FBXO7 mutations cause autosomal recessive, early-onset parkinsonian-pyramidal syndrome.

BACKGROUND: The combination of early-onset, progressive parkinsonism with pyramidal tract signs has been known as pallido-pyramidal or parkinsonian-pyramidal syndrome since the first description by Davison in 1954. Very recently, a locus was mapped in a single family with an overlapping phenotype, and an FBXO7 gene mutation was nominated as the likely disease cause. METHODS: We performed clinical and genetic studies in two families with early-onset, progressive parkinsonism and pyramidal tract signs. RESULTS: An FBXO7 homozygous truncating mutation (Arg498Stop) was found in an Italian family, while compound heterozygous mutations (a splice-site IVS7 + 1G/T mutation and a missense Thr22Met mutation) were present in a Dutch family. We also found evidence of expression of novel normal splice-variants of FBXO7. The phenotype associated with FBXO7 mutations consisted of early-onset, progressive parkinsonism and pyramidal tract signs, thereby matching clinically the pallido-pyramidal syndrome of Davison. The parkinsonism exhibits varying degrees of levodopa responsiveness in different patients. CONCLUSIONS: We conclusively show that recessive FBXO7 mutations cause progressive neurodegeneration with extrapyramidal and pyramidal system involvement, delineating a novel genetically defined entity that we propose to designate as PARK15. Understanding how FBXO7 mutations cause disease will shed further light on the molecular mechanisms of neurodegeneration, with potential implications also for more common forms of parkinsonism, such as Parkinson disease and multiple system atrophy.

Reductive effect of aspirin treatment on primary tumor growth and metastasis of implanted fibrosarcoma in rats.

For suppression of primary tumor growth and metastatic spread, aspirin and theophylline, either alone or combined, were given daily to inbred female BN rats after sc implantation of a syngeneic nonimmunogenic tumor. Treatment with 200 mg aspirin/kg (body wt) resulted in a statistically significant regression of tumor growth as well as of the number of metastases in the lungs. Aspirin given in a lower dose (20 mg/kg) did not show significant difference from the vehicle group. Theophylline (75 mg/kg) significantly increased primary tumor growth as well as lung metastases. Inhibition of in vitro platelet aggregation, determined in whole blood taken from non-tumor-bearing animals treated with the same therapeutic regimen, was most pronounced in those groups in which tumor growth and spread were significantly retarded. However, this positive correlation between inhibition of tumor spread and platelet aggregation was not associated with a favorable balance of prostacyclin and thromboxane A2 in these animals.

Light-dark-shift stress, with special reference to spontaneous tumor incidence in female BN rats.

As a way to induce mild chronic stress, light-dark (L-D)-shift stress was applied to inbred BN virgin female rats during their whole life-span (group I, 100 animals); the incidences of spontaneous tumor and nontumor processes were recorded. A group of rats (group II, 100 animals) exposed to a standard lighting system served as the control group. Total tumors of 128 in group I and of 154 in group II were found in 74 and 86 animals, respectively. Neither were these differences nor was the pattern of spontaneous tumors statistically significant. Although in earlier studies L-D-shift stress had proved to be effective, especially with regard to its capacity to induce a substantial decrease in cellular immune response, apparently such alterations did not unfavorably affect longevity of BN female rats. Although as a side issue of this study, a strong predisposition for tumor incidence appeared to exist, in particular for the incidence of Langerhans' islet tumors, in fat animals at weaning.

Influence of the linoleic acid content of the diet on tumor growth in transplantable rat tumor models.

Diets high (17.7 cal%) and low (3.3 cal%) in linoleic acid were given to groups of Brown Norway female rats before and after inoculation of syngeneic tumor models with different characteristics, with regard to tumor spread, malignancy, immunogenicity, growth rate, rat strain, and histopathological features. Despite the differences in characteristics, in most tumor models, tumor growth was identical in both experimental groups. However, in 2 tumor models, an adrenal cortical carcinoma and a myeloid leukemia, differences in growth were noted. In rats given the diet low in linoleic acid, growth of the cortical carcinoma was significantly increased, whereas the opposite effect was seen in rats with myeloid leukemia.

Spontaneous tumor incidence in female brown Norway rats after lifelong diets high and low in linoleic acid.

High linoleic acid (C18:2) (group I; 17.7 cal%) and low C18:2 (group II; 3.3 cal%) diets were given to groups of inbred Brown Norway virgin female rats (100 animals/group), during their whole life-span. A total of 140 tumors were found in group I and 123 tumors in group II; the median survival times of the 2 groups were 124.2 and 118.5 weeks, respectively. Total spontaneous tumor incidence and median survival times were not significantly different. However, significant differences were found in the incidences of some specific tumors: The numbers of reticuloendothelial tumors and adrenocortical carcinomas were significantly higher in the group of animals receiving the low-C18:2 diet. A high incidence of tumor multiplicity, however, resulted in a significantly greater number of mammary tumors in the high-C18:2 diet group.

Incidence of spontaneous tumors in a group of retired breeder female brown Norway rats.

A group of 80 female retired breeder inbred Brown Norway (BN) rats with recorded breeding histories was followed for 150 weeks with regard to spontaneous occurrence of tumors. The median survival time of the whole group was 134 weeks. Ninety tumors (42 benign tumors, 23 sarcomas, and 25 carcinomas) were found in 64 animals. Compared with previous findings on virgin female BN rats, the retired breeders used in the present study had a strikingly higher incidence (34%) of tumors of the genital system but a lower incidence (4%) of breast tumors. The breeding histories revealed no relationship between the recorded number of litters, number of newborns, age of the mother at the time of her first litter, preweanling mortality, and the occurrence of cancer or survival in general. Although all animals were kept under identical environmental conditions, animals born in the period July-December appeared to have a lower incidence of utero-vaginal tumors than animals born in the first half of the year. The growth rates of 32 tumors inoculated into syngeneic rats were monitored for 26 weeks. They did not correlate with the histopathologic characteristics of the specific tumor. Malignant or benign tumors showed the same growth variability.