Supplemental data
Short illustrative descriptions of four patients carrying the C9ORF72intermediate-length expansions.
Case 1.
A 78 year old woman came the first time to our observation fifteen years ago. The patient had extrapyramidal signs with moderate bilateral and symmetric rigidity, bradykinesia, and resting tremor on the right hand.Cognitive functions and brain MRIwere normal.She was diagnosed as typical PD, with Hoehn and Yahr (H/Y) stage of II-III. The patient was treated with levodopa/benserazide 100/25 mg q.i.d. with discrete response. Her family history was positive for parkinsonism with dementia with or without psychiatric disorders.
Five years later, she had minor response to levodopa, worse rigidity and bradykinesia, increasing postural instability and initial dysarthria and dysphagia. Cognitive status was still normal (MMSE = 29) .
After ten years of history, rigidity, bradykinesia, balance disorders and bulbar symptoms worsened and also evident pyramidal spasticity was present.
Atrecent follow-up visit, the patient showed a severe muscular hypertonia with both pyramidal and extrapyramidal features; marked gait disorder needing bilateral support was also present. Anarthria was complete and dysphagiawas treated two years before with a percutaneous endoscopic gastrostomy (PEG). Cognitive status was relatively preserved, while no autonomic disorders weredetected.
The patient was thus considered asnon-classical atypical Parkinsonism without dementia, not being able to be diagnosed with MSA P variant.Genetic screening documented the presence of 20 repeats in the hexanucleotide repeat expansion of the C9ORF72 gene.
Case 2.
A 89 year oldwoman presented about 13 years ago with bilateral rigidity, tremor and slowness of movement, predominant on the right side of the body. The diagnosis wasof typical PD inH/Y stage II with good cognitive status(MMSE of 28/30). Her family history was negative for dementia orextrapyramidal disorders. The patient was initially treated with levodopa-benserazide 100/25 mg, qid with good response.
After five years of good pharmacological response, she manifested signs of wearing-off phenomenon, unpredictable off periodsand moderate dyskinesias in on-phase.
This condition resulted in an increase of the daily doses of levodopa-benserazidebut a worsening of dyskinesias and unpredictable off periods were noted.
For this reason, the treating physician added 6 mg/day of ropinirole, which led to disturbing acute delusional-hallucinatory psychosis that lasted about three weeks. Because of this psychosis ropinirole was quickly stopped and quetiapine (50 mg/day), was administered..
After1 month, this psychosis was totally resolved. At the time cognitive functions were quite preserved with MMSE of 27/30.The clinical course of this patient wastypical PD with excellent response to levodopa. Genetic screening documented the presence of 22repeats in the hexanucleotide repeat expansion of the C9ORF72 gene.
Case 3
A 75 year oldwoman, came to our observation about 4 years ago. Neurological examination showed diffused rigidity with bradykinesia, hypomimia, camptochormic posture, reduction ofarm synkinesis during walk and conceptual slowing. The diagnosiswere compatible with a rigid-akinetic variant of Parkinson's disease in H/Y stage III.In addition, the patient presented apathy, anhedonia, anxiety, obsessive ideas and sometimes shaking. The neuropsychological assessment documented an MMSE score of 19, verbal long and short-term memory impairment, attentional-executive and visuo-spatial dysfunctions, in accordance with a diagnosis of mild-moderate dementia. Family history was negative for parkinsonism and/or dementia, but two sisters were treated for severe depression. The patient was treated with levodopa-benserazide 100/25 mg qid, with mild benefit, making doubt the diagnosis of PD with dementia.
This was in agreement with the patient's personal history that started about 7 years before with a clinical picture of clear psychosis characterised by serious visual hallucinations (vision of large animals with offensive and written for her dishonour and threatening towards him) and related delusional ideas.
The psychosis, defined by the psychiatrists as "schizo-affective psychosis late onset", was lived by the patient with significant suffering, anxiety, agitation and without insight.
The delusional-hallucinatory framework is now disappeared from several years, and the clinical picture is dominated by dementia and parkinsonism little responsive to levodopa, from apathy and anhedonia, and pathological anxiety with obsessive ideas. Genetic study has documented the presence of 23 repetitions of the hexanucleotide of C9ORF72.
Case 4
A 77-year-old woman came to our observation about 10-year ago. At the time of our first assessment, she was diagnosed as PD in stage II-III of H/Y; her MMSE was 26/30 and the Hamilton Depression Scale was 18, compatible with mild depression. Anxiety was also present. The patient presented rigidity and bradykinesia predominantly on the left-side,had depressive symptoms for many years and was under therapy with Clomipramine 75 mg at day.Her family history was positive for parkinsonism andcognitive disorders.
The patient was treated early with levodopa/carbidopa 100/25 mg qid, with discrete benefit. Over the next two years, a slow worsening of rigidity and bradykinesia was observed, with a progressive loss of interest in usual activities at home, with apathy, mixed anxiety and depression. Every physical and mental commitment to the patient became a serious obstacle to be overcome and the major cause of his suffering.
After 6 years, this clinical picture was well defined, with both motor and affective symptomatology poorly responsive to dopaminergic and antidepressant therapy. At the moment, the clinical status of the patient is consolidated with these symptoms: severe widespread plastic stiffness, apathy and anhedonia, depression and cognitive impairment. Now her H/Y stage in off-phase is IV-V.
The patient is still followed at our movement disorders center , but response to dopaminergic therapy in minimal.Genetic study has documented the presence of 28 repetitions of the hexanucleotide of C9ORF72 gene.