Striatal parvalbumin interneurons are activated in a mouse model of cerebellar dystonia.

Dystonia is thought to arise from abnormalities in the motor loop of the basal ganglia; however, there is an ongoing debate regarding cerebellar involvement. We adopted an established cerebellar dystonia mouse model by injecting ouabain to examine the contribution of the cerebellum. Initially, we examined whether the entopeduncular nucleus (EPN), substantia nigra pars reticulata (SNr), globus pallidus externus (GPe) and striatal neurons were activated in the model. Next, we examined whether administration of a dopamine D1 receptor agonist and dopamine D2 receptor antagonist or selective ablation of striatal parvalbumin (PV, encoded by Pvalb)-expressing interneurons could modulate the involuntary movements of the mice. The cerebellar dystonia mice had a higher number of cells positive for c-fos (encoded by Fos) in the EPN, SNr and GPe, as well as a higher positive ratio of c-fos in striatal PV interneurons, than those in control mice. Furthermore, systemic administration of combined D1 receptor agonist and D2 receptor antagonist and selective ablation of striatal PV interneurons relieved the involuntary movements of the mice. Abnormalities in the motor loop of the basal ganglia could be crucially involved in cerebellar dystonia, and modulating PV interneurons might provide a novel treatment strategy.

A heterozygous deletion of PDGFB gene causes paroxysmal kinesigenic dyskinesia with primary familial brain calcification.

BACKGROUND: Primary familial brain calcification (PFBC) is a neurodegenerative disease characterized with calcium deposition in multiple brain regions. Mutations in PDGFB have been discovered in sporadic and familial PFBC cases. While several known variants displayed loss-of function, no complete deletion of platelet-derived growth factor B (PDGFB) has been reported. METHODS: For the diagnostic purpose, brain computerized tomography or magnetic resonance imaging scanning and whole-genome sequencing were performed on the proband and family members in the pedigree. RESULTS: We identified a heterozygous PDGFB complete deletion in a Chinese pedigree. The proband presented with paroxysmal kinesigenic dyskinesia (PKD), a rare symptom in PFBC. The proband's mother carrying the same mutation was asymptomatic. CONCLUSIONS: For the first time, we reported a PFBC with a heterozygous deletion of PDGFB, and provided evidence of haploinsufficiency in the pathogenesis of PFBC.

Combined treatment with C16 peptide and angiopoietin-1 confers neuroprotection and reduces inflammation in 3-nitropropionic acid-induced dystonia mice.

Dystonia is a disorder associated with abnormalities in many brain regions including the basal ganglia and cerebellum. The toxin 3-Nitropropionic acid (3-NP) can induce neuropathologies in the mice striatum and nigra substance, including excitotoxicity, neuroinflammation, and extensive neuronal atrophy, characterized by progressive motor dysfunction, dystonia, and memory loss, mimicking those observed in humans. We established a mouse model of dystonia by administering 3-NP. Given the reported neuroprotective effects of the endothelial growth factor angiopoietin-1 (Ang-1) and the anti-inflammatory integrin αvß3 binding peptide C16, we performed this study to evaluate their combined effects on 3-NP striatal toxicity and their therapeutic potential with multiple methods using an in vivo mouse model. Sixty mice were equally and randomly divided into three groups: control, 3-NP treatment, and 3-NP+C16+Ang-1 treatment. Behavioral and electrophysiological tests were conducted and the effect of the combined C16+Ang-1 treatment on neural function recovery was determined. We found that C16+Ang-1 treatment alleviated 3-NP-induced behavioral, biochemical, and cellular alterations in the central nervous system and promoted function recovery by restoring vascular permeability and reducing inflammation in the micro-environment. In conclusion, our results confirmed the neuroprotective effect of combined C16+Ang-1 treatment and suggest their potential as a complementary therapeutic against 3-NP-induced dystonia.

Clinical and radiological characterization of novel FIG4-related combined system disease with neuropathy.

Variants in the FIG4 gene, which encodes a phosphatidylinositol-3,5-bisphosphatase lead to obstruction of endocytic trafficking, causing accumulation of enlarged vesicles in murine peripheral neurons and fibroblasts. Bi-allelic pathogenic variants in FIG4 are associated with neurological disorders including Charcot-Marie-Tooth disease type-4J (CMT4J) and Yunis-Varón syndrome (YVS). We present four probands from three unrelated families, all homozygous for a recurrent FIG4 missense variant c.506A>C p.(Tyr169Ser), with a novel phenotype involving features of both CMT4J and YVS. Three presented with infant-onset dystonia and one with hypotonia. All have depressed lower limb reflexes and distal muscle weakness, two have nerve conduction studies (NCS) consistent with severe sensorimotor demyelinating peripheral neuropathy and one had NCS showing patchy intermediate/mildly reduced motor conduction velocities. All have cognitive impairment and three have swallowing difficulties. MRI showed cerebellar atrophy and bilateral T2 hyperintense medullary swellings in all patients. These children represent a novel clinicoradiological phenotype and suggest that phenotypes associated with FIG4 missense variants do not neatly fall into previously described diagnoses but can present with variable features. Analysis of this gene should be considered in patients with central and peripheral neurological signs and medullary radiological changes, providing earlier diagnosis and informing reproductive choices.

The Role of Torsin AAA+ Proteins in Preserving Nuclear Envelope Integrity and Safeguarding Against Disease.

Torsin ATPases are members of the AAA+ (ATPases associated with various cellular activities) superfamily of proteins, which participate in essential cellular processes. While AAA+ proteins are ubiquitously expressed and demonstrate distinct subcellular localizations, Torsins are the only AAA+ to reside within the nuclear envelope (NE) and endoplasmic reticulum (ER) network. Moreover, due to the absence of integral catalytic features, Torsins require the NE- and ER-specific regulatory cofactors, lamina-associated polypeptide 1 (LAP1) and luminal domain like LAP1 (LULL1), to efficiently trigger their atypical mode of ATP hydrolysis. Despite their implication in an ever-growing list of diverse processes, the specific contributions of Torsin/cofactor assemblies in maintaining normal cellular physiology remain largely enigmatic. Resolving gaps in the functional and mechanistic principles of Torsins and their cofactors are of considerable medical importance, as aberrant Torsin behavior is the principal cause of the movement disorder DYT1 early-onset dystonia. In this review, we examine recent findings regarding the phenotypic consequences of compromised Torsin and cofactor activities. In particular, we focus on the molecular features underlying NE defects and the contributions of Torsins to nuclear pore complex biogenesis, as well as the growing implications of Torsins in cellular lipid metabolism. Additionally, we discuss how understanding Torsins may facilitate the study of essential but poorly understood processes at the NE and ER, and aid in the development of therapeutic strategies for dystonia.

Leber hereditary optic neuropathy plus dystonia, and transverse myelitis due to double mutations in MT-ND4 and MT-ND6.

Leber hereditary optic neuropathy (LHON) typically presents as painless central or centrocecal scotoma and is due to maternally inherited mitochondrial DNA (mtDNA) mutations. Over 95% of LHON cases are caused by one of three mtDNA "common" point mutations: m.3460G>A, m.11778G>A, or m.14484T>C, which are all in genes encoding structural subunits of complex I of the respiratory chain. Intriguing features of LHON include: incomplete penetrance, tissue specificity, and male predominance, indicating that additional genetic or environmental factors are modulating the phenotypic expression of the pathogenic mtDNA mutations. However, since its original description as a purely ophthalmological disorder, LHON has also been linked to multisystemic conditions with variable neurological, cardiac, and skeletal abnormalities. Although double "common" mutations have been reported to cause LHON and LHON-plus, they are extremely rare. Here, we present a patient with an unusual double point mutation (m.11778 G>A and m.14484T>C) with a multisystemic LHON-plus phenotype characterized by: optic neuropathy, ptosis, ataxia, dystonia, dysarthria, and recurrent extensive transverse myelitis.

Epidemiology of benign essential blepharospasm: A nationwide population-based retrospective study in Taiwan.

IMPORTANCE: This study provides a nationwide, population-based data on the incidence of benign essential blepharospasm in Asian adults. BACKGROUND: To describe the incidence, patient demographics, and risk factors associated with benign essential blepharospasm. DESIGN: Population-based retrospective study. PARTICIPANTS AND SAMPLES: A total of 1325 patients with benign essential blepharospasm were identified. METHODS: Patients with diagnosis of blepharopsasm between January 2000 and December 2013 were sampled using the Longitudinal Health Insurance Database 2000. Secondary blepharospasm that may be related to neurological, trauma, and ocular surface disease were excluded. MAIN OUTCOME MEASURED: Multivariate conditional logistic regression was used to estimate the odds ratios for potential risk factors of benign essential blepharospasm. RESULTS: The mean annual incidence was 0.10‰ (0.07‰ for males, and 0.12‰ for females). The peak incidence was in the 50 to 59-year-old age group (0.19‰). People living in urban regions have more risk of developing blepharospasm comparing to people living in less urban regions (p <0.01). White-collar workers also have higher chance of having blepharospasm (p<0.001). Significant difference between control group and case group in hyperlipidemia (p <0.001), sleep disorders (p <0.001), mental disorders (depression, anxiety, obsessive compulsive disorder) (p <0.001), dry eye-related diseases (dry eye, Sjögren's syndrome) (p <0.001), Parkinson's disease (p <0.004), and rosacea (p <0.021) were also identified. CONCLUSIONS AND RELEVANCE: Higher level of urbanization, white-collar work, sleep disorders, mental health diseases, dry eye-related diseases, Parkinsonism, and rosacea are possible risk factors for benign essential blepharospasm.

An unusual surgical indication for cerebral tuberculosis: status dystonicus. Case report.

Actual indications for surgery in tuberculosis are limited to obtaining a diagnosis, acquiring tissue for culture studies, treating hydrocephalus, aspiring a brain abscess, and reducing intracranial pressure in patients with multiple tuberculomas. Tuberculosis-related movement disorders are usually treated pharmacologically. We report on a child affected by post-tubercular generalized dystonia, who progressed to status dystonicus (SD) and underwent stereotactic bilateral pallidotomy. After surgery, SD resolved, and drugs were rapidly tapered. The successful reversal of SD and the motor improvement observed in our patient demonstrate the safety, feasibility, and clinical efficacy of pallidotomy in post-tuberculous-meningoencephalitis dystonia and SD.

Enhanced mu opioid receptor-dependent opioidergic modulation of striatal cholinergic transmission in DYT1 dystonia.

BACKGROUND: Mu opioid receptor activation modulates acetylcholine release in the dorsal striatum, an area deeply involved in motor function, habit formation, and reinforcement learning as well as in the pathophysiology of different movement disorders, such as dystonia. Although the role of opioids in drug reward and addiction is well established, their involvement in motor dysfunction remains largely unexplored. METHODS: We used a multidisciplinary approach to investigate the responses to mu activation in 2 mouse models of DYT1 dystonia (Tor1a+/Δgag mice, Tor1a+/- torsinA null mice, and their respective wild-types). We performed electrophysiological recordings to characterize the pharmacological effects of receptor activation in cholinergic interneurons as well as the underlying ionic currents. In addition, an analysis of the receptor expression was performed both at the protein and mRNA level. RESULTS: In mutant mice, selective mu receptor activation caused a stronger G-protein-dependent, dose-dependent inhibition of firing activity in cholinergic interneurons when compared with controls. In Tor1a+/- mice, our electrophysiological analysis showed an abnormal involvement of calcium-activated potassium channels. Moreover, in both models we found increased levels of mu receptor protein. In addition, both total mRNA and the mu opioid receptor splice variant 1S (MOR-1S) splice variant of the mu receptor gene transcript, specifically enriched in striatum, were selectively upregulated. CONCLUSION: Mice with the DYT1 dystonia mutation exhibit an enhanced response to mu receptor activation, dependent on selective receptor gene upregulation. Our data suggest a novel role for striatal opioid signaling in motor control, and more important, identify mu opioid receptors as potential targets for pharmacological intervention in dystonia. © 2017 International Parkinson and Movement Disorder Society.

Heterozygous Gnal Mice Are a Novel Animal Model with Which to Study Dystonia Pathophysiology.

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions and its pathophysiological mechanisms are still poorly understood. Dominant mutations of the GNAL gene are a cause of isolated dystonia (DYT25) in patients. Some mutations result in a complete loss of function of the encoded protein, Gαolf, an adenylyl-cyclase-stimulatory G-protein highly enriched in striatal projection neurons, where it mediates the actions of dopamine and adenosine. We used male and female heterozygous Gnal knock-out mice (Gnal+/-) to study how GNAL haplodeficiency is implicated in dystonia. In basal conditions, no overt dystonic movements or postures or change in locomotor activity were observed. However, Gnal haploinsufficiency altered self-grooming, motor coordination, and apparent motivation in operant conditioning, as well as spine morphology and phospho-CaMKIIß in the striatum. After systemic administration of oxotremorine, an unselective cholinergic agonist, Gnal+/- mice developed more abnormal postures and movements than WT mice. These effects were not caused by seizures as indicated by EEG recordings. They were prevented by the M1-preferring muscarinic antagonists, telenzepine, pirenzepine, and trihexyphenidyl, which alleviate dystonic symptoms in patients. The motor defects were worsened by mecamylamine, a selective nicotinic antagonist. These oxotremorine-induced abnormalities in Gnal+/- mice were replicated by oxotremorine infusion into the striatum, but not into the cerebellum, indicating that defects in striatal neurons favor the appearance of dystonia-like movement alterations after oxotremorine. Untreated and oxotremorine-treated Gnal+/- mice provide a model of presymptomic and symptomatic stages of DYT25-associated dystonia, respectively, and clues about the mechanisms underlying dystonia pathogenesis.SIGNIFICANCE STATEMENT Adult-onset dystonia DYT25 is caused by dominant loss-of-function mutations of GNAL, a gene encoding the stimulatory G-protein Gαolf, which is critical for activation of the cAMP pathway in the striatal projection neurons. Here, we demonstrate that Gnal-haplodeficient mice have a mild neurological phenotype and display vulnerability to developing dystonic movements after systemic or intrastriatal injection of the cholinergic agonist oxotremorine. Therefore, impairment of the cAMP pathway in association with an increased cholinergic tone creates alterations in striatal neuron functions that can promote the onset of dystonia. Our results also provide evidence that untreated and oxotremorine-treated Gnal-haplodeficient mice are powerful models with which to study presymptomic and symptomatic stages of DYT25-associated dystonia, respectively.

Phosphodiesterase-10A Inverse Changes in Striatopallidal and Striatoentopeduncular Pathways of a Transgenic Mouse Model of DYT1 Dystonia.

We report that changes of phosphodiesterase-10A (PDE10A) can map widespread functional imbalance of basal ganglia circuits in a mouse model of DYT1 dystonia overexpressing mutant torsinA. PDE10A is a key enzyme in the catabolism of second messenger cAMP and cGMP, whose synthesis is stimulated by D1 receptors and inhibited by D2 receptors preferentially expressed in striatoentopeducuncular/substantia nigra or striatopallidal pathways, respectively. PDE10A was studied in control mice (NT) and in mice carrying human wild-type torsinA (hWT) or mutant torsinA (hMT). Quantitative analysis of PDE10A expression was assessed in different brain areas by rabbit anti-PDE10A antibody immunohistochemistry and Western blotting. PDE10A-dependent cAMP hydrolyzing activity and PDE10A mRNA were also assessed. Striatopallidal neurons were identified by rabbit anti-enkephalin antibody.In NT mice, PDE10A is equally expressed in medium spiny striatal neurons and in their projections to entopeduncular nucleus/substantia nigra and to external globus pallidus. In hMT mice, PDE10A content selectively increases in enkephalin-positive striatal neuronal bodies; moreover, PDE10A expression and activity in hMT mice, compared with NT mice, significantly increase in globus pallidus but decrease in entopeduncular nucleus/substantia nigra. Similar changes of PDE10A occur in hWT mice, but such changes are not always significant. However, PDE10A mRNA expression appears comparable among NT, hWT, and hMT mice.In DYT1 transgenic mice, the inverse changes of PDE10A in striatoentopeduncular and striatopallidal projections might result over time in an imbalance between direct and indirect pathways for properly focusing movement. The decrease of PDE10A in the striatoentopeduncular/nigral projections might lead to increased intensity and duration of D1-stimulated cAMP/cGMP signaling; conversely, the increase of PDE10A in the striatopallidal projections might lead to increased intensity and duration of D2-inhibited cAMP/cGMP signaling.SIGNIFICANCE STATEMENT In DYT1 transgenic mouse model of dystonia, PDE10A, a key enzyme in cAMP and cGMP catabolism, is downregulated in striatal projections to entopeduncular nucleus/substantia nigra, preferentially expressing D1 receptors that stimulate cAMP/cGMP synthesis. Conversely, in DYT1 mice, PDE10A is upregulated in striatal projections to globus pallidus, preferentially expressing D2 receptors that inhibit cAMP/cGMP synthesis. The inverse changes to PDE10A in striatoentopeduncular/substantia nigra and striatopallidal pathways might tightly interact downstream to dopamine receptors, likely resulting over time to increased intensity and duration respectively of D1-stimulated and D2-inhibited cAMP/cGMP signals. Therefore, PDE10A changes in the DYT1 model of dystonia can upset the functional balance of basal ganglia circuits, affecting direct and indirect pathways simultaneously.

Mosaicism in ATP1A3-related disorders: not just a theoretical risk.

Mutations in ATP1A3 are involved in a large spectrum of neurological disorders, including rapid onset dystonia parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS), with recent descriptions of overlapping phenotypes. In AHC, a few familial cases of autosomal dominant inheritance have been reported, along with cases of de novo sporadic mutations. In contrast, autosomal dominant inheritance has frequently been associated with RDP and CAPOS. Here, we report on two unrelated sets of full siblings with ATP1A3 mutations, (c.2116G>A) p. Gly706Arg in the first family, and (c.2266C>T) p. Arg756Cys in the second family, presenting with familial recurrence of the disease. Both families displayed parental germline mosaicism. In the first family, the brother and sister presented with severe intellectual deficiency, early onset pharmacoresistant epilepsy, ataxia, and autistic features. In the second family, both sisters demonstrated severe encephalopathy with ataxia and dystonia following a regression episode during a febrile episode during infancy. To our knowledge, mosaicism has not previously been reported in ATP1A3-related disorders. This report, therefore, provides evidence that germline mosaicism for ATP1A3 mutations is a likely explanation for familial recurrence and should be considered during recurrence risk counseling for families of children with ATP1A3-related disorders.

The role of cerebellum in patients with late onset cervical/segmental dystonia?--evidence from the clinic.

BACKGROUND: There is evidence from animal studies, post-mortem pathology, functional imaging and neurophysiological studies to suggest that the cerebellum may be involved in the pathophysiology of dystonia. We sought to explore further the association of clinical and radiological abnormalities of the cerebellum in patients with dystonia. METHODS: We retrospectively reviewed patients from our movement disorders research database, with predominant cervical dystonia who have been seen within last 6 months and had available routine magnetic resonance imaging (MRI). The clinical details including presence of cerebellar signs, imaging findings and results of investigations were recorded on a proforma. The results were analysed using percentages and means with standard deviation. RESULTS: Out of 188 patients included 26 had evidence of cerebellar abnormality on neuroimaging. 17 patients showed cerebellar atrophy and 10 of these had cerebellar signs on examination. These patients were tested negative for common inherited ataxias. 9 patients had cerebellar lesions on MRI, reported as low grade tumour (n = 2), cerebellar infarct (n = 3), cyst (n = 2), white matter hyperintensity (n = 1) and ectopia (n = 1) out of these 4 had cerebellar signs. CONCLUSION: The findings from our study suggest that there may be overt clinical or radiological cerebellar involvement in 14% of cases with cervical/segmental dystonia. However, larger prospective studies are needed in this context.

Bitemporal epilepsy: A specific anatomo-electro-clinical phenotype in the temporal lobe epilepsy spectrum.

PURPOSE: Temporal lobe epilepsy (TLE) with bilateral ictal involvement (bitemporal epilepsy, BTLE) is an intriguing form of TLE whose characteristics need to be carefully identified as BTLE patients are not good surgical candidates. The purpose of this study was to define the anatomo-electro-clinical features differentiating BTLE from unilateral TLE (UTLE). METHODS: Forty-eight BTLE patients underwent long-term video-EEG monitoring (VEEG) and experienced seizures with bilateral temporal lobe involvement. Their main electro-clinical (demographics, interictal and ictal EEG, ictal signs) and neuro-imaging [brain magnetic resonance imaging (MRI)] data were compared with those of a group of 38 UTLE patients. RESULTS: In comparison with the UTLE patients, the BTLE cohort was significantly older at the time of epilepsy onset (p = 0.023), more frequently experienced bilateral asynchronous interictal epileptiform discharges during wakefulness (p = 0.001) and sleep (p < 0.001), bilateral upper limb dystonia (p = 0.005), and auditory auras (p = 0.027), and less frequently showed a recognisable initial ictal EEG pattern of focal flattening or low-voltage fast activity (p < 0.001), post-ictal memory of seizures (p = 0.001), staring (p < 0.001), head deviation (p = 0.004), oro-alimentary automatisms (p = 0.006), and positive brain MRI (p < 0.001). MRI revealed neoplastic lesions (p = 0.007) or alterations other than hippocampal sclerosis (p = 0.028) only in the UTLE patients. CONCLUSION: The possibility of recognising BTLE patients during pre-surgical evaluation or being able to suspect bitemporal seizures before VEEG by identifying particular anatomo-electro-clinical patterns is diagnostically important for epileptologists and can help to prevent possible surgical failures.

Disruption in the autophagic process underlies the sensory neuropathy in dystonia musculorum mice.

A homozygous mutation in the DST (dystonin) gene causes a newly identified lethal form of hereditary sensory and autonomic neuropathy in humans (HSAN-VI). DST loss of function similarly leads to sensory neuron degeneration and severe ataxia in dystonia musculorum (Dst(dt)) mice. DST is involved in maintaining cytoskeletal integrity and intracellular transport. As autophagy is highly reliant upon stable microtubules and motor proteins, we assessed the influence of DST loss of function on autophagy using the Dst(dt-Tg4) mouse model. Electron microscopy (EM) revealed an accumulation of autophagosomes in sensory neurons from these mice. Furthermore, we demonstrated that the autophagic flux was impaired. Levels of LC3-II, a marker of autophagosomes, were elevated. Consequently, Dst(dt-Tg4) sensory neurons displayed impaired protein turnover of autophagosome substrate SQTSM1/p62 and of polyubiquitinated proteins. Interestingly, in a previously described Dst(dt-Tg4) mouse model that is partially rescued by neuronal specific expression of the DST-A2 isoform, autophagosomes, autolysosomes, and damaged organelles were reduced when compared to Dst(dt-Tg4) mutant mice. LC3-II, SQTSM1, polyubiquitinated proteins and autophagic flux were also restored to wild-type levels in the rescued mice. Finally, a significant decrease in DNAIC1 (dynein, axonemal, intermediate chain 1; the mouse ortholog of human DNAI1), a member of the DMC (dynein/dynactin motor complex), was noted in Dst(dt-Tg4) dorsal root ganglia and sensory neurons. Thus, DST-A2 loss of function perturbs late stages of autophagy, and dysfunctional autophagy at least partially underlies Dst(dt) pathogenesis. We therefore conclude that the DST-A2 isoform normally facilitates autophagy within sensory neurons to maintain cellular homeostasis.

Changes of cerebral white matter in patients suffering from Pantothenate Kinase-Associated Neurodegeneration (PKAN): A diffusion tensor imaging (DTI) study.

BACKGROUND: To look for microstructural white matter alterations in patients with dystonia due to Pantothenate Kinase-Associated Neurodegeneration. MATERIAL AND METHODS: We examined 21 genetically confirmed patients and an age-matched group of 21 healthy controls by diffusion tensor imaging. Evaluation of data was performed by tract-based spatial statistics analysis and a voxel-wise comparison of calculated maps of fractional anisotropy. Findings were compared between groups and correlated to the dystonia score of the Burke-Fahn-Marsden Scale (p ≤ 0.05). RESULTS: Patients showed reductions of fractional anisotropy mainly in the periventricular substance surrounding the third ventricle, in the medial part of both putamina and in the frontal white matter including the anterior limbs of the internal capsules and the corpus callosum. Infratentorially, the cerebellar white matter and dorsal parts of the pons and medulla were affected. CONCLUSION: In addition to cortical grey matter changes, we now have a second structural finding pointing to a more widespread affection of cerebral tissue in PKAN dystonia than just the lesion and iron accumulation in the globus pallidus.

Late diagnosis of fucosidosis in a child with progressive fixed dystonia, bilateral pallidal lesions and red spots on the skin.

Fucosidosis is a rare lysosomal storage disease. A 14-year-old girl is presented, with recurrent infections, progressive dystonic movement disorder and mental retardation with onset in early childhood. The clinical picture was also marked by mild morphologic features, but absent dysostosis multiplex and organomegaly. MRI images at 6.5 years of age were reminiscent of pallidal iron deposition ("eye-of-the-tiger" sign) seen in neurodegeneration with brain iron accumulation (NBIA) disorders. Progressively spreading angiokeratoma corporis diffusum led to the correct diagnosis. This case extends the scope of clinical and neuroradiological manifestations of fucosidosis.

Dilatation of Virchow-Robin spaces in children hospitalized at pediatric neurology department.

BACKGROUND AND PURPOSE: Dilated Virchow-Robin spaces (dVRs) have been revealed by magnetic resonance imaging (MRI) in patients with various neurological disorders. However, their etiology and clinical importance have not been discovered yet. The aim of the study was to estimate dVRs occurrence in hospitalized children and determine dVRs localization and their association with different nervous system diseases. MATERIAL AND METHODS: Contrast-enhanced brain MRI examinations with the use of 1.5T GE device were performed in children with different diseases of nervous system, who were hospitalized at Pediatric Neurology Department, Chair of Children and Adolescent Neurology, Jagiellonian University in the years 2010-2011. The mean age of examined children was 11.58 years, and the studied group included 27 boys and 26 girls. RESULTS: Within two years, MRI examinations of the brain were performed in 1348 children and dVRs were found in 53 of them (3.93%). Among children with dVRs, 15 were diagnosed with headache (28.3%) and 18 with epilepsy (33.96%). Other diagnoses were less frequent and occurred in 37.7%. Generalized dVRs and those localized in the subcortical nuclei were most frequently found. CONCLUSIONS: Higher incidence of dVRs was found in children with headache and epilepsy. No association was found between localization of dVRs and symptomatology of different nervous system diseases except for large dVRs probably due to the pressure on the surrounding tissues.

A de novo nonsense PDGFB mutation causing idiopathic basal ganglia calcification with laryngeal dystonia.

Idiopathic basal ganglia calcification (IBGC) is characterized by brain calcification and a wide variety of neurologic and psychiatric symptoms. In families with autosomal dominant inheritance, three causative genes have been identified: SLC20A2, PDGFRB, and, very recently, PDGFB. Whereas in clinical practice sporadic presentation of IBGC is frequent, well-documented reports of true sporadic occurrence are rare. We report the case of a 20-year-old woman who presented laryngeal dystonia revealing IBGC. Her healthy parents' CT scans were both normal. We identified in the proband a new nonsense mutation in exon 4 of PDGFB, c.439C>T (p.Gln147*), which was absent from the parents' DNA. This mutation may result in a loss-of-function of PDGF-B, which has been shown to cause IBGC in humans and to disrupt the blood-brain barrier in mice, resulting in brain calcification. The c.439C>T mutation is located between two previously reported nonsense mutations, c.433C>T (p.Gln145*) and c.445C>T (p.Arg149*), on a region that could be a hot spot for de novo mutations. We present the first full demonstration of the de novo occurrence of an IBGC-causative mutation in a sporadic case.