Ryan J. Uitti

German-Canadian family (family A) with parkinsonism, amyotrophy, and dementia — Longitudinal observations

Etiology of Parkinsons disease (PD), amyotrophy lateral sclerosis (ALS), and Alzheimers disease (AD) remains uncertain. Environmental factors probably play a role, but genetic influences may predispose certain individuals to develop each of these major neurodegenerative disorders. We describe our longitudinal observations concerning a Canadian family traced to Northern Germany. Autosornal dominant inheritance has been established. Affected members present with L-dopa responsive parkinsonism and amyotrophy. In the German portion of the family some individuals displayed only dementia or focal dystonia. Linkage analysis studies performed with polymorphic markers associated with 13 candidate genes provided no significant evidence for linkage with any of the genes examined. Positron emission tomography with [(18)F]-6-fluoro-L-dopa (FD) and [su11C]-raclopride (raclopride) of one affected subject revealed reduced striatal FD uptake particularly in putamen, and an increased raclopride striatum/background ratio. Postmortem levels of dopamine and its metabolites were greatly reduced in caudate and putamen of two patients. There was substantial neuronal loss in the substantia nigra and the presence of abundant eosinophilic granules (different than Lewy bodies) in surviving neurons. One of them also showed mild loss of anterior horn cells, while another showed abundant senile plaques and some neurofibrillary tangles in distribution and intensity typical of mild to moderate AD. Our report further describes this unique family with a combination of clinical features of PD, ALS, and AD. By studying kindreds like this we may learn more about the pathophysiology of sporadic forms of PD, ALS, or even AD.

Familial Parkinson's Disease: Possible Role of Environmental Factors

We report here six families with Parkinsons disease in whom the onset of symptoms tended to occur at approximately the same time irrespective of the age of the patient. The mean difference in the time of onset in different generations was 4.6 years while the mean difference in age of onset in children and parents was 25.2 years. We construe this pattern of age separation within families as suggestive of an environmental rather than genetic cause. Support for this view derives from the lack of correlation between occurrence of the disease and the degree of consanguinity. We conclude that our findings are in accord with the hypothesis which attributes the cause of some cases of Parkinsons disease to early, subclinical environmental damage followed by age-related attrition of neurons within the central nervous system.

Variant ataxia-telangiectasia presenting as primary-appearing dystonia in Canadian Mennonites

Objective: To compare the phenotype of primary-appearing dystonia due to variant ataxia-telangiectasia (A-T) with that of other dystonia ascertained for genetics research. Methods: Movement disorder specialists examined 20 Canadian Mennonite adult probands with primary-appearing dystonia, as well as relatives in 4 families with parent-child transmission of dystonia. We screened for the exon 43 c.6200 C>A (p. A2067D) ATM mutation and mutations in DYT1 and DYT6. Clinical features of the individuals with dystonia who were harboring ATM mutations were compared with those of individuals without mutations. Result: Genetic analysis revealed a homozygous founder mutation in ATM in 13 members from 3 of the families, and no one harbored DYT6 or DYT1 mutations. Dystonia in ATM families mimicked other forms of early-onset primary torsion dystonia, especially DYT6, with prominent cervical, cranial, and brachial involvement. Mean age at onset was markedly younger in the patients with variant A-T (n = 12) than in patients with other dystonia (n = 23), (12 years vs 40 years, p < 0.05). The patients with A-T were remarkable for the absence of notable cerebellar atrophy on MRI, lack of frank ataxia on examination, and absence of ocular telangiectasias at original presentation, as well as the presence of prominent myoclonus-dystonia in 2 patients. Many also developed malignancies. Conclusion: Ataxia and telangiectasias may not be prominent features of patients with variant A-T treated for dystonia in adulthood, and variant A-T may mimic primary torsion dystonia and myoclonus-dystonia.

Neurodegenerative 'overlap' syndrome: Clinical and pathological features of Parkinson's disease, motor neuron disease, and Alzheimer's disease

Parkinsons disease (PD), Alzheimers disease (AD), and motor neuron disease (MND) share epidemiological, clinical, and pathological features. Few studies have reported comprehensively on individuals who demonstrate a neurodegenerative overlap syndrome, comprising idiopathic parkinsonism, dementia, and motor neuron dysfunction. We describe clinical, electrophysiological, and pathological features in six patients with neurodegenerative overlap syndrome. All had cardinal features of PD (duration 6-26 years), and any mixture of dementia (slowly advancing), fasciculations, hyperreflexia, Babinski signs and mild atrophy and weakness of distal muscles (slowly progressive). EMG often demonstrated a lack of denervation in conjunction with abnormal MEPs (high thresholds). Patients had either 6FD-PET or pathological studies consistent with PD. Pathological studies also demonstrated moderate numbers of neurofibrillary tangles and plaque formation, typically with sparing of motor neurons in the spinal cord. We conclude that neurodegenerative overlap syndrome may represent forme frustes of traditionally accepted diagnostic categories. Patients with parkinsonism, fasciculations, hyperreflexia and mild atrophy are unlikely to demonstrate active denervation on EMG; their prognosis is better than for classical MND. Neurodegenerative overlap syndrome (clinicopathological mixtures of PD, AD, and MND) may develop in some individuals as a reflection of common etiology, pathogenesis or susceptibility.

Pathogenesis of Idiopathic Parkinsonism

Idiopathic parkinsonism (Parkinsons disease) makes up the largest diagnostic subgroup of patients with parkinsonism. Various hypotheses exist regarding the pathogenesis of idiopathic parkinsonism: these include genetic predilection aging, environmental factors, oxidative stress, excitotoxicity, autoimmunity, and trauma. We suggest that the pathogenesis of idiopathic parkinsonism is likely to be multifactorial, deriving from environmental factor(s) acting upon a genetically predisposed individual. Because of the compelling evidence indicating common clinical and pathological findings in idiopathic parkinsonism, Alzheimers disease, and amyotrophic lateral sclerosis, we believe that these conditions result from pathological processes with more similarity than diversity. A primary glutamatergic cell neocortical abnormality provides an attractive unifying explanation which may explain the overlapping abnormalities found in idiopathic parkinsonism, Alzheimers disease, and amyotrophic lateral sclerosis.

Deprenyl and the issue of neuroprotection.

Deprenyl and the Issue of Neuroprotection F. Vingerhoets, MD, Neurodegenerative Disorders Centre, University Hospital, UBC Site, Purdy Pavilion, 2211 Wesbrook Mall, Vancouver, BC V6T 2B5 (Canada) The Parkinson Disease Study Group (PDSG) recently published its findings concerning antioxidant drug therapy for early Parkinson’s disease [1] (idiopathic parkinsonism (IP)) as follow-up to an earlier report published in 1989 [2]. After almost 4 years of controversy [3, 4], the sole firm conclusion that could be drawn concerning the use of deprenyl, a monoamine oxidase (MAO) type B inhibitor was that it allowed the introduction of levodopa treatment to be postponed by somewhat less than 1 year. For this reason, the authors argue, deprenyl should be considered among the available therapeutic options for the initial treatment of early Parkinson’s disease. A discussion of when and how symptomatic treatment of early Parkinson’s disease should be carried out is beyond the scope of this editorial and has recently been addressed elsewhere [5]. Our discussion here will be restricted to the issue of neuroprotection as illustrated by the DATATOP experience. Few would argue against neuroprotection being a goal worth pursuing. However, for the concept to be meaningfully assessed a specific definition is required. On the cellular level, the definition of neuroprotection is relatively straightforward. Most would accept an agent as neuroprotective if it reduced the death rate in a population of cells. In this context, visual examination of cells surviving in culture, following a toxic stressor, would allow conclusions regarding the neuroprotective effect of an agent. In experiments where neuropathological studies can be performed serially, for example in an experimental group of animals, comments concerning cellular neuroprotection can likewise be made. In this context, experimental models can be constructed, based on knowledge of a given deleterious phenomenon, including its mechanisms and natural evolution, and potential neuroprotective influences proposed (e.g. MPTP-induced parkinsonism – oxidative stress/excitotoxicity – MAO inhibitors). Similarly, when the cause of a human disease is known, as in the case of Wilson’s disease or subacute combined degeneration of the cord, chelation and vitamin therapy may be regarded as providing a kind of neuroprotection. By contrast, in the distinctly human condition of IP, the mechanism and natural evolution of the disorder are not known or quantifi-ably defined. Furthermore, practical access to visualizing neuronal populations from the brains of living patients is impossible. Consequently, it is difficult to define neuroprotection in this context. This difficulty has been recognized by the PDSG. The DATATOP design [1,2, 6] is representative of the framework for several human neuroprotective studies and therefore worthy of further consideration. Information from three sources seems essential for establishing a convincing neuroprotective story: (1) An ongoing pathogenic mechanism must be identified. In IP, some evidence suggests a disturbance in oxidative pathways in the substantia nigra. This has been taken, in the DATATOP study, as indicating a primary role for free radical/oxidative stress in the development of parkinsonism [6]. However, others speak with equal conviction and evidence against the oxidative stress hypothesis [7]. Alternatively, or perhaps additionally, it has been postulated that continuous exposure to an environmental pro-toxin may contribute to the demise of nigral neuronal function [6]. However, to date no relevant protoxin has been identified in the environment. Furthermore, it has been shown that, at least in some other forms of parkinsonism, a transient exposure to a toxic agent such as manganese [8] or MPTP [9] may lead to a chronically pro-gresssive condition. One can only speculate as to whether the cause(s) of IP is (are) an event or process [10].

LRRK2 (Leucine-Rich Repeat Kinase 2) Gene on PARK8 Locus in Families with Parkinsonism

It is estimated that about 10% to 30% of Parkinson’s disease (PD) cases are familial [1]. Eleven PD loci/mutations have already been identified [2] (Table 1). The PARK8 locus on chromosome 12p11.2-q13.1 was first found in 2002 in a large Japanese kindred known as the Sagamihara family [3]. The linkage analysis studies performed by our group on 21 caucasian families showed probable linkage to this locus in 10 kindreds [4]. In late April of 2004, we found the first mutation in the leucine-rich repeat kinase 2 (LRRK2) gene in family D (western Nebraska). Two weeks later the second mutation in this gene for family A (German-Canadian) [5] was discovered. Other groups have confirmed our discovery in a number of other families [6–9].