Clinical findings of autosomal-dominant striatal degeneration and PDE8B mutation screening in parkinsonism and related disorders.

BACKGROUND: Autosomal-dominant striatal degeneration (ADSD) is a rare neurodegenerative movement disorder caused by mutations in the Phosphodiesterase 8B (PDE8B) gene. OBJECTIVE: To summarize the clinical and imaging features of a Chinese ADSD family and determine whether mutations in PDE8B are associated with Parkinson's disease (PD) or Parkinsonism. METHODS: Clinical, imaging and genetic findings in a Chinese ADSD family are reported. Rare, potentially pathogenic variants in PDE8B were searched in whole-exome sequencing datasets from 1714 PD or parkinsonism patients and 1039 controls. RESULTS: An ADSD diagnosis was confirmed by a nonsense mutation in PDE8B (p.E102X) in a patient and a presymptomatic carrier. Clinically, the patient exhibited progressive parkinsonism without tremor and ataxia phenotype. Neuroimaging showed an inhomogeneous increased signal in the patient's striatum on T1-weighted images but a decreased signal in the presymptomatic carrier. Diffusion tensor imaging (DTI) showed a disturbance in the white matter fiber distribution, especially between the lentiform nucleus and caudate nucleus, which was more prominent in the patient than in the presymptomatic carrier. Within the 1714 patients, three PDE8B missense variants were identified that were unlikely to be the cause of the parkinsonism phenotype according to the functional prediction and mutation types reported in ADSD. CONCLUSIONS: For the first time, we described the typical ataxia phenotype in ADSD. A loss of white matter fiber integrity was shown on DTI scanning. No causative PDE8B mutation was discovered in our cohort of PD or Parkinsonism patients.

Transcriptome-wide effects of a POLR3A gene mutation in patients with an unusual phenotype of striatal involvement.

RNA polymerase III is essential for the transcription of non-coding RNAs, including tRNAs. Mutations in the genes encoding its largest subunits are known to cause hypomyelinating leukodystrophies (HLD7) with pathogenetic mechanisms hypothesised to involve impaired availability of tRNAs. We have identified a founder mutation in the POLR3A gene that leads to aberrant splicing, a premature termination codon and partial deficiency of the canonical full-length transcript. Our clinical and imaging data showed no evidence of the previously reported white matter or cerebellar involvement; instead the affected brain structures included the striatum and red nuclei with the ensuing clinical manifestations. Our transcriptome-wide investigations revealed an overall decrease in the levels of Pol III-transcribed tRNAs and an imbalance in the levels of regulatory ncRNAs such as small nuclear and nucleolar RNAs (snRNAs and snoRNAs). In addition, the Pol III mutation was found to exert complex downstream effects on the Pol II transcriptome, affecting the general regulation of RNA metabolism.

A novel mutation of PDE8B Gene in a Japanese family with autosomal-dominant striatal degeneration.

BACKGROUND: Autosomal-dominant striatal degeneration is a rare autosomal-dominant neurodegenerative movement disorder characterized by slowly progressive parkinsonism. Recently, a mutation of the cyclic nucleotide phosphodiesterase 8B gene was reported to be a causal gene mutation of this disease. METHODS: We report on the clinical characteristics of 2 patients of a Japanese family with autosomal-dominant striatal degeneration and the result of gene mutation analysis of this family. RESULTS: Clinical features of the patients are slowly progressive parkinsonism and brain MRI showing high signal intensity in T2-weighted images in the striatum. We found a heterozygous nonsense mutation in the first exon of cyclic nucleotide phosphodiesterase 8B gene, which is predicted to disrupt all important functional domains of the cyclic nucleotide phosphodiesterase 8B protein. CONCLUSIONS: This family is the second family with autosomal-dominant striatal degeneration after the first German family, confirming that cyclic nucleotide phosphodiesterase 8B gene is the causative gene for this disease.

Congenital ovine neuronal ceroid lipofuscinosis--a cathepsin D deficiency with increased levels of the inactive enzyme.

We recently showed that a form of neuronal ceroid lipofuscinosis (NCL) in white Swedish landrace sheep is caused by a missense mutation in the cathepsin D gene resulting in complete inactivation of the enzyme. Despite the lack of cathepsin D activity, the brains of the cathepsin D deficient sheep showed strongly increased staining for cathepsin D in immunohistochemistry. By Western blotting, a 5-10 fold increase in the level of cathepsin D was confirmed. These results indicate that the missense mutation in congenital NCL sheep results in the synthesis of an inactive yet stable cathepsin D.

Lethal syndrome of skeletal dysplasia and progressive central nervous system degeneration.

We describe 3 sibs (2 males and 1 female) with multiple congenital anomalies, poor growth, seizures, and progressive central nervous system (CNS) degeneration leading to death in infancy. Radiographic changes in all 3 were similar, and included moderate shortness of long bones, platyspondyly, and hypoplastic pelvis. Autopsies showed diffuse encephalomyelopathy and enlargement of the lateral and third ventricles. Lysosomal enzyme activities were normal. Collagen type II analysis on 2 of the sibs indicated normal collagen. Chromosomes appeared normal. Even though the radiographic and chondroosseous morphologic findings in these sibs have a certain similarity to Dyggve-Melchior-Clausen syndrome, their clinical course does not fit this condition. These infants appear to represent a new syndrome of bone dysplasia and CNS degeneration inherited as an autosomal recessive trait.