Yasuhiro Yamamura

Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism

Parkinsons disease is a common neurodegenerative disease with complex clinical features. Autosomal recessive juvenile parkinsonism (AR-JP), maps to the long arm of chromosome 6 (6q25.2-q27) and is linked strongly to the markers D6S305 and D6S253 (ref. 4); the former is deleted in one Japanese AR-JP patient. By positional cloning within this microdeletion, we have now isolated a complementary DNA clone of 2,960 base pairs with a 1,395-base-pair open reading frame, encoding a protein of 465 amino acids with moderate similarity to ubiquitin at the amino terminus and a RING-finger motif at the carboxy terminus. The gene spans more than 500 kilobases and has 12 exons, five of which (exons 3–7) are deleted in the patient. Four other AR-JP patients from three unrelated families have a deletion affecting exon 4 alone. A 4.5-kilobase transcript that is expressed in many human tissues but is abundant in the brain, including the substantia nigra, is shorter in brain tissue from one of the groups of exon-4-deleted patients. Mutations in the newly identified gene appear to be responsible for the pathogenesis of AR-JP, and we have therefore named the protein product ‘Parkin’.

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 Parkinsons 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. Ann Neurol 1999;45:668–672

Novel PINK1 mutations in early-onset parkinsonism

PINK1 was recently found to be associated with PARK6 as the causative gene. We performed mutation analysis in eight inbred families whose haplotypes link to the PARK6 region. We identified six pathogenic mutations (R246X, H271Q, E417G, L347P, and Q239X/R492X) in six unrelated families. All sites of mutations were novel, suggesting that PINK1 may be the second most common causative gene next to parkin in parkinsonism with the recessive mode of inheritance. Ann Neurol 2004;56:424–427

Paralysis agitans of early onset with marked diurnal fluctuation of symptoms

Yanagi, M.D., and Chikao Kono, M.D. . Although paralysis agitans is essentially a disease of older people, its occurrence in the earlier decades of life has long been known. Willige’ considered familial cases as constituting a separate nosologic entity under the name of paralysis agitans juveniiis familialis. Subsequently, paralysis agitans with early onset has been studied clinically and pathologically by many investigators, but there still is considerable divergence of opinion about it. In this paper the authors refer to a familial group of patients with paralysis agitans of early onset characterized by marked diurnal fluctuation of symptoms, which has only been reported by Nasu, Aoyama and Morisada2 and by the authors of this paper.3

Studies on familial amyloid polyneuropathy in Ogawa Village, Japan.

A newly discovered large concentration of familial amyloid polyneuropathy (FAP) in Japan is clinically outlined. The importance of the urinary secretion of IgA in these cases is stressed. Dimethyl sulfoxide administration to these patients induced clinical improvements accompanied by increased excretion of low molecular weight proteins. Amino acid composition of amyloid protein of the Ogawa village-type FAP cases was similar to that of primary amyloidosis.

Autosomal Recessive Juvenile Parkinsonism Maps to 6q25.2-q27 in Four Ethnic Groups: Detailed Genetic Mapping of the Linked Region

Parkinson disease (PD) is a common neurodegenerative condition associated with degeneration of dopaminergic neurons in the zona compacta of the substantia nigra. There is increasing evidence that genetic factors play a role in the etiology of PD, although genetic heterogeneity is likely. An autosomal dominant syndrome with many similarities to sporadic PD has been mapped to 4q21-22 in a large Italian pedigree and has been found to be due to mutation of the alpha-synuclein gene. However, this gene appears to account for only a minority of PD, and a susceptibility locus for autosomal dominant parkinsonism has recently been mapped, on 2p13. Autosomal recessive juvenile parkinsonism (JP), which shows marked clinical similarity to PD, maps to 6q25.2-q27. We found linkage to this region in a group of 15 families from four distinct ethnic backgrounds. A full genomic screen excluded other candidate regions. We have constructed a detailed genetic map of the linked region and have mapped the position of the manganese superoxide dismutase gene (SOD2). Recombination events restricted the JP locus to a 6.9-cM region and excluded SOD2. The apparent homozygosity for null alleles at D6S955 in one family suggested a deletion and finer localization of the JP locus.

PARK6-linked autosomal recessive early-onset parkinsonism in Asian populations

The authors performed linkage analysis in 39 families with autosomal recessive early-onset PD (AR-EOPD) negative for parkin and DJ-1 mutations. Eight families including three Japanese, two Taiwanese, one Turkish, one Israeli, and one Philippine showed evidence of linkage with PARK6 with multipoint log of the odds (lod) score of 9.88 at D1S2732. The results indicate worldwide distribution of PARK6-linked parkinsonism.

PARKIN as a pathogenic gene for autosomal recessive juvenile parkinsonism.

Parkinsons 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.

Low intensity areas observed on T2-weighted magnetic resonance imaging of the cerebral cortex in various neurological diseases

The cerebral cortex of patients with Alzheimers disease (AD) or amyotrophic lateral sclerosis (ALS) may show low signal intensity on T2-weighted magnetic resonance images (MRI). Since these low intensity areas (LIA) are also often observed in aged patients with other diseases, we suspected that they might be a non-specific finding. We conducted a retrospective study of LIA in 139 patients with various diseases of the central and peripheral nervous systems, and evaluated their relationship to age and other MRI findings. Brain atrophy, ventricular dilatation, white matter lesions, and LIA were visually evaluated on axial images of the spin echo sequences obtained with a 1.5 tesla (T) system. We found that LIA appeared after age 50 and became more common with advancing age. Their presence correlated with brain atrophy and white matter lesions. They were most frequent in the motor cortex, followed by the occipital and sensory cortices. Their incidence in the motor cortex was significantly higher in patients with central nervous system diseases than in those with peripheral neuropathy. We conclude that LIA are common in old patients with various neurological diseases and suggest that the deposition of iron in the cerebral cortices causes their development.

Clinical, pathologic and genetic studies on autosomal recessive early-onset parkinsonism with diurnal fluctuation

To clarify the genetic mode and clinical characteristics of familial early-onset parkinsonism with diurnal fluctuation, we studied 43 patients from 22 families. The estimated segregation ratio (0.2963) and absence of gender preponderance indicated autosomal recessive inheritance. Clinical features included the average age at onset of 26.1 years, parkinsonism with marked diurnal fluctuation, remarkable effect of levodopa, dyskinesias, dystonia, hyperreflexia, absence of dementia, and a benign course; autonomic symptoms were only mild if present. Autopsy study in one of our patients disclosed neuronal loss without Lewy bodies and the presence of melanin-poor neurons in the substantia nigra. Linkage analysis on 16 families mapped the disease gene to chromosome 6q25.2-27.