We previously reported triplication of α-synuclein in a large kindred with autosomal dominant parkinsonism1-5. Here we share videotapes of selected cases (see abbreviated pedigree, figure 1A).
Figure 1A.
Abridged pedigree. Affected individuals are shown in solid black.
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 three 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 twelve 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 expired due to pneumonia at age 49; no post-mortem 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 aged 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 two 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) 81: standing BP 86/60, 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 (Figure 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 following presentation, she has become bedridden and is severely rigid and is tube-fed. She has no spontaneous vocalizations. She is doubly incontinent and requires full-time care.
Figure 1B.
Progressive worsening of case 9-60’s constructional apraxia over a three year period.
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 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 due to orthostatic hypotension and hallucinosis. At his last examination, aged 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 marked slowness and severe postural instability, with one-person assistance. The patient was bedridden within the year, requiring tube feeding. The subject succumbed to pneumonia at age 43. Pathological examination was previously described7.
Case 9-246 (Video Segment 4)
The subject was diagnosed with Parkinson’s disease when 46 y.o. 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 described3.
Summary
This family has autosomal dominant parkinsonism due to 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 pre-symptomatic amphetamine/cocaine use in two of the cases described.
Supplementary Material
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 to the tremor. When walking, there is a markedly reduced arm swing bilaterally.
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.
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, whilst tremor is now mild.
Segment 4: Case 9-246 The subject demonstrates bradykinesis and mask facies. Asymmetric reduced arm swing is noted during gait. Walking pre-medication (at 52 seconds) demonstrates reduced arm swing and mild scissoring of gait with toe walking. Post-medication dyskinesia is apparent when retesting walking (at 67 seconds). Postural instability is noted.
Acknowledgements
Thanks to 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).
Full financial disclosures of all authors in the last year
| Katrina Gwinn |
Michael Devine |
Lee-Way Jin |
Janel Johnson |
Thomas Bird | Manfred Muenter |
Cheryl Waters | Charles Adler |
Richard Caselli |
Henry Houlden |
Grisel Lopez |
Amanda Singleton |
John Hardy | Andrew Singleton |
|
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
Stock Ownership in medically- related fields |
None | None | None | None | None | None | None | None | None | None | None | None | None | None |
| Consultancies | None | None | None | None | None | None |
Teva Pharmaceuticals |
Biogen Idec, Eli Lilly, Ipsen, Merz, MerkSerono |
None | None | None | None |
Eisai and MerkSerono Pharmaceuticals |
None |
| Advisory Boards | None | None | None | None | None | None | Teva | None | None | None | None | None | None | None |
| Partnerships | None | None | None | None | None | None | None | None | None | None | None | None | None | None |
| Honoraria | None | None | None | None |
Speaker’s Bureau, Athena Diagnostics |
None |
For speakng from GSK, Novartis, Teva, Boehringer |
None | None | None | None | None | None | None |
| Grants | None |
MRC (UK) |
None | None | None | None | None | None |
NIA/NIH (federal, none commercial) |
MRC (UK) | None | None | None | None |
|
Intellectual Property Rights |
None | None | None | None | None | None | None | None | None | None | None | None | None | None |
| Expert Testimony | None | None | None | None | None | None | None | None | None | None | None | None | None | None |
| Employment | NIH (NINDS) |
MRC (UK) |
University of California, Davis |
NIH |
VA Puget Sound Health Care System |
Retired | CU | None | Mayo Clinic | MRC (UK) | NIH | None | UCL | NIH |
| Contracts |
Project officer, NINDS DNA Repository |
None | None | None | None | None | None | None | None | None | None | None | None | None |
| Royalties | None | None | None | None |
Licensing fees, Athena Diagnostics |
None | Book | None | None | None | None | None | None | None |
| Other | None | None | None | None | None | None | None | None | None | None | None | None | None | None |
Footnotes
Financial disclosures / Conflict of interest pertaining to research herein: Nothing to disclose
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
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 to the tremor. When walking, there is a markedly reduced arm swing bilaterally.
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.
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, whilst tremor is now mild.
Segment 4: Case 9-246 The subject demonstrates bradykinesis and mask facies. Asymmetric reduced arm swing is noted during gait. Walking pre-medication (at 52 seconds) demonstrates reduced arm swing and mild scissoring of gait with toe walking. Post-medication dyskinesia is apparent when retesting walking (at 67 seconds). Postural instability is noted.