Allison Brashear

Mutations in the Na+/K+-ATPase α3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism

Rapid-onset dystonia-parkinsonism (RDP, DYT12) is a distinctive autosomal-dominant movement disorder with variable expressivity and reduced penetrance characterized by abrupt onset of dystonia, usually accompanied by signs of parkinsonism. The sudden onset of symptoms over hours to a few weeks, often associated with physical or emotional stress, suggests a trigger initiating a nervous system insult resulting in permanent neurologic disability. We report the finding of six missense mutations in the gene for the Na+/K+ -ATPase alpha3 subunit (ATP1A3) in seven unrelated families with RDP. Functional studies and structural analysis of the protein suggest that these mutations impair enzyme activity or stability. This finding implicates the Na+/K+ pump, a crucial protein responsible for the electrochemical gradient across the cell membrane, in dystonia and parkinsonism.

Rapid-onset dystonia-parkinsonism.

We studied a large family with a previously undescribed, autosomal dominant dystonia-parkinsonism syndrome. We chose to call the disorder “rapid-onset dystonia-parkinsonism” (RDP) based on the unusually rapid evolution of signs and symptoms. Affected individuals developed dystonia and parkinsonism between 14 and 45 years of age. The onset was acute in six individuals with the abrupt onset of symptoms over the course of several hours, and subacute in four others who had evolution over several days or weeks. Thereafter, progression of symptoms was usually very slow. Two had intermittent focal dystonia without parkinsonism, and one obligate gene carrier was asymptomatic at 68 years. CSF levels of homovanillic acid were decreased in the two individuals tested, but dopaminergic therapy provided only slight benefit. The DYT1 gene responsible for early-onset, generalized idiopathic torsion dystonia in Jewish and some non-Jewish families has been mapped to chromosome 9q34. Linkage analysis with three markers near the DYT1 gene showed several obligate recombinations, excluding DYT1 as a candidate gene for RDP. We believe RDP is unique and should be classified separately from other forms of hereditary dystonia-parkinsonism.

Distinct neurological disorders with ATP1A3 mutations

Genetic research has shown that mutations that modify the protein-coding sequence of ATP1A3, the gene encoding the α3 subunit of Na(+)/K(+)-ATPase, cause both rapid-onset dystonia parkinsonism and alternating hemiplegia of childhood. These discoveries link two clinically distinct neurological diseases to the same gene, however, ATP1A3 mutations are, with one exception, disease-specific. Although the exact mechanism of how these mutations lead to disease is still unknown, much knowledge has been gained about functional consequences of ATP1A3 mutations using a range of in-vitro and animal model systems, and the role of Na(+)/K(+)-ATPases in the brain. Researchers and clinicians are attempting to further characterise neurological manifestations associated with mutations in ATP1A3, and to build on the existing molecular knowledge to understand how specific mutations can lead to different diseases.

Botulinum neurotoxin versus tizanidine in upper limb spasticity: a placebo-controlled study

Background: While spasticity is commonly treated with oral agents or botulinum neurotoxin (BoNT) injection, these treatments have not been systematically compared. Methods: This study performed a randomised, double-blind, placebo-controlled trial to compare injection of BoNT-Type A into spastic upper limb muscles versus oral tizanidine (TZD), or placebo, in 60 subjects with upper-limb spasticity due to stroke or traumatic brain injury (TBI). Wrist flexors were systematically injected, while other upper limb muscles were injected as per investigator judgement. Participants were randomised into three groups: (1) intramuscular BoNT plus oral placebo; (2) oral TZD plus intramuscular placebo; (3) intramuscular placebo plus oral placebo. The primary outcome was the difference in change in wrist flexor modified Ashworth score (MAS) between groups. Other outcome measures included MAS at elbow and finger joints, Disability Assessment Scale (DAS) and adverse events (AE). Results: BoNT produced greater tone reduction than TZD or placebo in finger and wrist flexors at week 3 (p<0.001 vs TZD; p<0.02 vs placebo) and 6 (p = 0.001 vs TZD; p = 0.08 vs placebo), and greater improvement in the cosmesis domain of the DAS at week 6 (p<0.01). TZD was not superior to placebo in tone reduction at either time point (p⩾0.09). The incidence of AE related to study treatment was higher with TZD than in the BoNT (p<0.01) or placebo groups (p = 0.001). Conclusions: BoNT is safer and more effective than TZD in reducing tone and disfigurement in upper-extremity spasticity, and may be considered as first-line therapy for this disorder.

Long-term efficacy and safety of botulinum toxin type A (Dysport) in cervical dystonia

The aim of this study was to evaluate the efficacy and safety of intramuscular (IM) administration of botulinum toxin type A (Dysport((R)), Ipsen Biopharm Ltd.) for the treatment of cervical dystonia (CD) and the long-term safety and efficacy of repeated treatments. During the randomized, double-blind, placebo-controlled phase patients were randomized to 500 units Dysport (n = 55) or placebo (n = 61). Efficacy assessments included the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total and subscale scores, visual analogue scale (VAS) for pain, subject/investigators VAS for symptom assessments. Patients completing the double-blind treatment could enter an open-label extension phase and receive up to 4 additional Dysport treatments. Dysport produced a significant decrease from baseline in mean (+/-SE) TWSTRS total scores compared with placebo at Week 4 (primary efficacy endpoint; -15.6 +/- 2.0 vs. -6.7 +/- 2.0; p < 0.001) with significant improvements sustained to Week 12 (p = 0.019). Dysport also produced significant improvements in TWSTRS subscale scores, VAS pain scores, and subject/investigators VAS symptom assessments compared to placebo. The mean duration of open-label study participation was 51.9 weeks (range 3.9-94.0 weeks). During open-label treatment, all treatment cycles resulted in improvements in mean TWSTRS total and subscale scores at Week 4 post-treatment; greatest improvement was seen in cycle 1. The mean duration between treatment cycles was 15-17 weeks. Dysport demonstrated a good long-term safety profile; most adverse events were mild or moderate and typical of the known safety profile of Dysport in this indication. These results confirm that Dysport (500 units) is safe, effective, and well-tolerated in patients with CD.

Cross-national interrater agreement on the clinical diagnostic criteria for dementia.

We assessed the interobserver agreement on the clinical diagnosis of dementia syndrome and dementia subtypes as part of a cross-national project on the prevalence of dementia. Fourteen clinicians from the participating countries (Canada, Chile, Malta, Nigeria, Spain, and the United States) independently assessed the diagnosis of 51 patients whose clinical information was in standard records written in English. We used the DSM-III-R and ICD-10 criteria for dementia syndrome, the NINCDS-ADRDA criteria for Alzheimers disease (AD), and the ICD-10 criteria for other dementing diseases, and measured interobserver agreement. We found comparable levels of agreement on the diagnosis of dementia using the DSM-III-R (K = 0.67) as well as the ICD-10 criteria (K = 0.69). Cognitive impairment without dementia was a major source of disagreement (K = 0.10). The kappa values were 0.58 for probable AD, 0.12 for possible AD, and rose to 0.72 when the two categories were merged. The interrater reproducibility of the diagnosis of vascular dementia was 0.66 in terms of kappa index; the diagnoses of other dementing disorders as a whole reached a kappa value of 0.40. This study suggests that clinicians from different cultures and medical traditions can use the DSM-III-R and the ICD-10 criteria for dementia effectively and thus reliably identify dementia cases in cross-national research. The interrater agreement on the diagnosis of dementia might be improved if clear-cut guidelines in the definition of cognitive impairment are provided. To improve the reliability of AD diagnosis in epidemiologic studies, we suggest that the NINCDS-ADRDA “probable” and “possible” categories be merged.

Clinico-immunologic aspects of botulinum toxin type B treatment of cervical dystonia

In this multicenter study of 100 patients with cervical dystonia, we examined the immunogenicity of botulinum toxin type B (BTX-B) and correlated the clinical response with the presence of blocking antibodies (Abs) using a novel mouse protection assay. One-third of the patients who were negative for BTX-B Abs at baseline became positive for BTX-B Abs at last visit. Thus, the high antigenicity of BTX-B limits its long-term efficacy.

Rapid-onset dystonia-parkinsonism: linkage to chromosome 19q13.

Rapid‐onset dystonia–parkinsonism (RPD) is an autosomal dominant movement disorder characterized by sudden onset of persistent dystonia and parkinsonism, generally during adolescence or early adulthood. Symptoms evolve over hours or days, and generally stabilize within a few weeks, with slow or no progression. Other features include little or no response to L‐dopa, and low levels of homovanillic acid in the central nervous system. Neuroimaging studies indicate no degeneration of dopaminergic nerve terminals in RDP, suggesting that this disorder results from a functional deficit, as in dystonia, rather than neuronal loss, as in Parkinsons disease. We studied 81 members of two midwestern US families with RDP, 16 of whom exhibited classic features of RDP. We found significant evidence for linkage in these two families to markers on chromosome 19q13, with the highest multipoint LOD score at D19S198 (z = 5.77 at θ = 0.0). The flanking markers D19S587 and D19S900 define a candidate region of approximately 8 cM. Although RDP itself is a rare condition, it is important because it has clinical and biochemical similarities to both Parkinsons disease and dystonia. Identification of the genetic defect in RDP holds promise for understanding the underlying disease processes of both of these more common diseases. Ann Neurol 1999;46:176–182

ATP1A3 mutations in infants: a new rapid-onset dystonia-Parkinsonism phenotype characterized by motor delay and ataxia.

We report new clinical features of delayed motor development, hypotonia, and ataxia in two young children with mutations (R756H and D923N) in the ATP1A3 gene. In adults, mutations in ATP1A3 cause rapid‐onset dystonia–Parkinsonism (RDP, DYT12) with abrupt onset of fixed dystonia. The parents and children were examined and videotaped, and samples were collected for mutation analysis. Case 1 presented with fluctuating spells of hypotonia, dysphagia, mutism, dystonia, and ataxia at 9 months. After three episodes of hypotonia, she developed ataxia, inability to speak or swallow, and eventual seizures. Case 2 presented with hypotonia at 14 months and pre‐existing motor delay. At age 4 years, he had episodic slurred speech, followed by ataxia, drooling, and dysarthria. He remains mute. Both children had ATP1A3 gene mutations. To our knowledge, these are the earliest presentations of RDP, both with fluctuating features. Both children were initially misdiagnosed. RDP should be considered in children with discoordinated gait, and speech and swallowing difficulties.

PET imaging of the pre-synaptic dopamine uptake sites in rapid-onset dystonia-parkinsonism (RDP)

Rapid‐onset dystonia‐parkinsonism (RDP) is a genetic movement disorder characterized by abrupt onset over hours to days of bradykinesia, postural instability, dysphagia, dysarthria, and severe dystonic spasms with decreased levels of the dopamine metabolite, homovanillic acid (HVA), in cerebrospinal fluid (CSF).