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

Myopathy in CRPS-I: Disuse or neurogenic?

The diagnosis Complex Regional Pain Syndrome type I (CRPS-I) is based on clinical symptoms, including motor symptoms. Histological changes in muscle tissue may be present in the chronic phase of CRPS-I. Aim of this study was to analyze skeletal muscle tissue from amputated limbs of patients with CRPS-I, in order to gain more insight in factors that may play a role in changes in muscles in CRPS-I. These changes may be helpful in clarifying the pathophysiology of CRPS-I. Fourteen patients with therapy resistant and longstanding CRPS-I, underwent an amputation of the affected limb. In all patients histological analysis showed extensive changes in muscle tissue, such as fatty degeneration, fibre atrophy and nuclear clumping, which was not related to duration of CRPS-I prior to amputation. In all muscles affected, both type 1 and type 2 fibre atrophy was found, without selective type 2 fibre atrophy. In four patients, type grouping was observed, indicating a sequence of denervation and reinnervation of muscle tissue. In two patients even large group atrophy was present, suggesting new denervation after reinnervation. Comparison between subgroups in arms and legs showed no difference in the number of changes in muscle tissue. Intrinsic and extrinsic muscles were affected equally. Our findings show that in the chronic phase of CRPS-I extensive changes can be seen in muscle tissue, not related to duration of CRPS-I symptoms. Signs of neurogenic myopathy were present in five patients

Amputation for Long-Standing, Therapy-Resistant Type-I Complex Regional Pain Syndrome

Background: Some patients with long-standing, therapy-resistant typed complex regional pain syndrome consider an amputation. There is a lack of evidence regarding the risk of recurrence of the pain syndrome and patient outcomes after amputation. The goal of the present study was to evaluate the impact of an amputation on pain, participation in daily life activities, and quality of life as well as the use of a prosthesis and the risk of recurrence of the pain syndrome in patients with long-standing, therapy-resistant typed complex regional pain syndrome.Methods: From May 2000 to October 2008, twenty-two patients underwent an amputation of a nonfunctional limb at our institution because of long-standing, therapy-resistant typed complex regional pain syndrome. Twenty-one of these patients were included in our study. The median age was forty-six years (interquartile range [IQR], thirty-seven to fifty-one years), the median duration of the complex regional pain syndrome was six years (IQR, two to ten years), and the median interval between the amputation and the study was five years (IQR, three to seven years). A semistructured interview was conducted, physical examination of the residual limb was performed, and the patients completed two questionnaires.Results: Twenty patients (95%) reported an improvement in their lives. Nineteen patients (90%) reported a reduction in pain, seventeen patients (81%) reported an improvement in mobility, and fourteen (67%) reported an improvement in sleep. Eighteen of the twenty-one patients stated that they would choose to undergo an amputation again under the same circumstances. Ten of the fifteen patients with a lower-limb amputation and one of the six with an upper-limb amputation regularly used a prosthesis. The typed complex regional pain syndrome recurred in the residual limb of three patients (14%) and symptoms recurred in another limb in two patients (10%).Conclusions: Amputation may positively contribute to the lives of patients with long-standing, therapy-resistant type-I complex regional pain syndrome. Patients were likely to use a prosthesis after a lower-limb amputation. The risk of recurrence of the type-I complex regional pain syndrome was 24%.</p

First patho-anatomical investigation of the brain of a SCA19 patient

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Identification of Two Protein-Signaling States Delineating Transcriptionally Heterogeneous Human Medulloblastoma

The brain cancer medulloblastoma consists of different transcriptional subgroups. To characterize medulloblastoma at the phosphoprotein-signaling level, we performed high-throughput peptide phosphorylation profiling on a large cohort of SHH (Sonic Hedgehog), group 3, and group 4 medulloblastomas. We identified two major protein-signaling profiles. One profile was associated with rapid death post-recurrence and resembled MYC-like signaling for which MYC lesions are sufficient but not necessary. The second profile showed enrichment for DNA damage, as well as apoptotic and neuronal signaling. Integrative analysis demonstrated that heterogeneous transcriptional input converges on these protein-signaling profiles: all SHH and a subset of group 3 patients exhibited the MYC-like protein-signaling profile; the majority of the other group 3 subset and group 4 patients displayed the DNA damage/apoptotic/neuronal signaling profile. Functional analysis of enriched pathways highlighted cell-cycle progression and protein synthesis as therapeutic targets for MYC-like medulloblastoma