. Subsequently, ropinirole gave some benefit (Video Segment 1). Neuropsychometry (age 32) found no abnormalities. However, by age 41, there was significant reduction in IQ, working memory, executive functioning, visuospatial processing, and psychomotor speed. Donepezil was prescribed with some cognitive improvement. She was bedridden in 12 years. She suffered auditory and visual hallucinations, parasomnias, restless legs symptoms, and intermittent myoclonus. On her last examination (49 years), she exhibited severe bradykinesis and rigidity with contractures. Hypophonia limited mental status testing; however, audible speech content was appropriate. Eye movements remained full, but pursuits were severely saccadic. There was no tremor. Myoclonus was intermittent. She died due to pneumonia at age 49; no postmortem examination was done. Case 9-60 (Video Segment 2) This otherwise healthy woman with a history of methamphetamine abuse during her third and fourth decades was fired at age 44 for physical and mental "slowness." She was treated for depression with some benefit, but the motor problems persisted. Within 18 months, she noted activation tremor and symptoms of RBD. By age 46 her cognition and movement would fluctuate over hours/days. Her weight decreased from 130 to 100 pounds over the first 2 years of her illness. She had spontaneous visual and auditory hallucinations and complained of orthostatic dizziness. Carbidopa/levodopa gave moderate benefit in bradykinesis, donepezil improved cognitive fluctuations, clonazepam helped the RBD, and midodrine ameliorated orthostatic hypotension. Nonetheless, confusion mandated 24-hour care. On examination, sitting blood pressure (BP) was 98/67, and pulse (P) was 81; standing BP was 86/60 and P 90. Folstein Mini–Mental Status Examination score was 13/30, with particular difficulty on recall and sequential tasks. She scored 14 on the controlled oral word association test and 16/63 on the Beck Depression Inventory. She had marked constructional difficulties (Fig. 1B). She could not count backwards from 100, 20, or 12. She had anosmia (14/40, University of Pennsylvania Smell Identification Test). There was marked hypophonia, saccadic pursuits, and moderately masked facies. She had difficulty with rapid alternating movements. Gait was shuffling. She needed several corrective steps on the pull test. In the decade since presentation, she has become bedridden, is severely rigid, and is tube-fed. She has no spontaneous vocalizations. She is doubly incontinent and requires full-time care. Case 9-70 (Video Segment 3) This man noted the gradual onset of RUE resting and activation tremor at age 24. Tremor was worsened by anxiety and by intravenous cocaine, which he used prior to and during the first year of illness. Within that year, he suffered depression and attempted suicide; by age 34 he was being treated with fluoxetine, with good response. Parkinsonian symptoms progressed, with worsening tremor, rigidity, gait difficulties, and postural instability. Carbidopa/levodopa gave dramatic benefit but was discontinued several years later because of orthostatic hypotension and hallucinosis. At his last examination, at age 39 (Video Segment 3), he had severe bradykinesis and hypophonia; mental status testing was not possible. Eye movements were severely saccadic; there was severe rigidity throughout and no tremor. He could stand and walk with 1-person assistance, showing marked slowness and severe postural instability. The patient was bedridden within the year, requiring tube feeding. The subject succumbed to pneumonia at age 43. Pathological examination was previously described.6 Case 9-246 (Video Segment 4) The subject was diagnosed with Parkinson's disease when 46 years old, with complaints of slowed gait and right shoulder pain.3 She responded well to carbidopa/levodopa treatment initially. Subsequently motor fluctuations and postural instability developed. She developed "toe walking," cognitive impairment, and orthostatic hypotension and thereafter became wheelchair- and subsequently bed-bound. She succumbed after 6 years. Pathological examination has been previously described.3 Summary This family has autosomal dominant parkinsonism because of α-synuclein triplication. Dopamine-responsive parkinsonism, cognitive difficulties, RBD, and dysautonomia are common. End-stage illness includes contractures, myoclonus, and severe motor and cognitive impairment. Of note, there was presymptomatic amphetamine/cocaine use in 2 of the cases described. Legends to the Video Video Segment 1—Case 9-77. This subject has facial hypomimia (lips apart, reduced blinking), with rapid resting tremor of right arm and adduction tremor of both legs. There is bradykinesia of repetitive finger- and foot tapping bilaterally, also affecting rapid alternating movements, left more than right, which also reveals an activation component of the tremor. When walking, there is a markedly reduced arm swing bilaterally. Video Segment 2—Case 9-60. This subject exhibits facial hypomimia and fairly symmetric, marked bradykinesis, particularly evident during finger tapping. The clock test is abnormal. Apraxia manifests on testing of rapid alternating movements. When walking, her trunk is bent forward, and arm swing is reduced bilaterally, more so on the left. Video Segment 3—Case 9-70. This patient, at an advanced stage of disease, has marked facial hypomimia, with the mouth open and markedly reduced eye blinking. Hands are dystonic, more so on the right. He has severe bradykinesia, whereas tremor is now mild. Video Segment 4—Case 9-246. The subject demonstrates bradykinesis and mask facies. Asymmetric reduced arm swing is noted during gait. Walking premedication (at 52 seconds) demonstrates reduced arm swing and mild scissoring of gait with toe walking. Postmedication dyskinesia is apparent when retesting walking (at 67 seconds). Postural instability is noted. Acknowledgements We thank the family members who have been dedicated to this and other research into familial parkinsonism. Cell lines and DNA are anonymously available from this kindred from the NIGMS Repository (http://locus.umdnj.edu/nigms, case 60=GM15010, case 70=GM15009). Author Roles: Katrina Gwinn evaluated cases 9-58, 9-60, 9-70, 9-77, and 9-430, researched and built the pedigree, performed clinical and video documentation, and drafted the manuscript. Michael J. Devine reviewed and edited videos and drafted and submitted the manuscript. Lee-Way Jin carried out pathological diagnosis of case 9-70. Janel Johnson helped in family collection and mutation analysis. Thomas Bird carried out clinical investigations on case 9-70 and other family members. Henry Houlden performed clinical evaluation and fibroblast sampling of case 9-60. Manfred Muenter evaluated cases 9-58, 9-60, 9-70, and 9-77, built the pedigree, and performed clinical and video documentation. Grisel Lopez performed clinical evaluation of case 9-60 and IRB documentation. Cheryl Waters evaluated case 9-246 and did clinical and video documentation. Charles H. Adler evaluated cases 9-70 and 9-77 and did clinical and video documentation. Richard Caselli evaluated cases 9-70, 9-77 and did neuropsychometric testing interpretation. Amanda Singleton was the research coordinator of clinical and video evaluation. John Hardy obtained funding and drafted the manuscript. Andrew Singleton supervised mutation analysis Financial Disclosures: Katrina Gwinn is employed by NIH (NINDS) and is Project officer, of the NINDS DNA Repository. Michael Devine has grants from and is employed by MRC (UK). Lee-Way Jin is employed by the University of California, Davis. Janel Johnson is employed by the NIH. Thomas Bird has received honoraria from the Speaker's Bureau, Athena Diagnostics, is employed by VA Puget Sound Health Care System, and receives royalties for licensing fees, Athena Diagnostics. Manfred Muenter is retired. Cheryl Waters is a consultant for Teva Pharmaceuticals, has received honoraria for speaking from GSK, Novartis, Teva, and Boehringer, and is employed by CU. Charles Adler is a consultant for Biogen Idec, Eli Lilly, Ipsen, Merz, and MerkSerono. Richard Caselli has received grants from NIA/NIH (federal, none commercial) and is employed by the Mayo Clinic. Henry Houlden has received grants from and is employed by MRC (UK). John Hardy is a consultant for Eisai and MerkSerono Pharmaceuticals. Grisel Lopez, Amanda Singleton, and Andrew Singleton have nothing to declare. Supporting Information Additional Supporting Information may be found in the online version of this article. Filename Description MDS_23776_sm_suppinfoSg1.m4v9 MB Supporting Information MDS_23776_sm_suppinfoSg2.m4v15.5 MB Supporting Information MDS_23776_sm_suppinfoSg3.m4v12 MB Supporting Information MDS_23776_sm_suppinfoSg4.m4v15.5 MB Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. References 1 Singleton AB, Farrer M, Johnson J, et al. alpha-Synuclein locus triplication causes Parkinson's disease. Science. 2003; 302: 841. 2 Spellman GG. Report of familial cases of parkinsonism. Evidence of a dominant trait in a patient's family. JAMA. 1962; 179: 372– 374. 3 Waters CH, Miller CA. Autosomal dominant Lewy body parkinsonism in a four-generation family. Ann Neurol. 1994; 35: 59– 64. 4 Muenter MD, Forno LS, Hornykiewicz O, et al. Hereditary form of parkinsonism—dementia. Ann Neurol. 1998; 43: 768– 781. 5 Farrer M, Gwinn-Hardy K, Muenter M, et al. A chromosome 4p haplotype segregating with Parkinson's disease and postural tremor. Hum Mol Genet. 1999; 8: 81– 85. 6 Gwinn-Hardy K, Mehta ND, Farrer M, et al. Distinctive neuropathology revealed by alpha-synuclein antibodies in hereditary parkinsonism and dementia linked to chromosome 4p. Acta Neuropathol. 2000; 99: 663– 672. Katrina Gwinn MD*, Michael J. Devine , Lee-Way Jin MD, PhD , Janel Johnson BA*, Thomas Bird MD , Manfred Muenter MD§, Cheryl Waters MD¶, Charles H. Adler MD, PhD§, Richard Caselli MD§, Henry Houlden MD, PhD , Grisel Lopez MD**, Amanda Singleton BS*, John Hardy PhD , Andrew Singleton PhD , * National Institutes of Neurological Disorders and Stroke, Bethesda, Maryland, USA, Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square London, United Kingdom, University of Washington, Seattle, Washington, USA, § Mayo Clinic, Scottsdale, Arizona, USA, ¶ Columbia University College of Physicians and Surgeons, New York, New York, USA, ** National Human Genome Research Institute, Bethesda, Maryland, USA, National Institute for Aging, Bethesda, Maryland, USA. Citing Literature Volume26, Issue11September 2011Pages 2134-2136 FiguresReferencesRelatedInformation RecommendedRapidly progressive diffuse Lewy body diseaseCarles Gaig MD, Francesc Valldeoriola MD, PhD, Ellen Gelpi MD, PhD, Mario Ezquerra PhD, Sara Llufriu MD, Mariateresa Buongiorno MD, Maria Jesús Rey MD, PhD, Maria Jose Martí MD, PhD, Francesc Graus MD, PhD, Eduardo Tolosa MD, PhD, Movement DisordersMultiple organ involvement by alpha‐synuclein pathology in Lewy body disordersEllen Gelpi MD, Judith Navarro-Otano MD, Eduardo Tolosa MD, PhD, Carles Gaig MD, Yaroslau Compta MD, María Jesús Rey MD, Maria José Martí MD, Isabel Hernández MD, Francesc Valldeoriola MD, Ramon Reñé MD, Teresa Ribalta MD, Movement DisordersFulminant Lewy body diseaseIsabelle Momjian-Mayor MD, Gian Paolo Pizzolato MD, Karim Burkhardt MD, Theodor Landis MD, Alessandra Coeytaux MD, Pierre R. Burkhard MD, Movement DisordersParkinson's disease and α-synuclein expressionMichael J. Devine MB, BS, Katrina Gwinn MD, Andrew Singleton PhD, John Hardy PhD, Movement DisordersAlpha‐synuclein dysfunction in Lewy body diseasesGeorge K. Tofaris MD, PhD, Maria Grazia Spillantini PhD, Movement Disorders
Referência(s)