Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and familial pigmentary orthochromatic leukodystrophy (POLD) present as adult-onset dementia with motor impairment and epilepsy. ...They are regarded as distinct diseases. We review data from the literature that support their being a single entity. Apart from a slightly older age at onset, a more rapid course, and more prominent pyramidal tract involvement, familial POLD is clinically similar to HDLS. Moreover, the pathologic hallmarks of the two diseases, axonal spheroids in HDLS and pigmented macrophages in POLD, can be identified in both conditions. This supports HDLS and POLD being referred collectively as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).
Abstract Objective To describe the long-term outcome in 50 consecutive advanced Parkinson's disease (PD) patients treated with subthalamic nucleus deep brain stimulation (STN-DBS). Method Assessments ...were carried out at baseline, 6 months, 2 years, and 5 years postoperatively. Results Compared to baseline scores without medication, we found a highly significant improvement of UPDRS III with stimulation, maintained at 5 years ( p <0.001). This improvement, however, tended to diminish over time. Dyskinesia and off periods were also improved ( p <0.0001 for both). Seventeen patients died during follow-up, who tended to be older at surgery ( p <0.01). Conclusions STN-DBS is an effective treatment for advanced PD patients, and the beneficial effect is maintained at 5 years. However, worsening occurs over time due to disease progression.
Background and purpose: Whilst an association between the tau gene (MAPT)‐containing H1 haplotype and supranuclear gaze palsy (PSP) has long been recognized, the effect of H1 on risk for Parkinson’s ...disease (PD) has remained more contentious.
Methods: Herein, we examined the association of H1 and PD in three Caucasian PD patient–control series from Ireland, Norway, and the US (combined: n = 2619), by genotyping two H1/H2 single nucleotide polymorphisms (SNPs) in MAPT (rs1052553) and in the Saitohin gene (rs62063857) and one H1‐specific SNP (rs242557).
Results: We identified a significant association between H1/H2 and risk of PD (rs1052553 OR: 1.43, CI: 1.23–1.64; rs62063857 OR: 1.45, CI: 1.27–1.67), but no effect of the H1‐specific SNP rs242557 (OR: 0.92, CI: 0.82–1.03).
Conclusions: Our findings show that the H1 haplotype is a significant risk factor for PD. However, one H1‐specific SNP (rs242557) previously implicated in PSP did not alter the risk of PD, indicating that distinct H1 sub‐haplotypes probably drive the associations with PD and PSP.
Recently, mutations in DCTN1 were found to cause Perry syndrome, a parkinsonian disorder with TDP-43-positive pathology. Previously, mutations in DCTN1 were identified in a family with lower motor ...neuron disease, in amyotrophic lateral sclerosis (ALS), and in a family with ALS/frontotemporal dementia (FTD), suggesting a central role for DCTN1 in neurodegeneration.
In this study we sequenced all DCTN1 exons and exon-intron boundaries in 286 samples diagnosed with Parkinson disease (PD), frontotemporal lobar degeneration (FTLD), or ALS.
This analysis revealed 36 novel variants (9 missense, 5 silent, and 22 noncoding). Segregation analysis in families and association studies in PD, FTLD, and ALS case-control series did not identify any variants segregating with disease or associated with increased disease risk.
This study suggests that pathogenic mutations in DCTN1 are rare and do not play a common role in the development of Parkinson disease, frontotemporal lobar degeneration, or amyotrophic lateral sclerosis.
To report a new American family with hereditary diffuse leukoencephalopathy with spheroids (HDLS), including serial, presymptomatic and symptomatic, cranial MRIs from the proband.
We report clinical ...and genealogic investigations of an HDLS family, sequential brain MRIs of the proband, and autopsy slides of brain tissue from the proband's father.
We identified seven affected family members (five deceased). The mean age at symptomatic disease onset was 35 years (range: 20-57), and the mean disease duration was 16 years (range: 3-46). Five affected individuals initially manifested memory disturbance and behavioral changes, whereas two experienced a mood disorder as their presenting symptom. Our proband's father had been diagnosed clinically with vascular dementia, but his brain autopsy was consistent with HDLS. The proband had a cranial MRI prior to symptom onset, with two subsequent MRIs performed during follow-up. These serial images reveal a progressive, confluent, frontal-predominant leukoencephalopathy with symmetric cortical atrophy.
The proband of our newly identified hereditary diffuse leukoencephalopathy with spheroids (HDLS) kindred had subtle evidence of an incipient leukoencephalopathy on a presymptomatic cranial MRI. Conceivably, MRI may facilitate identifying affected presymptomatic individuals within known HDLS kindreds, increasing the likelihood of isolating the causative genes.
Background and purpose: Recent evidence suggests that variation in the SNCA, MAPT, and GSK3B genes interacts in affecting risk for Parkinson disease (PD). In the current study, we attempt to ...validate previously published findings, evaluating gene–gene interactions between SNCA, MAPT, and GSK3B in association with PD.
Methods: Three Caucasian PD patient–control series from the United States, Ireland, and Norway (combined n = 1020 patients and 1095 controls) were genotyped for SNCA rs356219, MAPT H1/H2‐discriminating SNP rs1052553, and GSK3B rs334558 and rs6438552.
Results: Our findings indicate that as previously reported, the SNCA rs356219‐G allele and MAPT rs1052553 (H1 haplotype) were both associated with an increased risk of PD, whilst contrary to previous reports, GSK3B variants were not. No pair‐wise interaction was observed between SNCA, MAPT, and GSK3B; the risk effects of SNCA rs356219‐G and MAPT rs1052553‐H1 were seen in a similar manner across genotypes of other variants, with no evidence suggesting synergistic, antagonistic, or deferential effects.
Conclusions: In the Caucasian patient–control series examined, risk for PD was influenced by variation in SNCA and MAPT but not GSK3B. Additionally, those three genes did not interact in determining disease risk.
To report the study of a multigenerational Swiss family with dopa-responsive dystonia (DRD).
Clinical investigation was made of available family members, including historical and chart reviews. ...Subject examinations were video recorded. Genetic analysis included a genome-wide linkage study with microsatellite markers (STR), GTP cyclohydrolase I (GCH1) gene sequencing, and dosage analysis.
We evaluated 32 individuals, of whom 6 were clinically diagnosed with DRD, with childhood-onset progressive foot dystonia, later generalizing, followed by parkinsonism in the two older patients. The response to levodopa was very good. Two additional patients had late onset dopa-responsive parkinsonism. Three other subjects had DRD symptoms on historical grounds. We found suggestive linkage to the previously reported DYT14 locus, which excluded GCH1. However, further study with more stringent criteria for disease status attribution showed linkage to a larger region, which included GCH1. No mutation was found in GCH1 by gene sequencing but dosage methods identified a novel heterozygous deletion of exons 3 to 6 of GCH1. The mutation was found in seven subjects. One of the patients with dystonia represented a phenocopy.
This study rules out the previously reported DYT14 locus as a cause of disease, as a novel multiexonic deletion was identified in GCH1. This work highlights the necessity of an accurate clinical diagnosis in linkage studies as well as the need for appropriate allele frequencies, penetrance, and phenocopy estimates. Comprehensive sequencing and dosage analysis of known genes is recommended prior to genome-wide linkage analysis.
Abstract Aim To describe a large family with autosomal dominant parkinsonism. Background Seven genes are directly implicated in autosomally inherited parkinsonism. However, there are several ...multigenerational large families known with no identifiable mutation. Material and methods Family members were evaluated clinically, by history and chart review. Genetic investigation included SCA2 , SCA3 , UCHL1 , SNCA , LRRK2 , PINK1 , PRKN , PGRN , FMR1 premutation, and MAPT . The proband underwent brain fluorodopa PET (FD-PET) scan, and one autopsy was available. Results Eleven patients had a diagnosis of Parkinson's disease (PD), nine women. Mean age of onset was 52 with tremor-predominant dopa-responsive parkinsonism. Disease progression was slow but severe motor fluctuations occurred. One patient required subthalamic nucleus deep-brain stimulation with a good motor outcome. One patient had mental retardation, schizophrenia and became demented, and another patient was demented. Three patients and also two unaffected subjects had mild learning difficulties. All genetic tests yielded negative results. FD-PET showed marked asymmetric striatal tracer uptake deficiency, consistent with PD. Pathological examination demonstrated no Lewy bodies and immunostaining was negative for α-synuclein. Conclusion Apart from a younger age of onset and a female predominance, the phenotype was indistinguishable from sporadic tremor-predominant PD, including FD-PET scan results. As known genetic causes of autosomal dominant PD were excluded, this family harbors a novel genetic defect.
PDF
