Francesco Soleti

PINK1 heterozygous rare variants: prevalence, significance and phenotypic spectrum†‡

Heterozygous rare variants in the PINK1 gene, as well as in other genes causing autosomal recessive parkinsonism, have been reported both in patients and healthy controls. Their pathogenic significance is uncertain, but they have been suggested to represent risk factors to develop Parkinson disease (PD). The few large studies that assessed the frequency of PINK1 heterozygotes in cases and controls yielded controversial results, and the phenotypic spectrum is largely unknown. We retrospectively analyzed the occurrence of PINK1 heterozygous rare variants in over 1100 sporadic and familial patients of all onset ages and in 400 controls. Twenty patients and 6 controls were heterozygous, with frequencies (1.8% vs. 1.5%) not significantly different in the two groups. Clinical features of heterozygotes were indistinguishable to those of wild‐type patients, with mean disease onset 10 years later than in carriers of two mutations but worse disease progression. A meta‐analysis indicated that, in PINK1 heterozygotes, the PD risk is only slightly increased with a non significant odds ratio of 1.62. These findings suggest that PINK1 heterozygous rare variants play only a minor susceptibility role in the context of a multifactorial model of PD. Hence, their significance should be kept distinct from that of homozygous/compound heterozygous mutations, that cause parkinsonism inherited in a mendelian fashion.

The long-term effect of tetrabenazine in the management of Huntington disease

Objectives: To enhance the knowledge on the long-term efficacy and safety of tetrabenazine (TBZ) in managing chorea. Methods: We analyzed 68 Huntington disease patients (mean disease duration, 55.8 ± 34.7 months) who had been treated with TBZ for a mean period of 34.4 ± 25.2 months (median, 34 months; mode, 48 months; range, 3-104 months). We measured the variation from pretreatment of the motor score of Unified Huntingtons Disease Rating Scale at the first follow-up visit and at the latest. Results: Mean Unified Huntingtons Disease Rating Scale-chorea underscore at the time of the pretreatment visit was 10.4 ± 4.1 (range, 0-28). At the first follow-up, 9.7 ± 7.8 months after the prescription of TBZ (mean dose, 35.3 ± 14.7 mg), mean score of chorea was 8.2 ± 4.1 (−21% compared with baseline), whereas at the latest follow-up visit (mean dose, 57.5 ± 14.7 mg), it was 9.5 ± 5.0 (9%). During the follow-up, the clinical benefit persisted, but the magnitude was reduced despite a progressive increase of the doses (up to 60%). Motor improvement was not influenced by sex, or doses or duration of therapy; age at onset was the only predictor of a good outcome. Five patients (7%) did not gain any improvement, and TBZ was discontinued. There were 2 withdrawals because of side effects; 34 patients reported at least 1 side effect. Conclusions: Tetrabenazine was well tolerated and produced long-term improvement of motor symptoms in Huntington disease patients, although a slight reduction of benefit occurred during the course of treatment. Abbreviations: HD, Huntington disease, TBZ, tetrabenazine

Punding and computer addiction in Parkinson's disease

Punding is a stereotypical behavior in which there is an intense fascination with repetitive handling and examining of mechanical objects, such as taking apart watches and radios or arranging common objects (lining up pebbles, rocks, or other small objects). This disabling condition, different from both obsessive–compulsive disorder and mania, is probably underreported. Punding is thought to be related to dopaminergic stimulation, although only a few observations of this condition in patients with Parkinsons disease (PD) under therapy has been reported. We report a man with PD who developed an unusual, severe, repetitive behavior characterized by spending most of his time on his computer; this abnormal behavior was concomitant with the introduction of L‐dopa (400 mg per day) and was not associated to a pattern of chronic inappropriate overuse of dopaminergic medication or other psychiatric symptoms. The patient had the feeling he was forced into a disruptive and unproductive behavior, and he made several attempts to quit without succeeding.

Outcome predictors, efficacy and safety of Botox and Dysport in the long-term treatment of hemifacial spasm.

Background and purpose:  To review the clinical characteristics and the long‐term outcome of patients with hemifacial spasm (HFS) who received botulinum neurotoxin (BoNT) over the past 10 years.

Effects of stimulation of the subthalamic nucleus on naming and reading nouns and verbs in Parkinson's disease.

UNLABELLED An impairment for verbs has been described in patients with Parkinsons disease (PD), suggesting that a disruption of frontal-subcortical circuits may result in dysfunction of the neural systems involved in action-verb processing. A previous study suggested that deep brain stimulation (DBS) of the subthalamic nucleus (STN) during verb generation may affect the ability to select from many competing lexical alternatives. In this study, 12 PD patients who had undergone bilateral STN DBS and completed an 8-year follow-up and 14 matched normal controls were administered action and object naming tasks and verb and noun reading tasks. Their responses were recorded using a microphone, resulting in a signal that marked the onset of the verbal response and allowed to measure response times (RTs). Accuracy was scored manually. RESULTS Overall performance in naming (independently of stimulation): In naming task controls were faster and more accurate than PD patients. In both groups, performance (accuracy and RTs) was worse on action naming than object naming. PD patients were significantly slower than controls in naming actions. Effect of stimulation: Compared with the OFF stimulation condition, in ON stimulation condition PD patients showed improved performance on object and action naming tasks (increased accuracy, faster RTs), with a decreased number of semantic errors. Some evidence also emerged that action naming in the ON stimulation condition improved more than object naming. On noun and verb reading tasks, although accuracy was at ceiling in both groups and no significant difference was observed in RTs for nouns and verbs, PD patients were slower than controls. CONCLUSIONS Our findings suggest that STN DBS may improve lexical search in PD patients. We hypothesize that STN stimulation may facilitate the motor components involved in naming and reading tasks (increased speed of speech onset), resulting in shorter RTs in both naming and reading and, to some extent, in increased accuracy in naming due to fewer omissions (no response within the 7500 ms time limit). However, to account for greater accuracy in naming due to decreased number of semantic errors in the ON stimulation condition, we hypothesize that STN stimulation restores the activity of the corticostriatal circuits involved in selection processes of a target word among different alternatives.

Movement disorders in multiple sclerosis: Causal or coincidental association?

Despite the relatively frequent involvement of the basal ganglia and subthalamic nucleus by multiple sclerosis (MS) plaques, movement disorders (MD), other than tremor secondary to cerebellar or brainstem lesions, are uncommon clinical manifestations of MS. MD were present in 12 of 733 patients with MS (1.6%): three patients had parkinsonism, two blepharospasm, five hemifacial spasm, one hemidystonia, and one tourettism. MD in patients with MS are often secondary to demyelinating disease. Also in cases without response to steroid treatment and demyelinating lesions in critical regions, it is not possible to exclude that MD and MS are causally related.

Frequency and phenotypes of LRRK2 G2019S mutation in Italian patients with Parkinson's disease

To evaluate the frequency of the LRRK2 G2019S mutation in Italy, we tested 1,072 probands with Parkinsons disease (PD; 822 sporadic and 250 familial): 20 patients (1.9%) carried the G2019S mutation, 11 patients (1.3%) were sporadic, and 9 (4.3%) had a positive family history. Considering only probands with autosomal dominant inheritance, the G2019S frequency raises to 5.2%. All presented a typical phenotype with variable onset and shared the common ancestral haplotype. Mutation frequency raised from 1.2% in early onset PD to 4.0% in late onset PD.

Treatment with botulinum toxin in a patient with myasthenia gravis and cervical dystonia

The therapeutic use of botulinum toxin (BTX) is contraindicated in patients with disorders of neuromuscular transmission (such as myasthenia gravis [MG]). In addition to the desired effect on muscles injected with BTX, instrument investigations reveal a remote cholinergic denervation distant from the injection site, consisting of an increase in jitter, evaluated by EMG-single fiber, and mild abnormalities of autonomic fibers evaluated by cardiovascular reflexes.1,2 We report the results of repeated treatments with BTX type A (BTX-A) in a patient with an association of MG and cervical dystonia (CD). A 23-year-old woman presented in May 2002. Her medical history was unremarkable (except for right esotropia present at birth) until 1998, when she had fluctuating ptosis and diplopia, later associated with generalized weakness involving limbs and neck extensor muscles. A good response to an anti-cholinesterase injection, CMAP decrement on low-rate RNS, and increased serum anti-acetylcholine receptor antibodies led to the diagnosis of MG. The patient was treated chronically …

Lithium treatment in patients with Huntington disease and suicidal behavior.

To the EditorsCASE REPORTSIn his original description, George Huntington (1872) mentioned suicidality as one of the major features of the illness bearing his name, and subsequent studies confirmed the high rate of suicides among patients affected by Huntington disease (HD).1,2 In our Movement Disord

Lithium Treatment in Patients With Huntington's Disease and Suicidal Behavior.

ham cohort (ie, 80.5%) was similar to that in the PPMI cohort (ie, 80.6%, because 19.6% of patients with SWEDD were hyposmic), although different cutoffs were used. The best cutoff to separate PD from SWEDD in the PPMI cohort was 29 or less (of 40 items in the UPSIT), with a sensitivity of 73.5% and a specificity of 77.4%. The higher cutoff in the PPMI sample derives from its overall higher UPSIT values compared with the Nottingham sample. Indeed, when using a cutoff of 20 or less, specificity increased to 95.2%, whereas sensitivity decreased to 39.1%.