Development of the nosological analysis of juvenile parkinsonism

In the nosological viewpoint concerning diseases with a pathophysiological dysfunction of the nigro-striatal dopaminergic system, juvenile parkinsonism (JP) is discussed in this paper in relation to hereditary progressive dystonia (HPD) and Parkinson's disease (PD). Most cases of JP have dystonia with parkinsonism, which is the main symptom of HPD. In the symptomatological analysis of complication with dystonia, an interesting observation arose as regards on the anatomical and functional development of the basal ganglia through patients with childhood onset HPD and JP. Genetic analysis revealed the disease entity of HPD to be an abnormality of the GTP-CH I gene. Consequently, it has been clarified that clinical differences between HPD and JP were not merely derived from differences in developmental processes. Furthermore, the autosomal recessive type of JP (AR-JP) was confirmed to be a disease entity by the detection of an abnormality of the 'parkin' gene. The nosological controversy about JP and PD in the clinical standpoint has been clarified. However, as more than half of patients with JP do not carry a mutation in the 'parkin' gene, more investigations concerning nosological entities should be carried out. The absence of Lewy bodies in most patients with AR-JP has been confirmed to be a characteristic neorupathological finding as compared with those with typical PD pathology. In this paper, we discuss the above findings.     

Diagnostic considerations in juvenile parkinsonism.

Juvenile parkinsonism (JP) describes patients in whom the clinical features of parkinsonism manifest before 21 years of age. Many reported cases that had a good response to levodopa have proved to have autosomal recessive juvenile parkinsonism (AR-JP) due to mutations in the parkin gene. With the exception of parkin mutations and dopa-responsive dystonia, most causes are associated with the presence of additional neurological signs, resulting from additional lesions outside of the basal ganglia. Lewy body pathology has only been reported in one case, suggesting that a juvenile form of idiopathic Parkinson's disease may be extremely rare.     

Parkinsonism and motor neuron diseases: Twenty‐seven patients with diverse overlap syndromes

It has long been recognized that signs of motor neuron disease (MND) may accompany clinical evidence of parkinsonism in different neurodegenerative conditions. By using the Columbia University Division of Movement Disorders database, we reviewed data from 5,500 cases of parkinsonism and recorded the presence of upper motor neuron (UMN) dysfunction, lower motor neuron (LMN) dysfunction, or both. Among the 27 patients so identified, we counted those with autonomic dysfunction, cerebellar dysfunction, or dementia. Among the 27 cases, seven had UMN signs and LMN signs as well as parkinsonism and were diagnosed with amyotrophic lateral sclerosis (ALS)‐parkinsonism (Brait‐Fahn disease). Three of the seven had dementia that was not deemed to be frontotemporal dementia (FTD). Six other patients had no LMN signs but had UMN signs and parkinsonism and were classified as having primary lateral sclerosis (PLS)‐parkinsonism. Four patients had both UMN and LMN signs with parkinsonism as well as the characteristic dementia of FTD; they were diagnosed with FTD‐parkinsonism‐ALS. Seven patients had MND, parkinsonism, and autonomic or cerebellar dysfunction, a combination compatible with multiple system atrophy (MSA). Three patients had syndromes compatible with hereditary spastic paraplegia (HSP). In sum, we found that MND occurs in association with diverse parkinsonian syndromes; some are heritable, others sporadic and causes are uncertain. Having MND may be a risk factor forparkinsonism. A prospective study may elucidate this possibility. © 2010 Movement Disorder Society.     

Intracranial dural arteriovenous fistula presenting as parkinsonism and cognitive dysfunction

There are few syndromes of parkinsonism with dementia which can be treated. We report two patients with dural arteriovenous fistula (DAVF) who presented with rapidly progressive parkinsonism and cognitive dysfunction. DAVF are rare lesions resulting from abnormal connections between meningeal arteries and dural sinuses. Angiography in both patients revealed DAVF associated with multiple occlusive changes in the dural venous sinus. This report emphasizes the need for a high level of clinical suspicion to diagnose DAVF and consider it as one of the causes of rapidly progressive cognitive dysfunction in patients with parkinsonism.     

18F]-Dopa positron emission tomography imaging in early-stage, non-parkin juvenile parkinsonism.

There are few reports of positron emission tomography (PET) in juvenile parkinsonism (JP). We report on the results of (18)F-6-fluoro-L-dopa (FD) PET in a 14-year-old patient with JP of 5 years duration associated with atypical features. This is the youngest subject to be investigated to date. There was a severe asymmetric reduction in striatal FD uptake, with a rostrocaudal gradient in the putamen similar to that seen in adult-onset idiopathic parkinsonism. Extensive DNA analysis in this patient did not show mutations in the parkin gene.     

SPECT imaging of the dopamine transporter in juvenile-onset dystonia

Juvenile-onset dystonia that improves after levodopa may occur in both dopa-responsive dystonia (DRD) and juvenile parkinsonism (JP), clinically similar conditions with different prognoses and management goals. The authors show normal striatal uptake of the dopamine transporter ligand FP-CIT with SPECT in a clinically atypical case of DRD, in contrast to the reduced uptake observed in JP.     

Autosomal recessive juvenile parkinsonism: A key to understanding nigral degeneration in sporadic Parkinson's disease

The contribution of genetic factors to the pathogenesis of Parkinson's disease (PD) is supported by the demonstration of the high concordance in twins studies using positron emission tomography (PET), the increased risk among relatives of PD patients in case–control and family studies, and the existence of familial PD and parkinsonism by single gene defect. Recently several genes have been mapped and/or identified. α‐Synuclein is involved in a rare dominant form of familial PD with dopa‐responsive parkinsonism features and Lewy body‐positive pathology. In contrast, parkin is responsible for the autosomal recessive form (AR‐JP) of early onset PD with Lewy body‐negative pathology. The clinical features of this form include early onset (in the 20s), levodopa‐responsive parkinsonism, diurnal fluctuation, and slow progression of the disease. Parkin consists of 12 exons and the estimated size is over 1.5 Mb. To date, variable mutations such as deletions or point mutations resulting in missense and nonsense changes have been reported in AR‐JP patients. In addition, the localization of parkin indicates that parkin may be involved in the axonal transport system. More recently we have found that parkin interacts with the ubiquitin‐conjugating enzyme E2 and is functionally linked to the Ub‐proteasome pathway as a ubiquitin ligase, E3. These findings fit the characteristics of a lack of Lewy bodies (these are cytoplasmic inclusions that are considered to be a pathological hallmark). Our findings should enhance the exploration of the mechanisms of neuronal death in PD as well as other neurodegenerative disorders of which variable inclusion bodies are observed.     

Relatively spared mesocorticolimbic dopaminergic system in juvenile parkinsonism

This study aims to examine the function of the mesocorticolimbic dopaminergic system, including the amygdala, in recognizing emotions in juvenile parkinsonism (JP). Eleven patients with JP and 16 age-matched controls selected one basic emotion (happiness, sadness, anger, fear, surprise, or disgust) that best described the emotional state represented by visual and auditory stimuli. There was no significant difference between the patients and normal controls in their recognition of emotions. The spared emotion recognition in JP could be attributed to the absence of any pathological changes or the normal dopamine concentrations in the mesocorticolimbic system in this condition.     

Movement disorders and AIDS: a review

Movement disorders are a potential neurologic complication of acquired immune deficiency syndrome (AIDS), and may sometimes represent the initial manifestation of HIV infection. Dopaminergic dysfunction and the predilection of HIV infection to affect subcortical structures are thought to underlie the development of movement disorders such as parkinsonism in AIDS patients. In this review, we will discuss the clinical presentations, etiology and treatment of the various AIDS-related hypokinetic and hyperkinetic movement disorders, such as parkinsonism, chorea, myoclonus and dystonia. This review will also summarize current concepts regarding the pathophysiology of parkinsonism in HIV infection.     

Olfactory dysfunction in Parkinson's disease

The olfactory system is one of the nonmotor systems severely affected in Parkinson's disease (PD). Olfactory dysfunction occurs early in the disease process, is independent of disease stage, duration, and treatment. However, olfactory dysfunction appears to be dependent on disease subtype. Olfaction is mildly impaired or preserved in most of the parkinsonism-plus syndromes (PPS). This provides a means of differential diagnosis between typical PD and PPS. Olfactory function is impaired also in familial forms of parkinsonism in which the genetic defect is known. In familial parkinsonism, olfactory function is impaired in both typical PD and PPS phenotypes. Olfactory dysfunction does not appear to be a manifestation of dopamine deficiency. Olfactory dysfunction is also associated with other neurodegenerative diseases such as Alzheimer's disease (AD), Huntington's disease (HD), as well as with normal aging. The neuropathological changes observed in the olfactory system in PD and other neurodegenerative diseases appear to be disease-specific, raising the possibility that olfactory dysfunction may be the result of a central rather than a peripheral process. The cellular and molecular mechanisms underlying olfactory dysfunction in PD and other neurodegenerative diseases remain unknown.     

The diagnosis of manganese-induced parkinsonism

Parkinsonism is a clinical syndrome consisting of tremor, bradykinesia, rigidity, gait, balance problems, in addition to various non-motor symptoms. There are many causes of parkinsonism such as neurodegenerative disease, drugs, vascular causes, structural lesions, infections, and toxicants. Parkinson's disease, or idiopathic parkinsonism, is the most common form of parkinsonism observed in the clinic. There is degeneration of the substantia nigra, pars compacta, which results in loss of striatal dopamine. Parkinson's disease is a slowly progressive condition in which there is a dramatic and sustained responsiveness to levodopa therapy. Manganese is an essential trace element that can be associated with neurotoxicity. Hypermanganism can occur in a variety of clinical settings. The clinical symptoms of manganese intoxication include non-specific complaints, neurobehavioral changes, parkinsonism, and dystonia. Although the globus pallidus is the main structure of damage, other basal ganglia areas can also be involved. MRI scans may show globus pallidus changes during (and for a short period after) exposure. Fluorodopa PET scans that assess the integrity of the substantia nigra dopaminergic system are abnormal in Parkinson's disease. However, these scans re-reported to be normal in a few cases studied with manganese-induced parkinsonism. The parkinsonism due to manganese may have some clinical features that occur less commonly in Parkinson's disease, such as kinetic tremor, dystonia, specific gait disturbances, and early mental, balance and speech changes. The clinical signs tend to be bilateral whereas Parkinson's disease begins on one side of the body. Patients with manganese-induced parkinsonism may be younger at the onset of the disease than with Parkinson's disease. Lastly, there appears to be a lack of response to levodopa therapy in manganese-induced parkinsonism. In summary it may be possible to differentiate manganese-induced parkinsonism from Parkinson's disease using clinical and imaging studies.     

Influence of neurotoxins and oxidative stress on the onset and progression of Parkinson's disease

It is generally accepted that progressive, irreversible and regionally specific neurodegeneration and the presence of Lewy bodies are the essential pathological hallmarks of idiopathic parkinsonism. The causes of these phenomena, however, remain to be elucidated. One of the leading hypotheses is that oxidative stress induced by reactive oxygen species (ROS), such as the hydroxyl radical, damages essential components of the neuron, resulting ultimately in cell death. Observations in the parkinsonian brain at post-mortem support this hypothesis; for example, widespread oxidative protein modification is evident. There are several potential sources of increased oxidative stress in Parkinson's disease, including mitochondrial dysfunction, increased free iron levels and impaired free radical defence mechanisms. Further, it is possible that glial, rather than neuronal, elements are primarily responsible for the initial increase in oxidative stress in the substantia nigra. It is likely that parkinsonism is the result of aberrations at multiple levels of neuronal function. Oxidative stress is no doubt one of the events involved in neurodegeneration, but is unlikely to be the initiating event. It is to be expected that the search for this event will continue for many years.     

Influence of neurotoxins and oxidative stress on the onset and progression of Parkinson’s disease

It is generally accepted that progressive, irreversible and regionally specific neurodegeneration and the presence of Lewy bodies are the essential pathological hallmarks of idiopathic parkinsonism. The causes of these phenomena, however, remain to be elucidated. One of the leading hypotheses is that oxidative stress induced by reactive oxygen species (ROS), such as the hydroxyl radical, damages essential components of the neuron, resulting ultimately in cell death. Observations in the parkinsonian brain at post-mortem support this hypothesis; for example, widespread oxidative protein modification is evident. There are several potential sources of increased oxidative stress in Parkinson’s disease, including mitochondrial dysfunction, increased free iron levels and impaired free radical defence mechanisms. Further, it is possible that glial, rather than neuronal, elements are primarily responsible for the initial increase in oxidative stress in the substantia nigra. It is likely that parkinsonism is the result of aberrations at multiple levels of neuronal function. Oxidative stress is no doubt one of the events involved in neurodegeneration, but is unlikely to be the initiating event. It is to be expected that the search for this event will continue for many years.

     

Neuronal intranuclear inclusion disease: report on a case originally diagnosed as dopa-responsive dystonia with Lewy bodies.

Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder with a heterogeneous clinical picture characterized by the presence of eosinophilic intranuclear inclusions in neuronal and glial cells. We describe a case, reported 12 years ago as dopa-responsive dystonia (DRD) with Lewy body pathology. Pathological re-examination has led to a revised diagnosis of neuronal intranuclear inclusion disease. This rare condition, which may be diagnosed in life with a full thickness rectal biopsy, needs to be considered in the differential diagnosis of any case presenting as progressive juvenile parkinsonism (JP) or dystonia.     

Juvenile parkinsonism: ventricular CSF biopterin levels and clinical features.

Total biopterin (T-BP) levels in the ventricular cerebrospinal fluid (CSF) and clinical features of 19 patients with juvenile parkinsonism (JP: Parkinson's disease manifesting below the age of 40) were evaluated and compared with 61 patients with classical Parkinson's disease (classical PD: symptoms developing at the age of 40 or above). The JP patients were divided into two subgroups: JP-I; those with good response to levodopa followed by marked motor fluctuations and dopa-induced dyskinesias (DID), JP-II; those with milder response than JP-I with less fluctuations and DID being more similar to classical PD. Both of the mean ventricular CSF T-BP concentrations in the JP and classical PD patients were significantly lower than that in neurological controls. Moreover, the mean T-BP level in the JP-I was markedly lower than that in the JP-II or classical PD. Total biopterin levels revealed a gaussian distribution in the classical PD. However, a bimodal distribution was noted in the JP, with the lower peak consisting of only JP-I patients. These results seem to indicate that JP-II represents early-onset classical PD, while JP-I represents a distinct subgroup having a different physiopathology from classical PD.     

Endolysosomal dysfunction in Parkinson's disease: Recent developments and future challenges

Increasingly, genetic, cell biological, and in vivo work emphasizes the role of the endolysosomal system dysfunction in Parkinson's disease pathogenesis. Yet many questions remain about the mechanisms by which primary endolysosomal dysfunction causes PD as well as how the endolysosomal system interacts with α‐synuclein‐mediated neurotoxicity. We recently described a new mouse model of parkinsonism in which loss of the endolysosomal protein Atp13a2 causes behavioral, neuropathological, and biochemical changes similar to those present in human subjects with ATP13A2 mutations. In this Scientific Perspectives, we revisit the evidence implicating the endolysosomal system in PD, current hypotheses of disease pathogenesis, and how recent studies refine these hypotheses and raise new questions for future research. © 2016 International Parkinson and Movement Disorder Society.     

A patient with HIV encephalopathy presenting with parkinsonism during HAART therapy]

We report the case of a 32-year-old man presenting symptoms of parkinsonism. Neurological examination revealed parkinsonism symptoms such as akinesia and postural instability, dementia and frontal lobe signs. He was diagnosed as having human immunodeficiency virus (HIV) encephalopathy. Brain MRI, 99mTc ECD-SPECT and 1H-MR spectroscopy demonstrated symmetrical cerebral white matter lesions, predominantly in the bilateral frontal lobes. Frontal lobe dysfunction could be responsible for his parkinsonism associated with HIV encephalopathy. His neurological symptoms improved transiently after the initiation of HAART but fluctuated when antiretroviral drugs were changed because of their side effects. Although HAART effectively decreased plasma HIV-RNA load and increased peripheral blood CD4 cell count, his parkinsonism and dementia eventually exacerbated. Our results suggest that a combination of antiretroviral drugs affects the therapeutic efficacy against HIV encephalopathy, and that CNS symptoms could be aggravated during HAART, even when plasma HIV-RNA load and CD4 cell count are maintained under favorable conditions.     

Analysis of L-threo-3, 4-dihydroxyphenylserine effect on motor and psychological symptoms in Parkinson's disease

Improvement of motor and psychological symptoms by L-DOPS (L-threo-3,4-dihydroxyphenylserine) in totally 20 cases with Parkinson's disease (PD), including 5 cases of juvenile or early onset parkinsonism (JP) and one case of pure akinesia was analysed. Improvement was obtained in about two thirds of the cases on symptoms of freezing in gait, difficulty of postural control, depressive mood and bradyphrenia. Severity of freezing in gait and that of the depressive mood were graded in five stage (from 0 to 4) scale and the improvement was evaluated by A (three stage improvement), B (two stage improvement), C (one stage improvement) and D (no change or worsened). Improvement of psychological symptoms was seen parallel to that of motor symptoms. It seems important that marked effect on both motor and psychological symptoms was obtained mostly in PD cases but not in the cases of JP. In MMPI test, depressive score (D) and hypochondriac score (Hs) were normalized in PD cases but not changed in JP, indicating differences in psychological traits between two groups. It was suggested that JP is a condition of mainly DA deficiency in nigro striatum but PD presents wider spectrum of symptoms covering both DA and NE deficiency. Importance of the role of aging of the brain in each individual patient is discussed and interpreted in relation to the difference of clinical pictures.     

Pathogenesis of Parkinson's disease, a molecular genetic approach

In juvenile parkinsonism (JP), unlike naturally occurring Parkinson's disease, high frequency of familial onset is observed, which suggests the involvement of some genetic factor(s) in the pathogenesis of the disease. In an attempt to conduct a molecular genetic approach to JP, we tried to isolate tyrosine hydroxylase (TH) cDNA from human pheochromocytoma, and demonstrated the existence of four types of cDNA (type 1, 2, 3 and 4), differing in the 5'-terminal region. All four cDNAs had the same sequence in common from ATG of the translation start codon to 90th nucleotide. However, in types 2, 3 and 4, characteristic sequences were inserted between 90th and 91 st nucleotides of type 1 cDNA. TH genomic DNA cloning showed that the multiple form of mRNA were produced from a single gene through alternative splicing. Four types of cDNA was expressed in COS cells. They exhibited different homospecific activities: type 1 TH having the highest activity, others less than 40% of type 1 TH. The question whether possible change in TH gene is related to the pathogenesis of JP is now being pursued based on these molecular biological understanding of TH gene.