Axon guidance receptors: Endocytosis, trafficking and downstream signaling from endosomes.

During the development of the nervous system, axons extend through complex environments. Growth cones at the axon tip allow axons to find and innervate their appropriate targets and form functional synapses. Axon pathfinding requires axons to respond to guidance signals and these cues need to be detected by specialized receptors followed by intracellular signal integration and translation. Several downstream signaling pathways have been identified for axon guidance receptors and it has become evident that these pathways are often initiated from intracellular vesicles called endosomes. Endosomes allow receptors to traffic intracellularly, re-locating receptors from one cellular region to another. The localization of axon guidance receptors to endosomal compartments is crucial for their function, signaling output and expression levels. For example, active receptors within endosomes can recruit downstream proteins to the endosomal membrane and facilitate signaling. Also, endosomal trafficking can re-locate receptors back to the plasma membrane to allow re-activation or mediate downregulation of receptor signaling via degradation. Accumulating evidence suggests that axon guidance receptors do not follow a pre-set default trafficking route but may change their localization within endosomes. This re-routing appears to be spatially and temporally regulated, either by expression of adaptor proteins or co-receptors. These findings shed light on how signaling in axon guidance is regulated and diversified - a mechanism which explains how a limited set of guidance cues can help to establish billions of neuronal connections. In this review, we summarize and discuss our current knowledge of axon guidance receptor trafficking and provide directions for future research.

A clinical diagnostic algorithm for early onset cerebellar ataxia.

Early onset cerebellar Ataxia (EOAc) comprises a large group of rare heterogeneous disorders. Determination of the underlying etiology can be difficult given the broad differential diagnosis and the complexity of the genotype-phenotype relationships. This may change the diagnostic work-up into a time-consuming, costly and not always rewarding task. In this overview, the Childhood Ataxia and Cerebellar Group of the European Pediatric Neurology Society (CACG-EPNS) presents a diagnostic algorithm for EOAc patients. In seven consecutive steps, the algorithm leads the clinician through the diagnostic process, including EOA identification, application of the Inventory of Non-Ataxic Signs (INAS), consideration of the family history, neuro-imaging, laboratory investigations, genetic testing by array CGH and Next Generation Sequencing (NGS). In children with EOAc, this algorithm is intended to contribute to the diagnostic process and to allow uniform data entry in EOAc databases.

[Parkinson syndromes: aspects of social medical care]. / Parkinson-Syndrome: Aspekte der sozialmedizinischen Versorgung.

Parkinson syndromes (PS) represent frequent neurodegenerative disorders. The demographic change suggests an increasing prevalence of PS in the near future. Treatment expenses, early retirement and need of long-term care result in rising public health care expenditures. Standardised concepts of care do not only improve the quality of patient-centered care, but also help to minimize its consequential costs. Their implementation requires profound knowledge of therapeutic strategies and sociomedical regulations. Medical treatment and sociomedical care have to be regularly reevaluated and adapted to the patient's needs and disease severity. An optimal therapy concept guarantees the patient's long term social integration and improves the compliance.

Involvement of the cholinergic basal forebrain nuclei in spinocerebellar ataxia type 2 (SCA2).

AIMS: Spinocerebellar ataxia type 2 (SCA2) belongs to the CAG repeat or polyglutamine diseases. Along with a large variety of motor, behavioural and neuropsychological symptoms the clinical picture of patients suffering from this autosomal dominantly inherited ataxia may also include deficits of attention, impairments of memory, as well as frontal-executive and visuospatial dysfunctions. As the possible morphological correlates of these cognitive SCA2 deficits are unclear we examined the cholinergic basal forebrain nuclei, which are believed to be crucial for several aspects of normal cognition and may contribute to impairments of cognitive functions under pathological conditions. METHODS: We studied pigment-Nissl-stained thick tissue sections through the cholinergic basal forebrain nuclei (that is, medial septal nucleus, nuclei of the diagonal band of Broca, basal nucleus of Meynert) of four clinically diagnosed and genetically confirmed SCA2 patients and of 13 control individuals according to the pathoanatomical approach. The pathoanatomical results were confirmed by additional quantitative investigations of these nuclei in the SCA2 patients and four age- and gender-matched controls. RESULTS: Our study revealed a severe and consistent neuronal loss in all of the cholinergic basal forebrain nuclei (medial septal nucleus: 72%; vertical nucleus of the diagonal band of Broca: 74%; horizontal limb of the diagonal band of Broca: 72%; basal nucleus of Meynert: 86%) of the SCA2 patients studied. Damage to the basal forebrain nuclei was associated with everyday relevant cognitive deficits only in our SCA2 patient with an additional Braak and Braak stage V Alzheimer's disease (AD)-related tau pathology. CONCLUSIONS: The findings of the present study: (1) indicate that the mutation and pathological process underlying SCA2 play a causative role for this severe degeneration of the cholinergic basal forebrain nuclei and (2) may suggest that degeneration of the cholinergic basal forebrain nuclei per se is not sufficient to cause profound and global dementia detrimental to everyday practice and activities of daily living.

Spinocerebellar ataxia type 1 (SCA1): new pathoanatomical and clinico-pathological insights.

AIMS: Spinocerebellar ataxia type 1 (SCA1) represents the first molecular genetically characterized autosomal dominantly inherited cerebellar ataxia and is assigned to the CAG-repeat or polyglutamine diseases. Owing to limited knowledge about SCA1 neuropathology, appropriate pathoanatomical correlates of a large variety of SCA1 disease symptoms are missing and the neuropathological basis for further morphological and experimental SCA1 studies is still fragmentary. METHODS: In the present study, we investigated for the first time serial tissue sections through the complete brains of clinically diagnosed and genetically confirmed SCA1 patients. RESULTS: Brain damage in the three SCA1 patients studied went beyond the well-known brain predilection sites of the underlying pathological process. Along with neuronal loss in the primary motor cortex, it included widespread degeneration of gray components of the basal forebrain, thalamus, brainstem and cerebellum, as well as of white matter components in the cerebellum and brainstem. It involved the motor cerebellothalamocortical and basal ganglia-thalamocortical circuits, the visual, auditory, somatosensory, oculomotor, vestibular, ingestion-related, precerebellar, basal forebrain cholinergic and midbrain dopaminergic systems. CONCLUSIONS: These findings show for the first time that the extent and severity of brain damage in SCA1 is very similar to that of clinically closely related spinocerebellar ataxias (that is, SCA2, SCA3 and SCA7). They offer suitable explanations for poorly understood SCA1 disease symptoms and will facilitate the interpretation of further morphological and experimental SCA1 studies.

Pathoanatomy of cerebellar degeneration in spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3).

The cerebellum is one of the well-known targets of the pathological processes underlying spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3). Despite its pivotal role for the clinical pictures of these polyglutamine ataxias, no pathoanatomical studies of serial tissue sections through the cerebellum have been performed in SCA2 and SCA3 so far. Detailed pathoanatomical data are an important prerequisite for the identification of the initial events of the underlying disease processes of SCA2 and SCA3 and the reconstruction of its spread through the brain. In the present study, we performed a pathoanatomical investigation of serial thick tissue sections through the cerebellum of clinically diagnosed and genetically confirmed SCA2 and SCA3 patients. This study demonstrates that the cerebellar Purkinje cell layer and all four deep cerebellar nuclei consistently undergo considerable neuronal loss in SCA2 and SCA3. These cerebellar findings contribute substantially to the pathogenesis of clinical symptoms (i.e., dysarthria, intention tremor, oculomotor dysfunctions) of SCA2 and SCA3 patients and may facilitate the identification of the initial pathological alterations of the pathological processes of SCA2 and SCA3 and reconstruction of its spread through the brain.

[Clinical details and genetics of recessive ataxias]. / Klinik und Genetik der rezessiven Ataxien.

Autosomal recessive cerebellar ataxias (ARCA) are a heterogeneous group of rare neurological diseases affecting both the central and the peripheral nervous systems. They are characterized by autosomal recessive inheritance, progressive ataxia and degeneration of the cerebellum and spinal cord. Onset is generally before the third decade of life. The most frequent of these rare disorders in the Caucasian population is Friedreich's ataxia followed by ataxias with oculomotor apraxia. ARCAs are caused by mutations at specific loci but not every affected gene is known to date. Clinical diagnosis can be confirmed by ancillary tests (biochemical, neuroimaging and electrophysiological investigations) and mutation analyses if the causative gene has been identified. Correct clinical and genetic diagnosis is necessary for prognosis, genetic counseling and pharmacological treatment. For the majority of ARCAs a curative treatment is not available.

Antineuronal antibodies in sporadic late-onset cerebellar ataxia.

Sporadic late-onset cerebellar ataxia of unknown cause is considered a neurodegenerative disorder whose underlying mechanisms are still unknown. To identify antineuronal autoantibodies, immunohistochemical and immunoblotting techniques were performed in 67 patients with sporadic cerebellar degeneration of unknown cause. Elevated P/Q-type voltage-gated calcium channel (VGCC)-specific antibodies were found in eight patients (11.9%). There was no hint of a paraneoplastic disorder in any of the patients. The present findings suggest an autoimmune contribution to the pathophysiology of a subgroup of sporadic late-onset cerebellar ataxia.

Involvement of the auditory brainstem system in spinocerebellar ataxia type 2 (SCA2), type 3 (SCA3) and type 7 (SCA7).

AIMS: The spinocerebellar ataxia type 2 (SCA2), type 3 (SCA3) and type 7 (SCA7) are clinically characterized by progressive and severe ataxic symptoms, dysarthria, dysphagia, oculomotor impairments, pyramidal and extrapyramidal manifestations and sensory deficits. Although recent clinical studies reported additional disease signs suggesting involvement of the brainstem auditory system, this has never been studied in detail in SCA2, SCA3 or SCA7. METHODS: We performed a detailed pathoanatomical investigation of unconventionally thick tissue sections through the auditory brainstem nuclei (that is, nucleus of the inferior colliculus, nuclei of the lateral lemniscus, superior olive, cochlear nuclei) and auditory brainstem fibre tracts (that is, lateral lemniscus, trapezoid body, dorsal acoustic stria, cochlear portion of the vestibulocochlear nerve) of clinically diagnosed and genetically confirmed SCA2, SCA3 and SCA7 patients. RESULTS: Examination of unconventionally thick serial brainstem sections stained for lipofuscin pigment and Nissl material revealed a consistent and widespread involvement of the auditory brainstem nuclei in the SCA2, SCA3 and SCA7 patients studied. Serial brainstem tissue sections stained for myelin showed loss of myelinated fibres in two of the auditory brainstem fibre tracts (that is, lateral lemniscus, trapezoid body) in a subset of patients. CONCLUSIONS: The involvement of the auditory brainstem system offers plausible explanations for the auditory impairments detected in some of our and other SCA2, SCA3 and SCA7 patients upon bedside examination or neurophysiological investigation. However, further clinical studies are required to resolve the striking discrepancy between the consistent involvement of the brainstem auditory system observed in this study and the comparatively low frequency of reported auditory impairments in SCA2, SCA3 and SCA7 patients.

Screening of the SPTBN2 (SCA5) gene in German SCA patients.

The spinocerebellar ataxias (SCAs) with autosomal dominant inheritance are a clinically and genetically heterogeneous group of neurodegenerative disorders. To date 27 different loci have been identified for these conditions. Recently, two deletions as well as one missense mutation in the beta-III spectrin gene (STBN2) were identified causing SCA5. To evaluate the clinical relevance of these mutations, we screened 310 familial and sporadic patients with ataxia. While none of the individuals tested had evidence for one of the known SCA5 mutations, additional sequencing of the coding region for 22 unrelated patients revealed three novel missense exchanges at evolutionary conserved amino acid positions. Even though each variation marks a unique genotype in 250 alleles, a disease causing capacity can be excluded with high probability. These results reflect the challenges for molecular analyses in SCA5.

High frequency of partial SPAST deletions in autosomal dominant hereditary spastic paraplegia.

BACKGROUND: Hereditary spastic paraplegia (HSP) is a genetically heterogeneous neurodegenerative disease. The most frequent cause of autosomal dominant HSP is mutation of SPAST (SPG4 locus), but additional pedigrees remain mutation negative by conventional screening despite linkage to SPG4. OBJECTIVE: To determine the frequency of genomic copy number aberrations of SPAST in autosomal dominant HSP. METHODS: We developed and validated a multiplex ligation-dependent probe amplification assay targeting SPAST and SPG3A, another gene frequently involved in autosomal dominant HSP. In a multicenter study we subsequently investigated 65 index patients with autosomal dominant HSP, all of whom had previously been screened negative for SPAST mutations. Independent secondary samples, additional family members, and cDNA were analyzed to confirm positive findings. RESULTS: Aberrant MLPA profiles were identified in 12 cases (18%). They exclusively affect SPAST, represent deletions, segregate with the disease, and are largely pedigree specific. Internal SPAST deletions entail expression of correspondingly shortened transcripts, which vary in stability. Age at onset in SPAST deletion carriers does not differ from that associated with other SPAST mutations. CONCLUSIONS: Partial SPAST deletions, but not SPAST amplifications and SPG3A copy number aberrations, represent an underestimated cause of autosomal dominant hereditary spastic paraplegia. Partial SPAST deletions are likely to act via haploinsufficiency.

Phase II study of MTX-HSA in combination with cisplatin as first line treatment in patients with advanced or metastatic transitional cell carcinoma.

PURPOSE: To assess the efficacy, tolerability and safety of MTX-HSA (methotrexate (MTX) covalently linked to human serum albumin (HSA)) combined with cisplatin as first line therapy for advanced bladder cancer. METHODS: Patients (pat) were treated with a loading dose of 110 mg/m(2) of MTX-HSA followed by a weekly dose of 40 mg/m(2) starting on day 8. Cisplatin was given on day 2 of each 28 day cycle at a dose of 75 mg/m(2). RESULTS: Tumor response evaluation was possible in 7 patients. Complete response (CR) and partial response (PR) was observed in 1 patient each (overall response rate: 29%). Key toxicities included CTC Grade (G) 3/4 stomatitis in 6 patients, vomiting G3 in 1 patient, fatigue G3 in 1 patient and thrombocytopenia G3 in 3 patients. CONCLUSION: The combination of MTX-HSA with cisplatin is feasible and shows antitumor activity against urothelial carcinomas combined with an acceptable toxicity profile.

The alpha-synuclein gene in multiple system atrophy.

BACKGROUND: The formation of alpha-synuclein aggregates may be a critical event in the pathogenesis of multiple system atrophy (MSA). However, the role of this gene in the aetiology of MSA is unknown and untested. METHOD: The linkage disequilibrium (LD) structure of the alpha-synuclein gene was established and LD patterns were used to identify a set of tagging single nucleotide polymorphisms (SNPs) that represent 95% of the haplotype diversity across the entire gene. The effect of polymorphisms on the pathological expression of MSA in pathologically confirmed cases was also evaluated. RESULTS AND CONCLUSION: In 253 Gilman probable or definite MSA patients, 457 possible, probable, and definite MSA cases and 1472 controls, a frequency difference for the individual tagging SNPs or tag-defined haplotypes was not detected. No effect was observed of polymorphisms on the pathological expression of MSA in pathologically confirmed cases.

The fragile X tremor ataxia syndrome in the differential diagnosis of multiple system atrophy: data from the EMSA Study Group.

The recent identification of fragile X-associated tremor ataxia syndrome (FXTAS) associated with premutations in the FMR1 gene and the possibility of clinical overlap with multiple system atrophy (MSA) has raised important questions, such as whether genetic testing for FXTAS should be performed routinely in MSA and whether positive cases might affect the specificity of current MSA diagnostic criteria. We genotyped 507 patients with clinically diagnosed or pathologically proven MSA for FMR1 repeat length. Among the 426 clinically diagnosed cases, we identified four patients carrying FMR1 premutations (0.94%). Within the subgroup of patients with probable MSA-C, three of 76 patients (3.95%) carried premutations. We identified no premutation carriers among 81 patients with pathologically proven MSA and only one carrier among 622 controls (0.16%). Our results suggest that, with proper application of current diagnostic criteria, FXTAS is very unlikely to be confused with MSA. However, slowly progressive disease or predominant tremor are useful red flags and should prompt the consideration of FXTAS. On the basis of our data, the EMSA Study Group does not recommend routine FMR1 genotyping in typical MSA patients.

Involvement of the cranial nerves and their nuclei in spinocerebellar ataxia type 2 (SCA2).

Although the cranial nerves, their nuclei and related fiber tracts are crucial for a variety of oculomotor, somatomotor, somatosensory, auditory, vestibular-related, autonomic and ingestion-related functions, knowledge regarding the extent of their involvement in spinocerebellar ataxia type 2 (SCA2) patients is incomplete. Accordingly, we performed a pathoanatomical analysis of these structures in six clinically diagnosed SCA2 patients. Unconventionally thick serial sections through the brainstem stained for lipofuscin pigment (aldehyde-fuchsin) and Nissl material (Darrow red) showed that all oculomotor, somatomotor, somatosensory, auditory, vestibular and autonomic cranial nerve nuclei may undergo neurodegeneration during SCA2. Similarly, examination of myelin-stained thick serial sections revealed that nearly all cranial nerves and associated fiber tracts may sustain atrophy and myelin loss in SCA2 patients. In view of the known functional role of the affected cranial nerves, their nuclei and associated fiber tracts, the present findings provide appropriate pathoanatomical explanations for some of the disease-related and unexplained symptoms seen in SCA2 patients: double vision, gaze palsy, slowing of saccades, ptosis, ingestion-related malfunctions, impairments of the optokinetic nystagmus and the vestibulo-ocular reaction, facial and tongue fasciculation-like movements, impaired centripetal transmission of temperature-related information from the face, dystonic posture of the neck, as well as abnormalities of the brainstem auditory evoked potentials.

Extended pathoanatomical studies point to a consistent affection of the thalamus in spinocerebellar ataxia type 2.

The involvement of the thalamus during the course of the currently known polyglutamine diseases is still a matter of debate. While it is well-known that this diencephalic nuclear complex undergoes neurodegeneration in some polyglutamine diseases such as Huntington's disease (HD), it has remained unclear whether and to what extent the thalamus is also involved in spinocerebellar ataxia type 2 (SCA2) patients. Encouraged by our recent post-mortem findings in one German SCA2 patient and the results of a recent nuclear magnetic resonance (NMR) study, we extended our pathoanatomical analysis to serial thick sections stained for lipofuscin granules and Nissl substance through the thalami of four additional German and Cuban SCA2 patients. According to this analysis the thalamus is consistently affected by the destructive process of SCA2. In particular, during our study we observed a consistent involvement of the lateral geniculate body, the lateral posterior, ventral anterior, ventral lateral, ventral posterior lateral, and ventral posterior medial thalamic nuclei as well as the extraterritorial reticular nucleus. In four of the SCA2 cases studied additional damage was seen in the inferior and lateral nuclei of the pulvinar, whereas in the minority of the patients a subset of the limbic nuclei of the thalamus (i.e. anterodorsal, anteroprincipal, laterodorsal, fasciculosus, mediodorsal, central lateral, central medial, cucullar, and paracentral nuclei, medial nucleus of the pulvinar) underwent neurodegeneration. These interindividual differences in the distribution pattern of thalamic neurodegeneration indicate that the thalamic nuclei differ in their proclivities to degenerate in SCA2 and may suggest that they become involved at different phases in the evolution of the underlying degenerative process.

Spinocerebellar ataxias types 2 and 3: degeneration of the pre-cerebellar nuclei isolates the three phylogenetically defined regions of the cerebellum.

The pre-cerebellar nuclei act as a gate for the entire neocortical, brainstem and spinal cord afferent input destined for the cerebellum. Since no pathoanatomical studies of these nuclei had yet been performed in spinocerebellar ataxia type 2 (SCA2) or type 3 (SCA3), we carried out a detailed postmortem study of the pre-cerebellar nuclei in six SCA2 and seven SCA3 patients in order to further characterize the extent of brainstem degeneration in these ataxic disorders. By means of unconventionally thick serial sections through the brainstem stained for lipofuscin pigment and Nissl material, we could show that all of the pre-cerebellar nuclei (red, pontine, arcuate, prepositus hypoglossal, superior vestibular, lateral vestibular, medial vestibular, interstitial vestibular, spinal vestibular, vermiform, lateral reticular, external cuneate, subventricular, paramedian reticular, intercalate, interfascicular hypoglossal, and conterminal nuclei, pontobulbar body, reticulotegmental nucleus of the pons, inferior olive, and nucleus of Roller) are among the targets of both of the degenerative processes underlying SCA2 and SCA3. These novel findings are in contrast to the current neuropathological literature, which assumes that only a subset of pre-cerebellar nuclei in SCA2 and SCA3 may undergo neurodegeneration. Widespread damage to the pre-cerebellar nuclei separates all three phylogenetically and functionally defined regions of the cerebellum, impairs their physiological functions and thus explains the occurrence of gait, stance, limb and truncal ataxia, dysarthria, truncal and postural instability with disequilibrium, impairments of the vestibulo-ocular reaction and optokinetic nystagmus, slowed and saccadic smooth pursuits, dysmetrical horizontal saccades, and gaze-evoked nystagmus during SCA2 and SCA3.