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Background Acute hyperammonemia without signs of common causes in the elderly might be challenging to identify. We report the oldest case known to date of a female patient with late onset ornithine carbamyltransferase deficiency (OTC), which was unmasked after a protein overload due to nutritional supplements. Our case illustrates how environmental factors (protein overload) in previously unknown OTC in the elderly leads to hyperammonemic encephalopathy and highlights that early treatment prevents persisting neurological deficits and should be considered in absence of common causes of hyperammonemic encephalopathy. Case presentation A 68-year-old woman presented with acute confusion, which progressed into a deep coma (Glasgow-Coma-Scale score 3) within a few hours. The only remarkable finding was a plasma ammonia (NH3) concentration of 697 μmmol/l (range 12–47 μmmol/). Third party history revealed that the patient disliked meat for most of her life (meat = protein, which needs to be metabolized) and had taken nutritional supplements (since supplements often have a high protein-ratio) 2 days before the symptoms started. Protein catabolism results in NH3, which is metabolized via the urea cycle. Consequently, the acute hyperammonemia in our patient was thought to be related to an inherited metabolic disorder, which only unmasked itself as a result of an overload of the corresponding metabolite (in this case protein). Since ornithine carbamyltransferase deficiency (OTC) is the most common inherited urea cycle disorder, this diagnosis became likely and was confirmed later via genetic and metabolic testing (amino acids, orotic acid, etc.). After 2 weeks of treatment (dialysis, low-protein-diet, nitrogen-lowering medication) the patient was discharged in a healthy condition without any neurological deficits. Conclusion OTC is a x-chromosomal linked disorder, that usually manifests in newborn infants and children, but also rarely in adults and even rarer in the elderly (50- till 60-years-old), where it is probably underdiagnosed. In case of hyperammonemic encephalopathy – regardless of the underlying cause -, treatment should be started early to prevent persisting neurological deficits. OTC should be considered in absence of common causes of hyperammonemic encephalopathy.

The perception of a scene involves grasping the global space of the scene, usually called the spatial layout, as well as the objects in the scene and the relations between them. The main brain areas involved in scene perception, the parahippocampal place area (PPA) and retrosplenial cortex (RSC), are supposed to mostly support the processing of spatial layout. Here we manipulated the objects and their relations either by arranging objects within rooms in a common way or by scattering them randomly. The rooms were then varied for spatial layout by keeping or removing the walls of the room, a typical layout manipulation. We then combined a visual search paradigm, where participants actively search for an object within the room, with multivariate pattern analysis (MVPA). Both left and right PPA were sensitive to the layout properties, but the right PPA was also sensitive to the object relations even when the information about objects and their relations is used in the cross-categorization procedure on novel stimuli. The left and right RSC were sensitive to both spatial layout and object relations, but could only use the information about object relations for cross-categorization to novel stimuli. These effects were restricted to the PPA and RSC, as other control brain areas did not display the same pattern of results. Our results underline the importance of employing paradigms that require participants to explicitly retrieve domain-specific processes and indicate that objects and their relations are processed in the scene areas to a larger extent than previously assumed.

Whole-brain voxel-based morphometry (VBM) studies revealed patterns of patchy atrophy within the cerebellum of Friedreich’s ataxia patients, missing clear clinico-anatomic correlations. Studies so far are lacking an appropriate registration to the infratentorial space. To circumvent these limitations, we applied a high-resolution atlas template of the human cerebellum and brainstem (SUIT template) to characterize regional cerebellar atrophy in Friedreich’s ataxia (FRDA) on 3-T MRI data. We used a spatially unbiased voxel-based morphometry approach together with T2-based manual segmentation, T2 histogram analysis, and atlas generation of the dentate nuclei in a representative cohort of 18 FRDA patients and matched healthy controls. We demonstrate that the cerebellar volume in FRDA is generally not significantly different from healthy controls but mild lobular atrophy develops beyond normal aging. The medial parts of lobule VI, housing the somatotopic representation of tongue and lips, are the major site of this lobular atrophy, which possibly reflects speech impairment. Extended white matter affection correlates with disease severity across and beyond the cerebellar inflow and outflow tracts. The dentate nucleus, as a major site of cerebellar degeneration, shows a mean volume loss of about 30%. Remarkably, not the atrophy but the T2 signal decrease of the dentate nuclei highly correlates with disease duration and severity.

Objectives To investigate the hemostatic efficacy of combined desmopressin (1-deamino-8-D-arginine vasopressin) and platelet transfusion in reducing hematoma expansion in acute, spontaneous intracerebral hemorrhage under antiplatelet treatment. Design Single-center, nonrandomized study, performed between 2006 and 2014. Setting Tertiary University Hospital of Tuebingen, Germany. Patients Adult patients with intracerebral hemorrhage under antiplatelet treatment and follow-up CT at 24 ± 12 hours were included. Exclusion criteria included other intracerebral hemorrhage causes, anticoagulation, coagulopathy, or immediate surgery after baseline-CT. Interventions Treatment with IV 1-deamino-8-D-arginine vasopressin (0.4 µg/kg) + platelet transfusion (2 U) within 60 minutes of intracerebral hemorrhage under antiplatelet treatment diagnosis on brain imaging. Measurements and main results Primary outcome was relative hematoma expansion from baseline to follow-up CT. Secondary outcomes included secondary intraventricular hemorrhage or hydrocephalus upon follow-up CT, thromboembolic events before discharge, and the 3-month functional outcome (assessed by modified Rankin Scale). One-hundred forty patients were included, 72 treated versus 68 controls. Times of symptom-onset-to-baseline-CT (hr) (median [interquartile range]: 3 [4] vs 5 [5]; p = 0.468) and follow-up CT (26 [18] vs 19 [12]; p = 0.352) were similar between groups. No between-group differences of total intracerebral hematoma expansion (%) (median [interquartile range]: 8.5 [12.4] vs 9.1 [16.5]; p = 0.825), intraparenchymal (10.7 [23.1] vs 9.2 [20.7]; p = 0.900), and intraventricular hematoma expansion (14.5 [63.2] vs 6.1 [40.4]; p = 0.304) were noted. Among patients with hematoma expansion greater than or equal to 33% compared with baseline, 16 (52%) received treatment versus 15 (48%) controls. The occurrence of hematoma expansion greater than or equal to 33% was similar between groups (p = 0.981). Rates of secondary intraventricular hemorrhage, hydrocephalus, and thromboembolic events were similar between groups. Treatment with 1-deamino-8-D-arginine vasopressin + platelet transfusion was not associated with the 3-month functional outcome (adjusted odds ratio, 1.570; 95% CI, 0.721-3.419; p = 0.309). Conclusions In line with the randomized Platelet Transfusion Versus Standard Care After Acute Stroke Due to Spontaneous Cerebral Hemorrhage Associated With Antiplatelet Therapy trial, our results suggest no hemostatic efficacy of early platelet transfusion in intracerebral hemorrhage under antiplatelet treatment. Contrary to results of preclinical and clinical nonintracerebral hemorrhage studies, adjunct 1-deamino-8-D-arginine vasopressin showed no benefit in limiting hematoma expansion or improving functional outcome.

BACKGROUND: Falls are common among people with idiopathic Parkinson's disease (IPD) and are suggested to be associated with white matter hyperintensities (WMH) of the brain.OBJECTIVE: To investigate the contribution of brain area-specific WMH to the risk of falls in IPD.METHODS: In fifty participants with IPD, occurrence and severity of WMH in specific brain areas were determined using Scheltens (without lateralization) and Age-related white matter changes (ARWMC) (with lateralization) scores. Falls were evaluated with the fall item of the Unified PD Rating Scale (UPDRS). Correlations between area-specific WMH and falls were tested with stepwise backward regression and multivariate regression analyses.RESULTS: In this cohort of participants with IPD, left temporal WMH were associated with occurrence of falls. Frontal WMH of both hemispheres showed tendencies towards significance for the association with falls.CONCLUSION: According to our study, WMH in the left temporal area are significantly associated with falls in IPD. Potential reasons for this association could be deficits in memory, navigation, orientation, auditory processing, and fear conditioning, which are all associated with pathologies of the left temporal lobe.

Purpose The aim of this study was to translate the T1ρ‐based dynamic glucose‐enhanced (DGEρ) experiment from ultrahigh magnetic field strengths to a clinical field strength of 3 T. Although the protocol would seem to be as simple as gadolinium‐enhanced imaging, several obstacles had to be addressed, including signal‐to‐noise ratio (SNR), robustness of contrast, and postprocessing, especially motion correction. Methods Spin‐lock based presaturation and a 3D gradient‐echo snapshot readout were optimized for 3 T with regard to robustness, chemical exchange saturation transfer effect strength, and SNR. Postprocessing steps, including dynamic B0 and motion correction, were analyzed and optimized in 7 healthy volunteers. The final protocol, including glucose injection, was applied to 3 glioblastoma patients. Results With appropriate postprocessing, motion‐related artifacts could be drastically reduced, and an SNR of approximately 90 could be achieved for a single dynamic measurement. In 2 patients with blood–brain barrier breakdown, a significant glucose uptake could be observed with a DGEρ effect strength in the range of 0.4% of the water signal. Thorough analysis of possible residual motion revealed that the statistical evidence can decrease when tested against pseudo effects attributed to uncorrected motion. Conclusion DGEρ imaging was optimized for clinical field strengths of 3 T, and a robust protocol was established for broader application. Early experience shows that DGEρ seems possible at 3 T and could not only be attributed to motion artifacts. Observed DGEρ maps showed unique patterns, partly matching with the T1‐ce tumor ring enhancement. However, effect sizes are small and careful clinical application is necessary.

The endoplasmic reticulum enzyme fatty acid 2-hydroxylase (FA2H) plays a major role in the formation of 2-hydroxy glycosphingolipids, main components of myelin. FA2H deficiency in mice leads to severe central demyelination and axon loss. In humans it has been associated with phenotypes from the neurodegeneration with brain iron accumulation (fatty acid hydroxylase-associated neurodegeneration, FAHN), hereditary spastic paraplegia (HSP type SPG35) and leukodystrophy (leukodystrophy with spasticity and dystonia) spectrum. We performed an in-depth clinical and retrospective neurophysiological and imaging study in a cohort of 19 cases with biallelic FA2H mutations. FAHN/SPG35 manifests with early childhood onset predominantly lower limb spastic tetraparesis and truncal instability, dysarthria, dysphagia, cerebellar ataxia, and cognitive deficits, often accompanied by exotropia and movement disorders. The disease is rapidly progressive with loss of ambulation after a median of 7 years after disease onset and demonstrates little interindividual variability. The hair of FAHN/SPG35 patients shows a bristle-like appearance; scanning electron microscopy of patient hair shafts reveals deformities (longitudinal grooves) as well as plaque-like adhesions to the hair, likely caused by an abnormal sebum composition also described in a mouse model of FA2H deficiency. Characteristic imaging features of FAHN/SPG35 can be summarized by the WHAT' acronym: white matter changes, hypointensity of the globus pallidus, ponto-cerebellar atrophy, and thin corpus callosum. At least three of four imaging features are present in 85% of FA2H mutation carriers. Here, we report the first systematic, large cohort study in FAHN/SPG35 and determine the phenotypic spectrum, define the disease course and identify clinical and imaging biomarkers.

The limbic system is a phylogenetically old, behaviorally defined system that serves as a center for emotions. It controls the expression of anger, fear, and joy and also influences sexual behavior, vegetative functions, and memory. The system comprises a collection of tel-, di-, and mesencephalic structures whose components have evolved and increased over time. Previous animal research indicates that the anterior nuclear group of the thalamus (ANT), as well as the habenula (Hb) and the adjacent mediodorsal nucleus (MD) each play a vital role in the limbic circuitry. Accordingly, diffusion imaging data of 730 subjects obtained from the Human Connectome Project and the masks of six nuclei (anterodorsal, anteromedial, anteroventral, lateral dorsal, Hb, and MD) served as seed regions for a direct probabilistic tracking to the rest of the brain using diffusion-weighted imaging. The results revealed that the ANT nuclei are part of the limbic and the memory system as they mainly connect via the mammillary tract, mammillary body, anterior commissure, fornix, and retrosplenial cortices to the hippocampus, amygdala, medio-temporal, orbito-frontal and occipital cortices. Furthermore, the ANT nuclei showed connections to the mesencephalon and brainstem to varying extents, a pattern rarely described in experimental findings. The habenula—usually defined as part of the epithalamus—was closely connected to the tectum opticum and seems to serve as a neuroanatomical hub between the visual and the limbic system, brainstem, and cerebellum. Finally, in contrast to experimental findings with tracer studies, directly determined connections of MD were mainly confined to the brainstem, while indirect MD fibers form a broad pathway connecting the hippocampus and medio-temporal areas with the mediofrontal cortex.

As a result of a whole-exome sequencing study, we report three mutant alleles in SEC24D, a gene encoding a component of the COPII complex involved in protein export from the ER: the truncating mutation c.613C>T (p.Gln205∗) and the missense mutations c.3044C>T (p.Ser1015Phe, located in a cargo-binding pocket) and c.2933A>C (p.Gln978Pro, located in the gelsolin-like domain). Three individuals from two families affected by a similar skeletal phenotype were each compound heterozygous for two of these mutant alleles, with c.3044C>T being embedded in a 14 Mb founder haplotype shared by all three. The affected individuals were a 7-year-old boy with a phenotype most closely resembling Cole-Carpenter syndrome and two fetuses initially suspected to have a severe type of osteogenesis imperfecta. All three displayed a severely disturbed ossification of the skull and multiple fractures with prenatal onset. The 7-year-old boy had short stature and craniofacial malformations including macrocephaly, midface hypoplasia, micrognathia, frontal bossing, and down-slanting palpebral fissures. Electron and immunofluorescence microscopy of skin fibroblasts of this individual revealed that ER export of procollagen was inefficient and that ER tubules were dilated, faithfully reproducing the cellular phenotype of individuals with cranio-lentico-sutural dysplasia (CLSD). CLSD is caused by SEC23A mutations and displays a largely overlapping craniofacial phenotype, but it is not characterized by generalized bone fragility and presented with cataracts in the original family described. The cellular and morphological phenotypes we report are in concordance with the phenotypes described for the Sec24d-deficient fish mutants vbi (medaka) and bulldog (zebrafish).

Objective: To identify a novel disease gene in 2 families with autosomal recessive hereditary spastic paraplegia (HSP). Methods: We used whole-exome sequencing to identify the underlying genetic disease cause in 2 families with apparently autosomal recessive spastic paraplegia. Endogenous expression as well as subcellular localization of wild-type and mutant protein were studied to support the pathogenicity of the identified mutations. Results: In 2 families, we identified compound heterozygous or homozygous mutations in the kinesin gene KIF1C to cause hereditary spastic paraplegia type 58 (SPG58). SPG58 can be complicated by cervical dystonia and cerebellar ataxia. The same mutations in a heterozygous state result in a mild or subclinical phenotype. KIF1C mutations in SPG58 affect the domains involved in adenosine triphosphate hydrolysis and microtubule binding, key functions for this microtubule-based motor protein. Conclusions: KIF1C is the third kinesin gene involved in the pathogenesis of HSPs and is characterized by a mild dominant and a more severe recessive disease phenotype. The identification of KIF1C as an HSP disease gene further supports the key role of intracellular trafficking processes in the pathogenesis of hereditary axonopathies.

Despite extensive efforts, half of patients with rare movement disorders such as hereditary spastic paraplegias and cerebellar ataxias remain genetically unexplained, implicating novel genes and unrecognized mutations in known genes. Non-coding DNA variants are suspected to account for a substantial part of undiscovered causes of rare diseases. Here we identified mutations located deep in introns of POLR3A to be a frequent cause of hereditary spastic paraplegia and cerebellar ataxia. First, whole-exome sequencing findings in a recessive spastic ataxia family turned our attention to intronic variants in POLR3A, a gene previously associated with hypomyelinating leukodystrophy type 7. Next, we screened a cohort of hereditary spastic paraplegia and cerebellar ataxia cases (n = 618) for mutations in POLR3A and identified compound heterozygous POLR3A mutations in ∼3.1% of index cases. Interestingly, >80% of POLR3A mutation carriers presented the same deep-intronic mutation (c.1909+22G>A), which activates a cryptic splice site in a tissue and stage of development-specific manner and leads to a novel distinct and uniform phenotype. The phenotype is characterized by adolescent-onset progressive spastic ataxia with frequent occurrence of tremor, involvement of the central sensory tracts and dental problems (hypodontia, early onset of severe and aggressive periodontal disease). Instead of the typical hypomyelination magnetic resonance imaging pattern associated with classical POLR3A mutations, cases carrying c.1909+22G>A demonstrated hyperintensities along the superior cerebellar peduncles. These hyperintensities may represent the structural correlate to the cerebellar symptoms observed in these patients. The associated c.1909+22G>A variant was significantly enriched in 1139 cases with spastic ataxia-related phenotypes as compared to unrelated neurological and non-neurological phenotypes and healthy controls (P = 1.3 × 10−4). In this study we demonstrate that (i) autosomal-recessive mutations in POLR3A are a frequent cause of hereditary spastic ataxias, accounting for about 3% of hitherto genetically unclassified autosomal recessive and sporadic cases; and (ii) hypomyelination is frequently absent in POLR3A-related syndromes, especially when intronic mutations are present, and thus can no longer be considered as the unifying feature of POLR3A disease. Furthermore, our results demonstrate that substantial progress in revealing the causes of Mendelian diseases can be made by exploring the non-coding sequences of the human genome.

Voxel-based morphometry is still mainly based on T1-weighted MRI scans. Misclassification of vessels and dura mater as gray matter has been previously reported. Goal of the present work was to evaluate the effect of multimodal segmentation methods available in SPM12, and their influence on identification of age related atrophy and lesion detection in epilepsy patients. 3D T1-, T2- and FLAIR-images of 77 healthy adults (mean age 35.8 years, 19–66 years, 45 females), 7 patients with malformation of cortical development (MCD) (mean age 28.1 years,19–40 years, 3 females), and 5 patients with left hippocampal sclerosis (LHS) (mean age 49.0 years, 25–67 years, 3 females) from a 3 T scanner were evaluated. Segmentation based on T1-only, T1+T2, T1+FLAIR, T2+FLAIR, and T1+T2+FLAIR were compared in the healthy subjects. Clinical VBM results based on the different segmentation approaches for MCD and for LHS were compared. T1-only segmentation overestimated total intracranial volume by about 80 ml compared to the other segmentation methods. This was due to misclassification of dura mater and vessels as GM and CSF. Significant differences were found for several anatomical regions: the occipital lobe, the basal ganglia/thalamus, the pre- and postcentral gyrus, the cerebellum, and the brainstem. None of the segmentation methods yielded completely satisfying results for the basal ganglia/thalamus and the brainstem. The best correlation with age could be found for the multimodal T1+T2+FLAIR segmentation. Highest T-scores for identification of LHS were found for T1+T2 segmentation, while highest T-scores for MCD were dependent on lesion and anatomical location. Multimodal segmentation is superior to T1-only segmentation and reduces the misclassification of dura mater and vessels as GM and CSF. Depending on the anatomical region and the pathology of interest (atrophy, lesion detection, etc.), different combinations of T1, T2 and FLAIR yield optimal results.

Friedreich's ataxia (FA) is a multisystemic degenerative disease, but the prevalence of restless legs syndrome (RLS) is unknown. FA patients might be particularly susceptible to develop RLS as FA presents with features commonly associated with RLS, e.g. multisystemic network dysfunction, peripheral neuropathy and disturbances in subcellular brain iron homeostasis. In this work, we assessed the following: (1) the prevalence of RLS; (2) the prevalence of sonographic hypoechogenicity of the substantia nigra (SN), which is known to be associated with idiopathic RLS; and (3) the relation between both in 28 FA patients. Thirty-two percent of the patients suffered from RLS, thus clearly exceeding the prevalence rate in the general population. SN hypoechogenicity was more frequent in FA patients (61%) compared to healthy controls (7%) and was significantly associated with RLS. However, as SN echogenicity also correlated inversely with disease severity, it seems to be related not only to RLS, but also to the neurodegenerative process in FA itself. The high prevalence of RLS in FA patients warrants specific assessment by neurologists involved in the care of FA patients as treatments are readily available. Similar to patients with idiopathic RLS, reduced SN echogenicity is a frequent finding in FA, possibly indicating regional changes in subcellular brain iron regulation in FA.

Hereditary spastic paraplegias (HSP) are a group of clinically and genetically heterogeneous disorders with the hallmark of progressive spastic gait disturbance. We used advanced neuroimaging to identify brain regions involved in SPG4, the most common HSP genotype. Additionally, we analyzed correlations between imaging and clinical findings. We performed 3T MRI scans including isotropic high-resolution 3D T1, T2-FLAIR, and DTI sequences in 15 adult patients with genetically confirmed SPG4 and 15 age- and sex-matched healthy controls. Brain volume loss of gray and white matter was evaluated through voxel-based morphometry (VBM) for supra- and infratentorial regions separately. DTI maps of axial diffusivity (AD), radial diffusivity (RD), mean diffusivity (MD), fractional anisotropy (FA), and measured anisotropy (MA1) were analyzed through tract-based special statistics (TBSS). VBM and TBSS revealed a widespread affection of gray and white matter in SPG4 including the corpus callosum, medio-dorsal thalamus, parieto-occipital regions, upper brainstem, cerebellum, and corticospinal tract. Significant correlations with correlation coefficients r > 0.6 between clinical data and DTI findings could be demonstrated for disease duration and disease severity as assessed by the spastic paraplegia rating scale for the pontine crossing tract (AD) and the corpus callosum (RD and FA). Imaging also provided evidence that SPG4 underlies a primarily axonal rather than demyelinating damage in accordance with post-mortem data. DTI is an attractive tool to assess subclinical affection in SPG4. The correlation of imaging findings with disease duration and severity suggests AD, RD, and FA as potential progression markers in interventional studies.

The fusiform face area (FFA) has often been used as an example of a brain module that was developed through evolution to serve a specific purpose—face processing. Many believe, however, that FFA is responsible for holistic processing associated with any kind of expertise. The expertise view has been tested with various stimuli, with mixed results. One of the main stumbling blocks in the FFA controversy has been the fact that the stimuli used have been similar to faces. Here, we circumvent the problem by using radiological images, X-rays, which bear no resemblance to faces. We demonstrate that FFA can distinguish between X-rays and other stimuli by employing multivariate pattern analysis. The sensitivity to X-rays was significantly better in experienced radiologists than that in medical students with limited radiological experience. For the radiologists, it was also possible to use the patterns of FFA activations obtained on faces to differentiate X-ray stimuli from other stimuli. The overlap in the FFA activation is not based on visual similarity of faces and X-rays but rather on the processes necessary for expertise with both kinds of stimulus. Our results support the expertise view that FFA’s main function is related to holistic processing.

Patterns of dysarthria in spinocerebellar ataxias (SCAs) and their discriminative features still remain elusive. Here we aimed to compare dysarthria profiles of patients with (SCA3 and SCA6 vs. Friedreich ataxia (FRDA), focussing on three particularly vulnerable speech parameters (speaking rate, prosodic modulation, and intelligibility) in ataxic dysarthria as well as on a specific oral non-speech variable of ataxic impairment, i.e., the irregularity of oral motor diadochokinesis (DDK). 30 Patients with SCA3, SCA6, and FRDA, matched for group size (n = 10 each), disease severity, and disease duration produced various speech samples and DDK tasks. A discriminant analysis was used to differentiate speech and non-speech parameters between groups. Regularity of DDK was specifically impaired in SCA3, whereas impairments of speech parameters, i.e., rate and modulation were stronger affected in SCA6. Speech parameters are particularly vulnerable in SCA6, while non-speech oral motor features are notably impaired in SCA3.

Background: Hereditary spastic paraplegias (HSP) are clinically and genetically highly heterogeneous. Recently, two novel genes, SPG11 ( spatacsin ) and SPG15 ( spastizin ), associated with autosomal recessive HSP, were identified. Clinically, both are characterised by complicated HSP and a rather similar phenotype consisting of early onset spastic paraplegia, cognitive deficits, thin corpus callosum (TCC), peripheral neuropathy and mild cerebellar ataxia. Objective: To compare the frequency of SPG11 and SPG15 in patients with early onset complicated HSP and to further characterise the phenotype of SPG11 and SPG15. Results: A sample of 36 index patients with early onset complicated HSP and a family history compatible with autosomal recessive inheritance was collected and screened for mutations in SPG11 and SPG15. Overall frequency of SPG11 was 14% (5/36) but was considerably higher in patients with TCC (42%). One patient with mental retardation and thinning of the corpus callosum was compound heterozygous for two novel SPG15 mutations. Additionally, several new polymorphisms and sequence variants of unknown significance have been identified in the SPG15 gene. Conclusions: TCC seems to be the best phenotypic predictor for SPG11 as well as SPG15. No clinical features could discriminate between SPG11 and SPG15. Therefore, priority of genetic testing should be driven by mutation frequency that appears to be substantially higher in SPG11 than in SPG15.

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal dominant disease caused by mutations within the colony stimulating factor 1 receptor (CSF1R) gene. While a small number of reports on imaging findings in routine MRI exist, reported imaging findings in DWI and spectroscopy are scarce, and limited to not genetically proven case reports. We assessed MRI including DWI and MR spectroscopy in six patients with HDLS and two asymptomatic mutation carriers. A total of 13 MRIs were evaluated and a score of the white-matter lesion (WML) load was calculated. The course of MR abnormalities was followed for 6-19 months in four patients and 95 months in one carrier. MRI revealed widespread white-matter lesions of patchy or confluent pattern especially in the frontal and occipital lobe. The pyramidal tract was less affected than the surrounding tissue in all symptomatic patients on conventional T2WI. Three of four cases with DWI showed small dots of diffusion restriction within WML. Spectroscopy showed increased levels of mIns, Cho and lactate while NAA was decreased. Asymptomatic mutation carriers had, for the age of the patients, unusually pronounced unspecific WMLs. No diffusion restriction or alterations in metabolite levels could be detected in asymptomatic mutation carriers. Microbleeds were not found in any patient. Diffusion restriction seems to be a typical imaging pattern visible in patients with active disease progression in HDLS. Spectroscopic findings and the absence of microbleeds differ clearly from reported findings in CADASIL and subcortical arteriosclerotic encephalopathy. While the distribution and character of WMLs in asymptomatic cases remain unspecific they are likely to represent subclinical markers of HDLS.

Spinal muscular atrophies (SMA) are a genetically and clinically heterogeneous group of disorders predominantly of the anterior horn. While the large majority of recessive SMA cases can be explained by mutations in SMN1 , the genetic basis of dominant SMA has remained largely elusive. Although mutations have been identified in >12 genes, mutations are found only in less than 30% of dominant SMA cases.1 Recently, BICD2 has been identified to cause dominant SMA.1–3 Here, we provide additional evidence that BICD2 is a cause of dominant SMA and report detailed clinical, electrophysiological and MRI data from a three-generation family with cosegregation of a novel BICD2 mutation. These findings extend current notions of BICD2 , demonstrating that it can present with adult-onset combined proximal and distal lower extremity SMA. Our clinical observations not only extend the phenotype of BICD2 -related disease, but might also provide novel insights in the pathophysiology of the disease. The 44-year-old German female index patient (III-2, figure 1A) presented with a 3-year history of a mild symmetric proximal (Medical Research Council (MRC) grade 4) and distal (MRC grade 3) paresis of lower extremities. While able to ambulate independently, she was unable to walk on heels and had difficulties walking on toes and climbing >10 stairs. There was areflexia of lower limbs, high-arched feet (figure 1C) and complete atrophy of the quadriceps muscle (figure 1D) without genu recurvatum. She recalled minor problems in jumping during sports at school, however had not sought medical advice so far. …

Friedreich ataxia (FRDA) is the most frequent recessive ataxia in the Western world. Dysarthria is a cardinal feature of FRDA, often leading to severe impairments in daily functioning, but its exact characteristics are only poorly understood so far. We performed a comprehensive evaluation of dysarthria severity and the profile of speech motor deficits in 20 patients with a genetic diagnosis of FRDA based on a carefully selected battery of speaking tasks and two widely used paraspeech tasks, i.e., oral diadochokinesis and sustained vowel productions. Perceptual ratings of the speech samples identified respiration, voice quality, voice instability, articulation, and tempo as the most affected speech dimensions. Whereas vocal instability predicted ataxia severity, tempo turned out as a significant correlate of disease duration. Furthermore, articulation predicted the overall intelligibility score as determined by a systematic speech pathology assessment tool. In contrast, neurologists' ratings of intelligibility--a component of the 'Scale for the Assessment and Rating of Ataxia'--were found to be related to perceived speech tempo. Obviously, clinicians are more sensitive to slowness of speech than to any other feature of spoken language during dysarthria evaluation. Our results suggest that different components of speech production and trunk/limb motor functions are differentially susceptible to FRDA pathology. Furthermore, evidence emerged that paraspeech tasks do not allow for an adequate scaling of speech deficits in FRDA.

An 18-year-old German woman presented with progressive cerebellar ataxia since early childhood, delayed cognitive development, and hypogonadotropic hypogonadism. MRI demonstrated diffuse cerebral hypomyelination, cerebellar atrophy, and thin corpus callosum; X-ray revealed persistent milk teeth and hypoplastic crowns and roots (figure), indicative of 4H syndrome (hypomyelination, hypodontia, hypogonadotropic hypogonadism). POLR3B sequencing(1) revealed 2 compound heterozygous mutations (C527R [C.1579T>C] and the common ancestral V523E [C.1568T>A](2)).

Background Leukoencephalopathy with brain stem and spinal cord involvement and brain lactate elevation (LBSL) was recently shown to be caused by mutations in the DARS2 gene, encoding a mitochondrial aspartyl-tRNA synthetase. So far, affected individuals were invariably compound heterozygous for two mutations in DARS2 , and drug treatments have remained elusive. Methods Prospective 2-year follow-up of the natural history of the main presenting symptoms in a homozygous DARS2 mutation carrier, followed by a 60 day treatment with acetazolamide in two different doses and with two random treatment interruptions. Results The patient presented with exercise-induced paroxysmal gait ataxia and areflexia as an atypical phenotype associated with a novel homozygous DARS2 mutation. These features showed an excellent dose-dependent, sustained treatment response to a carbonic anhydrase inhibitor. Pathogenic mutations in episodic ataxia genes were excluded, thus making it highly unlikely that this phenotype was because of episodic ataxia as a second disorder besides LBSL. Conclusions This case demonstrates that DARS2 mutation homozygosity is not lethal, as suggested earlier, but compatible with a rather benign disease course. More importantly, it extends the phenotypic spectrum of LBSL and reveals that at least some DARS2 -associated phenotypic features might be readily treatable. However, future observations of paroxsymal ataxia and, possibly, areflexia in other DARS2 -mutated patients are warranted to further corroborate our finding that DARS2 mutations can lead to a paroxsymal ataxia phenotype.

The cortical systems involved in eye movement control in humans have been investigated extensively using fMRI. In contrast, there is virtually no data concerning the functional status of the human oculomotor brainstem nuclei. This lack of evidence has usually been explained by technical constraints of EPI based imaging and anatomical characteristics of the brainstem. Against this assumption, we successfully localised nuclei of the oculomotor system using high-resolution fMRI based on standard EPI sequences in a group of healthy subjects executing reflexive horizontal saccades. A random-effects group analysis revealed task-related BOLD increases in the superior colliculus, the oculomotor nucleus, the abducens nucleus and in the paramedian pontine reticular formation. This group analysis was complemented by individual positive findings in up to 94% of single subject analyses. A visual control paradigm led to increased signal levels in the superior colliculus consistent with its visual properties but no corresponding signal changes in other brainstem nuclei. These results are consistent with findings in animal studies and demonstrate the feasibility to detect BOLD signal increases associated with oculomotor tasks even in the human brainstem using conventional EPI imaging techniques.

Background: Friedreich’s ataxia (FA) is essentially characterized by degeneration of the dorsal root ganglia, the dorsal nuclei of Clarke, and the long spinal fiber tracts, yet there is accumulating evidence that neurodegeneration extends beyond these predilection sites. Transcranial sonography (TCS) has evolved as a valuable complementary neuroimaging tool in the assessment of neurodegenerative diseases due to its capacity to well depict structural changes and the accumulation of heavy metals. Its use for assessing cerebellar neurodegeneration, however, has not yet been investigated.Here we investigated whether TCS allows to assess particular features of cerebellar as well as midbrain and forebrain abnormalities in FA. Methods: Comprehensive TCS imaging of 34 FA patients and 34 age-matched healthy controls. Results: Hyperechogenicity of the dentate nucleus was very frequent in FA patients (85%) and could even be observed in patients with short disease duration, suggesting that dentate alterations are a common and probably early feature of FA. Substantia nigra was significantly hypoechogenic, possibly indicating regional changes in subcellular brain iron regulation. FA patients showed significantly enlarged 4th, 3rd, and lateral ventricles, thus corroborating earlier MRI and postmortem findings of substantial cerebellar and forebrain atrophy in FA. Conclusions: TCS provides a quick-to-apply and inexpensive in vivo assessment of both cerebellar and noncerebellar abnormalities in FA, in particular highlighting dentate hyperechogenicity as a core feature. It might serve as a promising tool for imaging aspects of cerebellar neurodegeneration also in other neurodegenerative disorders.