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.     

Preserved myocardial [123I]metaiodobenzylguanidine uptake in autosomal recessive juvenile parkinsonism: first case report.

A decrease in myocardial uptake of iodine-123-labeled metaiodobenzylguanidine (123I-MIBG) has been reported in idiopathic Parkinson's disease (PD) using 123I-MIBG myocardial scintigraphy. However, the patient with autosomal recessive juvenile parkinsonism (AR-JP), caused by the parkin gene, presented here showed normal 123I-MIBG myocardial uptake, suggesting that AR-JP is a distinct disease entity from PD. Although the clinical features of AR-JP are sometimes quite similar to those of late-onset idiopathic PD, 123I-MIBG myocardial scintigraphy may be a powerful tool to differentiate PD from other parkinsonian syndromes, including AR-JP.     

Immunohistochemical and subcellular localization of Parkin protein: absence of protein in autosomal recessive juvenile parkinsonism patients.

Autosomal recessive juvenile parkinsonism (AR-JP) is a distinct clinical entity characterized by a selective degeneration of nigral neurons. Recently, the parkin gene responsible for AR-JP has been identified. Now, we report the subcellular localization of Parkin protein in patients with AR-JP or Parkinson's disease (PD) and in controls by immunoblotting and immunohistochemistry using antibodies raised against the Parkin molecule. Parkin protein was absent in all regions of the brains of patients with AR-JP. Parkin protein was not decreased in the brains of sporadic PD patients. Immunoreactivity was detected in a few Lewy bodies. Parkin protein was located in both the Golgi complex and cytosol.     

Parkin gene and its function; a key to understand nigral degeneration]

In most patients with Parkinson's disease (PD), the contribution of genetic factors as well as environmental factors remains to be elucidated. But, it has become clear that genetic factors contribute to the pathogenesis of PD after identification of the distinct genetic loci for certain forms of familial PD. We recently identified the novel large gene "parkin" responsible for an autosomal recessive form of familial parkinsonism (AR-JP). AR-JP is a distinct clinical and genetic entity characterized by early onset before 40 years. Pathological changes in this form revealed selective degeneration of the pigmented neurons in the substantia nigra and locus coeruleus, but no Lewy bodies were found. The parkin gene encodes a novel protein of 465 amino acids. The parkin gene is mildly homologous to ubiquitin at the N-terminal portion and has a RING-finger motif at the C-terminal portion. We found variable different homozygous deletions involving exons 3, 4, 5, 3 to 4, 3 to 5, and 3 to 7 in AR-JP families from Japan. In addition to exonic deletions, we identified a one base deletion in exon 5 in two AR-JP families. Although we have identified several mutations in parkin gene, characterization of its gene product, "Parkin protein" has not yet been established. To elucidate the molecular mechanism underlying the disease, we have analyzed the subcellular localization of the Parkin protein by immunohistochemical and immunoblotting studies on patients with AR-JP and sporadic PD using two antibodies. Parkin protein was absent in all regions of the brains of AR-JP patients. Parkin protein was not decreased in brains of sporadic PD patients. Parkin protein was located in both Golgi complex and cytosol. Taken together, the Parkin protein may play a role in vesicular transport system in association with the Golgi complex.     

GTP-cyclohydrolase I gene mutations in hereditary progressive and dopa-responsive dystonia

Recently, mutations of the GTP-cyclohydrolase I (GTP-CH I) gene, which catalyzes the first step in the tetrahydrobiopterin (BH₄) biosynthesis, were discovered in Japanese patients with hereditary progressive dystonial/dopa-responsive dystonia (HPD/DRD). However, it has not been confirmed that non-Japanese patients also contain mutations in the same gene, or whether these mutations are specific to HPD/DRD. In this study, two novel nonsense mutations in exon 1 of the GTP-CH I gene and a new mutation at the splice acceptor site of intron 1 were identified in an autopsied case of English-Irish descent and 2 Japanese patients with HPD/DRD. In the latter, cerebrospinal fluid (CSF) neopterin levels (which may reflect the GTP-CH I activity in the brain) were reduced to 18% and 37% of controls. A therapeutic trial of oral BH₄ was ineffective, however, in a genetically proven patient. In contrast, no mutations in any exons of the GTP-CH I gene were found in 2 patients with early-onset parkinsonism with dystonia (EOP-D) who developed dopa-responsive parkinsonism and dystonia at 6 and 8 years old, respectively. Neopterin levels in CSF were well preserved in 6 EOP-D patients. These data suggest that, among patients of different racial backgrounds, the pathogenesis of HPD/DRD, unlike EOP-D, involves partial reduction of the brain GTP-CH I activity consequent to mutations in the GTP-CH I gene. Measurement of CSF neopterin concentration may be useful for the differential diagnosis between HPD/DRD and EOP-D.     

Juvenile parkinsonism

Juvenile parkinsonism (JP) is a clinically and etiologically heterogeneous entity. Unlike in the adult form, secondary causes, hereditary and metabolic conditions, are the predominant causes of JP. Idiopathic Parkinson's disease is very rare in this age group. In most cases of JP, parkinsonism is accompanied by other neurologic features, such as dystonia, cognitive impairment, seizures, oculomotor and visual dysfunction, and ataxia. Systemic findings, such as liver dysfunction or hepatosplenomegaly, may be present depending on the cause. This review article describes the clinical characteristics, classification, genetic basis, pathophysiology, biochemistry, pathology, and treatment of JP.     

Sensory neuropathy in autosomal recessive juvenile parkinsonism (PARK2)

Autosomal recessive juvenile parkinsonism (ARJP/PARK2) is a distinct clinical and genetic entity characterized by early-onset levodopa-responsive parkinsonism, foot dystonia, sleep benefit, and hyperactive tendon reflexes. We report a patient with genetically confirmed ARJP, who showed mild sensory disturbance and diminished deep tendon reflexes in the advanced stage. Nerve conduction studies revealed a sensory dominant neuropathy, which has not been described in ARJP. We suggest that peripheral neuropathy may occur in patients with advanced ARJP due to the loss of parkin protein function, although the function of parkin in the peripheral nervous system remains to be clarified.     

Clinical and neuropathological aspects of autosomal recessive juvenile parkinsonism

The onset of autosomal recessive-type parkinsonism is usually at a relatively young age (i.e. before the age of 40 years) and is thus called autosomal recessive juvenile parkinsonism (AR-JP). Here the clinical features, laboratory and imaging findings, neuropathological features, differential diagnosis and treatment options of AR-JP are described. We have treated 17 patients with AR-JP; they presented with sleep benefit in parkinsonian symptoms and foot dystonia as specific signs. The parkinsonian triad was mild, and the tremor was usually fine postural. A postural instability and adiadochokinesia were rather prominent. Gait freezing and hyperreflexia were frequently observed. The levodopa efficacy was sufficient and the clinical course was benign; however, choreic limb dyskinesia and the wearing-off phenomenon occurred easily. A neuropathological examination of one of the patients revealed that in the substantia nigra pars compacta and locus ceruleus, the number of neurons was low, and the content of neuromelanin in the neurons was small. There were focal degenerations (e.g. gliosis and extraneuronal free melanin) in the substantia nigra pars compacta. In addition, Lewy bodies were not found anywhere in the central nervous system. Considering these specific clinical and neuropathological findings, AR-JP seems to constitute one disease entity.

     

Progressive supranuclear palsy and tau hyperphosphorylation in a patient with a C212Y parkin mutation

Autosomal recessive-juvenile parkinsonism (AR-JP) is one of the most common forms of familial Parkinson's disease (PD) and is related to mutations in the Park-2 gene, encoding for a protein ligase of ubiquitin, parkin. Different mutations located along the parkin gene have been observed in different AR-JP affected families, possibly interfering with the normal function of parkin and the proteasome system. Two cases of patients with AR-JP have been recently described presenting different homo- and heterozygous parkin mutations and limited tau pathology. We report here the case of a patient with clinical and pathological findings compatible with progressive supranuclear palsy (PSP), carrier of a single, heterozygous mutation of the parkin gene, and homozygous for the H1/H1 haplotype in the tau gene. Abnormal tau hyperphosphorylation has been observed in our patient brain samples, suggesting that a partial deficit of parkin, a protein with ubiquitin-ligase function, may trigger tau pathology in individuals with molecular genetic risk factors.     

Decline of striatal dopamine release in parkin-deficient mice shown by ex vivo autoradiography

Parkin is the causal gene of autosomal recessive juvenile parkinsonism (AR-JP). Dopamine (DA) metabolism has been linked to Parkinson's disease (PD). To understand the pathogenesis of AR-JP, we generated parkin-deficient mice to assess the status of DA signaling pathway and examine DA release and DA receptor by ex vivo autoradiography. Ex vivo autoradiography using [11C]raclopride showed a clear decrease in endogenous DA release after methamphetamine challenge in parkin-deficient mice. Furthermore, parkin deficiency was associated with considerable upregulation of DA (D1 and D2) receptor binding in vivo in the striatum and increased DA levels in the midbrain. Our results suggest that dopaminergic neurons could behave abnormally before neuronal death.     

PARKIN as a pathogenic gene for autosomal recessive juvenile parkinsonism

Parkinson's disease is a common neurodegenerative disease with complex clinical features. Recently, we idenfied a novel gene named Parkin to be responsible for the pathogenesis of autosomal recessive juvenile parkinsonism (AR-JP). Various mutations were found in AR-JP patients of Japanese and other ethnic origins, providing a definitive evidence for the Parkin to be a causative gene for AR-JP. The predicted structure of Parkin protein and its mutation provide important clues for studying the functional role of the Parkin protein in leading to selective degeneration of nigral neurons in the brains of AR-JP patients.     

Positional cloning of the autosomal recessive juvenile parkinsonism (AR-JP) gene and its diversity in deletion mutations

Autosomal recessive juvenile parkinsonism (AR-JP) is a distinct clinical and genetic entity characterized by highly selective neuronal cell death in the substantia nigra and the locus coeruleus with no Lewy body formation. We succeeded in positional cloning of the AR-JP gene by screening the Keio BAC library with a microsatellite marker, D6S305, which is located AR-JP locus (6q25.2-q27). The gene was named as parkin; parkin consists of 12 exons spanning about 1 Mb with 1395 bp coding sequence. Patients with AR-JP showed various deletions in 14 Japanese families and two different types of point mutations in two Turkish families. AR-JP appears to have world-wide distribution.     

Importance of familial Parkinson's disease and parkinsonism to the understanding of nigral degeneration in sporadic Parkinson's disease

We review here familial Parkinson's disease (PD) from clinical as well as molecular genetic aspects. The contribution of genetic factors to the pathogenesis of PD is supported by the demonstration of the high concordance in twins, increased risk among relatives of PD patients in case control and family studies, and the existence of familial PD and parkinsonism based on single gene defects. Recently, several genes have been mapped and/or identified in patients with familial PD. Alpha-synuclein is involved in a rare dominant form of familial PD with dopa responsive parkinsonian features and Lewy body positive pathology. In contrast, parkin is responsible for autosomal recessive form of early-onset PD with Lewy body-negative pathology. This form is identified world-wide among patients with young-onset PD. Furthermore, ubiquitin carboxy terminal hydrolase L1 gene is responsible for an autosomal dominant form of typical PD, although only a single family has so far been identified with a mutation of this gene, and tau has been identified as a causative gene for frontotemporal dementia and parkinsonism. In addition, five other chromosome loci have been identified to be linked to familial PD or dystonia-parkinsonism. The presence of different loci or different causative genes indicates that PD is not a single entity but a highly heterogeneous. Identification and elucidation of the causative genes should enhance our understanding of the pathogenesis of sporadic PD.     

Comparison of dystonia between Parkinson's disease and atypical parkinsonism: The clinical usefulness of dystonia distribution and characteristics in the differential diagnosis of parkinsonism

Objective

Dystonia is occasionally found in patients with Parkinson's disease (PD) and atypical parkinsonisms. However, systematic comparative analysis of the association between dystonia and parkinsonism have seldom been reported. The goals of this study are to compare the clinical characteristics and distributions of dystonia between PD, multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD).

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.     

Internal globus pallidotomy in dystonia secondary to Huntington's disease.

INTRODUCTION AND METHOD: The prototypic motor feature of Huntington's disease (HD) is chorea, but parkinsonism and involuntary movements such as dystonia and myoclonus can also be present. Pallidotomy has been shown to be an effective treatment for medically refractory Parkinson's disease (PD). We performed bilateral microelectrode guided-stereotactic pallidotomies targeted at globus pallidum internus (GPi) to treat a 13-year-old patient diagnosed with Westphal variant of HD with intractable generalized dystonia and parkinsonism. RESULTS: Intraoperative microelectrode recordings of GPi cells showed a relatively low firing rate, 29 +/- 14 Hz, with most neurons showing pauses. Acutely, after surgery, limb dystonia mildly improved but trunk dystonia persisted. Postoperative follow up 3 months later showed minimal clinical improvement in dystonic features with marked worsening of spasticity. CONCLUSION: In our case, bilateral pallidotomy produced modest palliative functional improvement in dystonic features. Cellular firing patterns were markedly different than in PD and were similar to those found in dystonia.     

The long journey to the discovery of PARK2]

It was acknowledged long ago that Parkinson's disease (PD) occur rarely in familial aggregations. Willige and Mj?nes noted no difference between the clinical features of the familial form and those of sporadic PD. Research into this aspect remained at a standstill for several decades thereafter. The resurgence of research into familial parkinsonism was the discovery by Japanese neurologists of autosomal recessive form of PD. In 1965, at Nagoya University, our research group examined familial cases of early onset parkinsonism. Clinical features included autosomal recessive inheritance, symptomatic alleviation after sleep, hyperreflexia, foot dystonia, good response to medication, and benign course without dementia. The clinical study of four families of the disease (EPDF) was published in Neurology in 1973. Subsequently, I kept on with my study of EPDF at Hiroshima University. Pathological study by our group in 1993 revealed neuronal loss in the substantia nigra without Lewy bodies. Based on these clinical and pathological evidences, EPDF was successfully defined as a distinct disease entity. Screening for the EPDF gene was started in 1994 in collaboration with Juntendo University. With the discovery of parkin gene in 1998, EPDF was designated as PARK2. Of our 16 families examined for gene analysis, fifteen proved to be PARK2, and the resting one, PARK6.     

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.