Deciphering the causes of sporadic late-onset cerebellar ataxias: a prospective study with implications for diagnostic work.

The management of sporadic late-onset cerebellar ataxias represents a very heterogeneous group of patients and remains a challenge for neurologist in clinical practice. We aimed at describing the different causes of sporadic late-onset cerebellar ataxias that were diagnosed following standardized, exhaustive investigations and the population characteristics according to the aetiologies as well as at evaluating the relevance of these investigations. All patients consecutively referred to our centre due to sporadic, progressive cerebellar ataxia occurring after 40 years of age were included in the prospective, observational study. 80 patients were included over a 2 year period. A diagnosis was established for 52 patients (65%) corresponding to 18 distinct causes, the most frequent being cerebellar variant of multiple system atrophy (n = 29). The second most frequent cause was inherited diseases (including spinocerebellar ataxias, late-onset Friedreich's disease, SLC20A2 mutations, FXTAS, MELAS, and other mitochondrial diseases) (n = 9), followed by immune-mediated or other acquired causes. The group of patient without diagnosis showed a slower worsening of ataxia (p < 0.05) than patients with multiple system atrophy. Patients with later age at onset experienced faster progression of ataxia (p = 0.001) and more frequently parkinsonism (p < 0.05) than patients with earlier onset. Brain MRI, DaT scan, genetic analysis and to some extent muscle biopsy, thoracic-abdominal-pelvic tomodensitometry, and cerebrospinal fluid analysis were the most relevant investigations to explore sporadic late-onset cerebellar ataxia. Sporadic late-onset cerebellar ataxias should be exhaustively investigated to identify the underlying causes that are numerous, including inherited causes, but dominated by multiple system atrophy.

A discriminative feature selection approach for shape analysis: Application to fetal brain cortical folding.

The development of post-processing reconstruction techniques has opened new possibilities for the study of in-utero fetal brain MRI data. Recent cortical surface analysis have led to the computation of quantitative maps characterizing brain folding of the developing brain. In this paper, we describe a novel feature selection-based approach that is used to extract the most discriminative and sparse set of features of a given dataset. The proposed method is used to sparsely characterize cortical folding patterns of an in-utero fetal MR dataset, labeled with heterogeneous gestational age ranging from 26 weeks to 34 weeks. The proposed algorithm is validated on a synthetic dataset with both linear and non-linear dynamics, supporting its ability to capture deformation patterns across the dataset within only a few features. Results on the fetal brain dataset show that the temporal process of cortical folding related to brain maturation can be characterized by a very small set of points, located in anatomical regions changing across time. Quantitative measurements of growth against time are extracted from the set selected features to compare multiple brain regions (e.g. lobes and hemispheres) during the considered period of gestation.

Cerebral tumors: specific features in children.

Brain tumors are the second leading cause of cancer in children. Primary tumors predominate and are of very varied histological types. Their prognosis and treatment depend on the histological type and grade. The diagnostic approach to these includes analysis of the site of the lesion and appearances on computed tomography and MR, and taking account of the age and clinical features of the child. CT is used to diagnose the tumor in an emergency situation. Conventional MR provides a morphological approach and allows a staging assessment to be carried out before surgery. Advanced MR techniques (diffusion-weighted and perfusion imaging, MR spectroscopy) provide further information for the differential diagnosis, presumptive diagnosis of type and grade and to guide biopsy towards the most malignant areas in the lesion.

Probabilistic tractography using Q-ball imaging and particle filtering: application to adult and in-utero fetal brain studies.

By assuming that orientation information of brain white matter fibers can be inferred from Diffusion-Weighted Magnetic Resonance Imaging (DW-MRI) measurements, tractography algorithms provide an estimation of the brain connectivity in vivo. The two key ingredients of tractography are the diffusion model (tensor, high-order tensor, Q-ball, etc.) and the means to deal with uncertainty during the tracking process (deterministic vs probabilistic mathematical framework). In this paper, we investigate the use of an analytical Q-ball model for the diffusion data within a well-formalized particle filtering framework. The proposed method is validated and compared to other tracking algorithms on the MICCAI'09 contest Fiber Cup phantom. Tractographies of in vivo adult and fetal brain Diffusion-Weighted Images (DWIs) are also shown to illustrate the robustness of the algorithm.

Tips and traps in neurological imaging: imaging the perimedullary spaces.

The spinal canal is frequently a source of difficulties, traps and diagnostic errors. Pitfalls related to artifacts are resolved by using appropriate sequences. Good knowledge of the appearance of certain particular anatomical structures (the cauda equina roots, the radicular veins of the lumbar spine and conus medullaris, the dorsal root ganglion) and of frequent variants (fibrolipoma of the filum terminale, common root sheaths, root cysts) will avoid a good many errors. Dilatation of epidural veins in intracranial hypotension can simulate the contrast enhancement of a tumour. An increase in epidural fat can induce pathogenic stenosis of the dural sheath.

Osteosclerotic bone dysplasia in siblings with a Fam20C mutation.

Raine syndrome is an autosomal recessive disorder caused by mutations in the FAM20C gene. FAM20C codes for the human homolog of DMP4, a dentin matrix protein highly expressed in odontoblasts and moderately in bone. DMP4 is probably playing a role in the mineralization process. Since the first case reported in 1989 by Raine et al. 21 cases have been published delineating a phenotype which associates dysmorphic features, cerebral calcifications, choanal atresia or stenosis and thoracic/pulmonary hypoplasia. Kan and Kozlowski suggested the name of Raine syndrome to describe this new lethal osteosclerotic bone dysplasia. All the cases described were lethal during the neonatal period except for the last two reported patients aged 8 and 11 years who presented severe mental retardation. Here we describe two sisters, with an attenuated phenotype of Raine syndrome, who present an unexpectedly normal psychomotor development at ages 4 and 1, respectively. Identification of a homozygous mutation in the FAM20C gene confirmed the Raine syndrome diagnosis, thus contributing to the expansion of the Raine syndrome phenotype. This case report also prompted us to revisit the FAM20 gene classification and allowed us to highlight the ancestral status of Fam20C.

On super-resolution for fetal brain MRI.

Super-resolution techniques provide a route to studying fine scale anatomical detail using multiple lower resolution acquisitions. In particular, techniques that do not depend on regular sampling can be used in medical imaging situations where imaging time and resolution are limited by subject motion. We investigate in this work the use of a super-resolution technique for anisotropic fetal brain MR data reconstruction without modifying the data acquisition protocol. The approach, which consists of iterative motion correction and high resolution image estimation, is compared with a previously used scattered data interpolation-based reconstruction method. To optimize acquisition time, an evaluation of the influence of the number of input images and image noise is also performed. Evaluation on simulated MR images and real data show significant improvements in performance provided by the super-resolution approach.

Neuroimaging in Cockayne syndrome.

CS is an autosomal recessive multisystem disorder, which is mainly characterized by neurologic and sensory impairment, cachectic dwarfism, and photosensitivity. We describe the neuroimaging features (MR imaging, ¹H-MR spectroscopy, and CT) in the various clinical subtypes of CS from a cohort of genetically and biochemically proved cases. Hypomyelination, calcifications, and brain atrophy were the main imaging features. Calcifications were typically found in the putamen and less often in the cortex and dentate nuclei. Severe progressive atrophy was seen in the supratentorial white matter, the cerebellum, the corpus callosum, and the brain stem. Patients with early-onset disease displayed more severe hypomyelination and prominent calcifications in the sulcal depth of the cerebral cortex, but atrophy was less severe in late-onset patients. On proton MR spectroscopy, lactate was detected and Cho and NAA values were decreased. These combined neuroradiologic findings can help in the differential diagnosis of CS, distinguishing it from other leukoencephalopathies and/or cerebral calcifications in childhood.

T-type current modulation by the actin-binding protein Kelch-like 1.

We report a novel form of modulation of T-type calcium currents carried out by the neuronal actin-binding protein (ABP) Kelch-like 1 (KLHL1). KLHL1 is a constitutive neuronal ABP localized to the soma and dendritic arbors; its genetic elimination in Purkinje neurons leads to dendritic atrophy and motor insufficiency. KLHL1 participates in neurite outgrowth and upregulates voltage-gated P/Q-type calcium channel function; here we investigated KLHL1's role as a modulator of low-voltage-gated calcium channels and determined the molecular mechanism of this modulation with electrophysiology and biochemistry. Coexpression of KLHL1 with Ca(V)3.1 or Ca(V)3.2 (alpha(1G) or alpha(1H) subunits) caused increases in T-type current density (35%) and calcium influx (75-83%) when carried out by alpha(1H) but not by alpha(1G). The association between KLHL1 and alpha(1H) was determined by immunoprecipitation and immunolocalization in brain membrane fractions and in vitro in HEK-293 cells. Noise analysis showed that neither alpha(1H) single-channel conductance nor open probability was altered by KLHL1, yet a significant increase in channel number was detected and further corroborated by Western blot analysis. KLHL1 also induced an increase in alpha(1H) current deactivation time (tau(deactivation)). Interestingly, the majority of KLHL1's effects were eliminated when the actin-binding motif (kelch) was removed, with the exception of the calcium influx increase during action potentials, indicating that KLHL1 interacts with alpha(1H) and actin and selectively regulates alpha(1H) function by increasing the number of alpha(1H) channels. This constitutes a novel regulatory mechanism of T-type calcium currents and supports the role of KLHL1 in the modulation of cellular excitability.

Kelch-like 1 protein upregulates T-type currents by an actin-F dependent increase in α(1H) channels via the recycling endosome.

The neuronal protein Kelch-like 1 (KLHL1) is a novel actin-binding protein that modulates neuronal structure and function. KLHL1 knockout mice exhibit dendritic atrophy in cerebellar Purkinje neurons and motor dysfunction. Interestingly, KLHL1 upregulates high and low voltage-gated calcium currents (Ca(V)2.1 and Ca(V)3.2) and interacts with their respective principal subunits, α(1A) and α(1H). We reported the mechanism of enhanced Ca(V)3.2 (α(1H)) current density (and calcium influx) by KLHL1 is due to an increase in channel number (N) that requires the binding of actin. In this report we further elucidate the role of the actin cytoskeleton in this process using pharmacological tools to disrupt or stabilize actin filaments and to prevent protein trafficking and vesicle recycling. Disruption of the cytoskeleton did not affect the basal activity of α(1H), but did eliminate its modulation by KLHL1. In contrast, actin-F stabilization on its own increased basal α(1H) activity similar to KLHL1 but without synergy in its presence, suggesting KLHL1 requires actin-polymerization to increase α(1H) currents. Noise analysis revealed that actin polymerization induced an increase in N and P(o), in contrast to increased N in the presence of KLHL1. Interestingly, pharmacological or genetic disruption of endosomal recycling eliminated the increase in channel number by KLHL1 demonstrating this effect occurs via enhanced α(1H) re-insertion through the recycling endosome. Our findings afford insight on a novel mechanism of T-type channel modulation that could have overall functional implications for T-type channel function in the brain.

[Imaging spinal cord cystic lesions in adults]. / Imagerie des lésions kystiques du canal rachidien chez l'adulte.

Intrarachidian cystic lesions are frequent, with highly varied causes. They can be classified according to their location into intramedullary cystic lesions and extramedullary cystic lesions. In these two categories, they can then be regrouped according to the tissue from which they develop. MRI is the first-choice examination for the study of the intracanal contents and the differential diagnosis between the various lesions.

The Kelch-like protein 1 modulates P/Q-type calcium current density.

The actin-binding protein Kelch-like 1 (KLHL1) is a neuronal protein that belongs to the evolutionarily-conserved Kelch protein super-family. The mammalian KLHL1 is brain-specific, cytosolic and can form multimers and bind actin filaments. KLHL1's function is likely that of an actin-organizing protein, possibly modulating neurite outgrowth, the dynamic morphology of dendritic spine heads; or anchoring proteins essential for post-synaptic function, like ion channels. Targeted deletion of the KLHL1 gene in Purkinje neurons results in dendritic deficits in these neurons, abnormal gait, and progressive loss of motor coordination in mice [He Y, Zu T, Benzow KA, Orr HT, Clark HB, Koob MD (2006) Targeted deletion of a single SCA8 ataxia locus allele in mice causes abnormal gait, progressive loss of motor coordination, and Purkinje cell dendritic deficits. J Neurosci 26:9975-9982]. Here we tested the hypothesis that KLHL1 may interact and modulate voltage-gated calcium channels by assessing the interaction of the principal subunit of P/Q-type channels, alpha(1A), with KLHL1. Experiments in human embryonic kidney line HEK 293 (HEK) cells and cerebellar primary cultures revealed co-incidence of alpha(1A) and KLHL1 immunoreactivity when testing both the endogenous or epitope-tagged versions of the proteins. Similarly, co-immunoprecipitation experiments in HEK cells and brain tissue exposed the presence of KLHL1 in protein samples immunoprecipitated with FLAG-tagged or alpha(1A) antibodies. Functional studies of KLHL1 on P/Q-type current properties probed with whole-cell patch clamp revealed a significant increase in mean current density in the presence of KLHL1 (80% increase; from -13.2+/-2.0 pA/pF to -23.7+/-4.2 pA/pF, P<0.02), as well as a shift in steady state activation V(50) of -5.5 mV (from 12.8+/-1.8 mV to 7.3+/-1.0 mV, P<0.02). Our data are consistent with a modulatory effect of KLHL1 on the P/Q-type calcium channel function and suggest a possible novel role for KLHL1 in cellular excitability.

Accuracy of delayed post-contrast FLAIR MR imaging for the diagnosis of leptomeningeal infectious or tumoral diseases.

AIMS: To compare unenhanced, gadolinium enhanced, delayed gadolinium enhanced FLAIR images, gadolinium enhanced and delayed gadolinium enhanced T1 images in different types of leptomeningeal diseases, and to determine the most accurate MRI sequence for the diagnosis of leptomeningeal disease. MATERIAL: and methods: Ten patients (6 men, 4 women, age: 52,7+/-16,4) clinically suspected of cerebral leptomeningeal infectious or tumoral disease underwent brain MR examination: Axial FLAIR and T1 SE images were acquired before, immediately after administration of gadobenate dimeglumine (0.1 mmol per kilogram of body weight) (early enhancement), and 20 minutes after injection of contrast media (delayed enhancement). Images were analysed to determine the more appropriate technique for the diagnosis of leptomeningeal disease. RESULTS: Early enhanced FLAIR and delayed enhanced T1 were always more or equally accurate for the diagnosis of leptomeningeal diasease, as compared to, respectively, unenhanced FLAIR and early enhanced T1 images Delayed enhanced FLAIR was always more accurate for the diagnosis of leptomeningeal disease as compared to early enhanced FLAIR images. Delayed enhanced FLAIR was in most of the cases more accurate for the diagnosis of leptomeningeal disease as compared to delayed enhanced T1 images. CONCLUSION: Delayed enhanced FLAIR MR sequence seems to improve the diagnosis of leptomeningeal infectious or tumoral diseases as compared to other MR sequences.

[Normal and abnormal meningeal enhancement: MRI features]. / Les prises de contraste méningées normales et pathologiques en IRM.

The authors describe normal imaging of the meninges and meningeal spaces and MR (magnetic resonance) imaging findings in tumoral and nontumoral diseases. Dural or/and pial enhancement may be related to tumoral, infectious or granulomatous diseases.

SCA8 CTG repeat: en masse contractions in sperm and intergenerational sequence changes may play a role in reduced penetrance.

We recently described an untranslated CTG expansion that causes a previously undescribed form of spinocerebellar ataxia (SCA8). The SCA8 CTG repeat is preceded by a polymorphic but stable CTA tract, with the configuration (CTA)(1-21)(CTG)(n). The CTG portion of the repeat is elongated on pathogenic alleles, which nearly always change in size when transmitted from generation to generation. To better understand the reduced penetrance and maternal penetrance bias associated with SCA8 we analyzed the sequence configurations and instability patterns of the CTG repeat in affected and unaffected family members. In contrast to other triplet repeat diseases, expanded alleles found in affected SCA8 individuals can have either a pure uninterrupted CTG repeat tract or an allele with one or more CCG, CTA, CTC, CCA or CTT interruptions. Surprisingly, we found six different sequence configurations of the CTG repeat on expanded alleles in a seven generation family. In two instances duplication of CCG interruptions occurred over a single generation and in other instances duplications that had occurred in different branches of the family could be inferred. We also evaluated SCA8 instability in sperm samples from individuals with expansions ranging in size from 80 to 800 repeats in blood. Surprisingly the SCA8 repeat tract in sperm underwent contractions, with nearly all of the resulting expanded alleles having repeat lengths of <100 CTGs, a size that is not often associated with disease. These en masse repeat contractions in sperm likely underlie the reduced penetrance associated with paternal transmission.

The SCA8 transcript is an antisense RNA to a brain-specific transcript encoding a novel actin-binding protein (KLHL1).

Spinocerebellar ataxia type 8 (SCA8) is a neurodegenerative disorder caused by the expansion of a CTG trinucleotide repeat that is transcribed as part of an untranslated RNA. As a step towards understanding the molecular pathology of SCA8, we have defined the genomic organization of the SCA8 RNA transcripts and assembled a 166 kb segment of genomic sequence containing the repeat. The most striking feature of the SCA8 transcripts is that the most 5' exon is transcribed through the first exon of another gene that is transcribed in the opposite orientation. This gene arrangement suggests that the SCA8 transcript is an endogenous antisense RNA that overlaps the transcription and translation start sites as well as the first splice donor sequence of the sense gene. The sense transcript encodes a 748 amino acid protein with a predicted domain structure typical of a family of actin-organizing proteins related to the Drosophila Kelch gene, and so has been given the name Kelch-like 1 (KLHL1). We have identified the full-length cDNA sequence for both the human and mouse KLHLI genes, and have elucidated the general genomic organization of the human gene. The predicted open reading frame and promoter region are highly conserved, and both genes are primarily expressed in specific brain tissues, including the cerebellum, the tissue most affected by SCA8. Transfection studies with epitope-tagged KLHL1 demonstrate that the protein localizes to the cytoplasm, suggesting that it may play a role in organizing the actin cytoskeleton of the brain cells in which it is expressed.

Nuclear localization of the spinocerebellar ataxia type 7 protein, ataxin-7.

Spinocerebellar ataxia type 7 (SCA7) belongs to a group of neurological disorders caused by a CAG repeat expansion in the coding region of the associated gene. To gain insight into the pathogenesis of SCA7 and possible functions of ataxin-7, we examined the subcellular localization of ataxin-7 in transfected COS-1 cells using SCA7 cDNA clones with different CAG repeat tract lengths. In addition to a diffuse distribution throughout the nucleus, ataxin-7 associated with the nuclear matrix and the nucleolus. The location of the putative SCA7 nuclear localization sequence (NLS) was confirmed by fusing an ataxin-7 fragment with the normally cytoplasmic protein chicken muscle pyruvate kinase. Mutation of this NLS prevented protein from entering the nucleus. Thus, expanded ataxin-7 may carry out its pathogenic effects in the nucleus by altering a matrix-associated nuclear structure and/or by disrupting nucleolar function.

An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8)

Myotonic dystrophy (DM) is the only disease reported to be caused by a CTG expansion. We now report that a non-coding CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). This expansion, located on chromosome 13q21, was isolated directly from the genomic DNA of an ataxia patient by RAPID cloning. SCA8 patients have expansions similar in size (107-127 CTG repeats) to those found among adult-onset DM patients. SCA8 is the first example of a dominant SCA not caused by a CAG expansion translated as a polyglutamine tract.

Incidence of dominant spinocerebellar and Friedreich triplet repeats among 361 ataxia families.

OBJECTIVE: To determine the incidence of spinocerebellar ataxia (SCA) types 1, 2, 3, 6, and 7 and Friedreich's ataxia (FA) among a large panel of ataxia families. BACKGROUND: The ataxias are a clinically and genetically heterogeneous group of neurodegenerative diseases that variably affect the cerebellum, brainstem, and spinocerebellar tracts. Trinucleotide repeat expansions have been shown to be the mutational mechanism for five dominantly inherited SCAs as well as FA. METHODS: We collected DNA samples and clinical data from patients representing 361 families with adult-onset ataxia of unknown etiology. Patients with a clinical diagnosis of FA were specifically excluded from our collection. RESULTS: Among the 178 dominant kindreds, we found SCA1 expansion at a frequency of 5.6%, SCA2 expansion at a frequency of 15.2%, SCA3 expansion at a frequency of 20.8%, SCA6 expansion at a frequency of 15.2%, and SCA7 expansion at a frequency of 4.5%. FA alleles were found in 11.4% of apparently recessive and 5.2% of apparently sporadic patients. Among these patients the repeat sizes for one or both FA alleles were relatively small, with sizes for the smaller allele ranging from 90 to 600 GAA repeats. The clinical presentation for these patients is atypical for FA, with one or more of the following characteristics: adult onset of disease, retained tendon reflexes, normal plantar response, and intact or partially intact sensory perceptions. CONCLUSIONS: Pathogenic trinucleotide repeat expansions were found among 61% of the dominant kindreds. Among patients with apparently recessive or negative family histories of ataxia, 6.8% and 4.4% tested positive for a CAG expansion at one of the dominant loci, and 11.4 and 5.2% of patients with apparently recessive or sporadic forms of ataxia had FA expansions. Because of the significant implications that a dominant versus recessive inheritance pattern has for future generations, it is important to screen patients who do not have a clearly dominant inheritance pattern for expansions at both the FA and the dominant ataxia loci.