16 research outputs found
Clinical and pathologic phenotype of a large family with heterozygous STUB1 mutation
Objective
To describe the clinical and pathologic features of a novel pedigree with heterozygous STUB1
mutation causing SCA48.
Methods
We report a large pedigree of Dutch decent. Clinical and pathologic data were reviewed, and
genetic analyses (whole-exome sequencing, whole-genome sequencing, and linkage analysis)
were performed on multiple family members.
Results
Patients presented with adult-onset gait disturbance (ataxia or parkinsonism), combined with
prominent cognitive decline and behavioral changes. Whole-exome sequencing identified
a novel heterozygous frameshift variant c.731_732delGC (p.C244Yfs*24) in STUB1 segregating with the disease. This variant was present in a linkage peak on chromosome 16p13.3.
Neuropathologic examination of 3 cases revealed a consistent pattern of ubiquitin/p62-positive
neuronal inclusions in the cerebellum, neocortex, and brainstem. In addition, tau pathology was
present in 1 case.
Conclusions
This study confirms previous findings of heterozygous STUB1 mutations as the cause of SCA48
and highlights its prominent cognitive involvement, besides cerebellar ataxia and movement
disorders as cardinal features. The presence of intranuclear inclusions is a pathologic hallmark
of the disease. Future studies will provide more insight into its pathologic heterogeneity
Longitudinal cognitive biomarkers predicting symptom onset in presymptomatic frontotemporal dementia
Neuro Imaging Researc
Modelling the cascade of biomarker changes in GRN-related frontotemporal dementia
ObjectiveProgranulin-related frontotemporal dementia (FTD-GRN) is a fast progressive disease. Modelling the cascade of multimodal biomarker changes aids in understanding the aetiology of this disease and enables monitoring of individual mutation carriers. In this cross-sectional study, we estimated the temporal cascade of biomarker changes for FTD-GRN, in a data-driven way.MethodsWe included 56 presymptomatic and 35 symptomatic GRN mutation carriers, and 35 healthy non-carriers. Selected biomarkers were neurofilament light chain (NfL), grey matter volume, white matter microstructure and cognitive domains. We used discriminative event-based modelling to infer the cascade of biomarker changes in FTD-GRN and estimated individual disease severity through cross-validation. We derived the biomarker cascades in non-fluent variant primary progressive aphasia (nfvPPA) and behavioural variant FTD (bvFTD) to understand the differences between these phenotypes.ResultsLanguage functioning and NfL were the earliest abnormal biomarkers in FTD-GRN. White matter tracts were affected before grey matter volume, and the left hemisphere degenerated before the right. Based on individual disease severities, presymptomatic carriers could be delineated from symptomatic carriers with a sensitivity of 100% and specificity of 96.1%. The estimated disease severity strongly correlated with functional severity in nfvPPA, but not in bvFTD. In addition, the biomarker cascade in bvFTD showed more uncertainty than nfvPPA.ConclusionDegeneration of axons and language deficits are indicated to be the earliest biomarkers in FTD-GRN, with bvFTD being more heterogeneous in disease progression than nfvPPA. Our data-driven model could help identify presymptomatic GRN mutation carriers at risk of conversion to the clinical stage.Neuro Imaging Researc
A case of co-occurrence of radiation-induced leukoencephalopathy and CADASIL
Consider an underlying genetic cause in patients with progressive deterioration and leukoencephalopathy after prophylactic radiotherapy.Neuro Imaging Researc
Familial aggregation of parkinsonism in progressive supranuclear palsy
Background: Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disorder characterized by aggregates of the microtubule-associated protein tau (MAPT). A nonsignificant trend for positive family history has been observed in two case-control studies and several pedigrees with familial clustering of parkinsonism have been described. Occasionally, mutations in MAPT are found in patients with a clinical phenotype similar to PSP. In this case-control study, we compared the occurrence of dementia and parkinsonism among first-degree relatives of patients with PSP with an age-and sex-matched control group. Methods: Family history of dementia and parkinsonism was collected from all first-degree relatives of patients with PSP who fulfilled the international National Institute of Neurological Disorders and Stroke criteria for PSP. Age-and sex-matched controls were selected from the Rotterdam Study. Genetic testing and pathologic examination was performed in a subset of familial PSP cases. Results: Fifty-seven (33%) of the 172 patients with PSP had at least one first-degree relative who had dementia or parkinsonism compared to 131 (25%) of the control subjects (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.01-2.13). In patients with PSP, more first-degree relatives with parkinsonism were observed compared to controls, with an OR 3.9 (95% CI 1.99-7.61). Twelve patients with PSP (7%) fulfilled the criteria for an autosomal dominant mode of transmission. The intrafamilial phenotype within these pedigrees varied among PSP, dementia, tremor, and parkinsonism. Genetic studies revealed one patient with a P301L mutation in MAPT. Pathologic examination of five familial cases confirmed the clinical diagnosis of PSP, with predominant four repeat tau pathology in affected brain areas. Conclusion: This study demonstrates familial aggregation of parkinsonism in progressive supranuclear palsy. Neurology(R) 2009; 73: 98-10
Midcingulate involvement in progressive supranuclear palsy and tau positive frontotemporal dementia
Background Progressive supranuclear palsy (PSP)
patients often exhibit cognitive decline and behavioural
changes during the disease course. In a subset, these
symptoms may be the presenting manifestation and can
be similar to those in frontotemporal dementia (FTD).
However, correlation studies between quantitative
imaging measures and detailed neuropsychological
assessment are scarce. The aim of this study was to
investigate the functional role of affected brain regions in
cognition in PSP compared with controls and
subsequently examine these regions in FTD patients with
known tau pathology (FTD tau).
Methods 21 PSP patients, 27 healthy controls and 11
FTD tau patients were enrolled. All participants
underwent neuropsychological testing and technetium99m-hexamethyl-propylenamine-oxime single photon
emission CT. Regression slope analyses were performed
in statistical parametric mapping to find significant
associations between neuropsychological test results
and brain perfusion.
Results PSP patients showed hypoperfusion in the
midcingulate cortex (MCC) of which the posterior part
correlated with Stroop III and Weigl. In FTD tau patients,
MCC involvement was located more anterior and
correlated with Stroop III and Wisconsin Card Sorting
Test concepts. The degree of hypoperfusion in the
anterior cortex and MCC in the disorders differed in the
subgenual anterior cingulate cortex only.
Conclusions T
Cognition and gray and white matter characteristics of presymptomatic C9orf72 repeat expansion
Neuro Imaging Researc
Distinct genetic forms of frontotemporal dementia
Background: Frontotemporal dementia (FTD) is the second most common type of presenile dementia and can be distinguished into various clinical variants. The identification of MAPT and GRN defects and the discovery of the TDP-43 protein in FTD have led to the classification of pathologic and genetic subtypes. In addition to these genetic subtypes, there exist familial forms of FTD with unknown genetic defects. Methods: We investigated the frequency, demographic, and clinical data of patients with FTD with a positive family history in our prospective cohort of 364 patients. Genetic analysis of genes associated with FTD was performed on all patients with a positive family history. Immunohistochemical studies were carried out with a panel of antibodies (tau, ubiquitin, TDP-43) in brains collected at autopsy. Results: In the total cohort of 364 patients, 27% had a positive family history suggestive for an autosomal mode of inheritance, including MAPT (11%) and GRN (6%) mutations. We identified a new Gln300X GRN mutation in a patient with a sporadic FTD. The mean age at onset in GRN patients (61.8 +/- 9.9 years) was higher than MAPT patients (52.4 +/- 5.9 years). In the remaining 10% of patients with suggestive autosomal dominant inheritance, the genetic defect has yet to be identified. Neuropathologically, this group can be distinguished into familial FTLD + MND and familial FTLD-U with hippocampal sclerosis. Conclusion: Future genetic studies need to identify genetic defects in at least two distinct familial forms of frontotemporal dementia (FTD) with unknown genetic defects: frontotemporal lobe degeneration with ubiquitin-positive inclusions with hippocampal sclerosis and frontotemporal lobe degeneration with motor neuron disease