Antonio E. Elia

PINK1 mutations are associated with sporadic early-onset parkinsonism.

We have recently reported homozygous mutations in the PINK1 gene in three consanguineous families with early‐onset parkinsonism (EOP) linked to the PARK6 locus. To further evaluate the pathogenic role of PINK1 in EOP and to draw genotype–phenotype correlates, we performed PINK1 mutation analysis in a cohort of Italian EOP patients, mostly sporadic, with onset younger than 50 years of age. Seven of 100 patients carried missense mutations in PINK1. Two patients had two PINK1 mutations, whereas in five patients only one mutation was identified. Age at onset was in the fourth‐fifth decade (range, 37–47 years). The clinical picture was characterized by a typical parkinsonian phenotype with asymmetric onset and rare occurrence of atypical features. Slow progression and excellent response to levodopa were observed in all subject. Two of 200 healthy control individuals also carried one heterozygous missense mutation. The identification of a higher number of patients (5%) than controls (1%) carrying a single heterozygous mutation, along with previous positron emission tomography studies demonstrating a preclinical nigrostriatal dysfunction in PARK6 carriers, supports the hypothesis that haploinsufficiency of PINK1, as well as of other EOP genes, may represent a susceptibility factor toward parkinsonism. However, the pathogenetic significance of heterozygous PINK1 mutations still remains to be clarified. Ann Neurol 2004;56:336–341

EFNS guidelines on diagnosis and treatment of primary dystonias

Objectives:  To provide a revised version of earlier guidelines published in 2006.

The PINK1 phenotype can be indistinguishable from idiopathic Parkinson disease.

Mutations in the PINK1 gene cause autosomal recessive parkinsonism characterized by early onset and a variable phenotypic presentation. A patient homozygous for the Ala168Pro mutation has been fully characterized clinically. Apart from onset at age 39 years and the excellent and sustained response to levodopa, all clinical and laboratory features, including SPECT and assessment of autonomic function, were indistinguishable from typical idiopathic Parkinson disease.

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.

Phenotypic Characterisation of Autosomal Recessive PARK6-Linked Parkinsonism in Three Unrelated Italian Families

The clinical features of nine patients (three women and six men) affected by PARK6‐linked parkinsonism, belonging to three unrelated Italian families, are reported. The occurrence of affected men and women within one generation suggested an autosomal recessive mode of inheritance in all three families. Mean age at disease onset was 36 ± 4.6 years; all cases except one presented with asymmetrical signs, consisting of tremor and akinesia of one upper limb or unilateral short step gait. Affected individuals had a mean age of 57 ± 8.5 years, and average disease duration was 21 ± 7.8 years. Parkinsonian features included benign course, early onset of drug‐induced dyskinesias, and a good and persistent response to levodopa. There were no other associated features (i.e., pyramidal or cerebellar signs, dysautonomia, or diurnal fluctuations unrelated to drug treatment). Cognition was unaffected. The clinical picture was remarkably similar in all patients; no relevant family‐related differences were found. PARK6 disease is a new form of early‐onset parkinsonism without other atypical clinical features.

Tauroursodeoxycholic acid in the treatment of patients with amyotrophic lateral sclerosis

Tauroursodeoxycholic acid (TUDCA) is a hydrophilic bile acid that is produced in the liver and used for treatment of chronic cholestatic liver diseases. Experimental studies suggest that TUDCA may have cytoprotective and anti‐apoptotic action, with potential neuroprotective activity. A proof of principle approach was adopted to provide preliminary data regarding the efficacy and tolerability of TUDCA in a series of patients with amyotrophic lateral sclerosis (ALS).

Treatment of essential tremor: A systematic review of evidence and recommendations from the Italian Movement Disorders Association

Essential tremor (ET) is one of the most common movement disorders of adults, characterized by postural and kinetic tremor. It often causes embarrassment and more rarely serious disability, requiring treatment. To assess the current state of knowledge on ET therapy and produce recommendations based on the analysis of evidence the authors reviewed the literature regarding pharmacologic and surgical therapies, providing a quality assessment of the studies and the strength of recommendations for each treatment. A committee of experts selected clinical-based questions to guide the search. A systematic literature review was performed to identify all the studies conducted on patients with ET published until September 2010. Articles were classified according to GRADE evidence profile, a system for grading the quality of evidence and the strength of recommendation based on the quality of the studies. The quality of evidence was often rated as “low” or “very low” for the studies analyzed. Propranolol, long-acting propranolol, primidone, and topiramate are recommended as first-line therapy, with restrictions for their side effects. Arotinolol, sotalol, ICI 118.551 and LI 32.468 (experimental drugs), zonisamide, gabapentin, alprazolam, clozapine, and olanzapine are recommended as a second-line treatment. Botulinum toxin type A and thalamic deep-brain stimulation are recommended for refractory ET. The results highlight the need of well-designed direct comparison trials aimed at evaluating relative effectiveness and safety of the drugs currently used in clinical practice. Furthermore, additional controlled clinical trials are required to define other possible treatment strategies for ameliorating the management of ET.

In Vivo Evidence for GABAA Receptor Changes in the Sensorimotor System in Primary Dystonia

Preclinical and clinical evidence suggests that impaired gamma‐aminobutyric (GABA) control, leading to disinhibition within the sensorimotor system, might play a role in dystonia. Aim of this study is the in vivo assessment of the GABAergic system in dystonia using positron emission tomography (PET) and 11C‐flumazenil, a selective GABAA receptor ligand.

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.

Non-DYT1 Early-Onset Primary Torsion Dystonia: Comparison with DYT1 Phenotype and Review of the Literature

To investigate the clinical features of early‐onset primary torsion dystonia (EO‐PTD), 57 consecutive genetically characterized patients with onset before 21 years were studied. Sex, ethnic origin, family history of dystonia, age at onset, disease duration, site of dystonia onset and distribution at latest examination, dystonia progression, time to generalization, and motor disability were noted. The 14 patients (25%) with GAG deletion (904_906/907_909delGAG) in the DYT1 gene were compared with the remaining non‐DYT1 patients. Cranial involvement was present in 49% of non‐DYT1 cases, but only 14% of DYT1 cases; non‐DYT1 patients were younger at time of generalization. DYT1 cases had features similar to sporadic non‐DYT1 cases but differed markedly from familial non‐DYT1 cases, the latter having later age at onset, less common limb onset, more frequent cervical involvement, and slower progression than DYT1 PTD. These findings indicate that non‐DYT1 forms of EO‐PTD differ clinically from those of DYT1 forms. Cranial involvement before 21 years of age is the strongest predictor of non‐DYT1 status. Positive family history and cervical involvement are associated with less severe progression in non‐DYT1 forms.