PCDH12 variants are associated with basal ganglia anomalies and exudative vitreoretinopathy.

PCDH12 is a member of the non-clustered protocadherins that mediate cell-cell adhesion, playing crucial roles in many biological processes. Among these, PCDH12 promotes cell-cell interactions at inter-endothelial junctions, exerting essential functions in vascular homeostasis and angiogenesis. However, its exact role in eye vascular and brain development is not completely understood. To date, biallelic loss of function variants in PCDH12 have been associated with a neurodevelopmental disorder characterized by the typical neuroradiological findings of diencephalic-mesencephalic junction dysplasia and intracranial calcifications, whereas heterozygous variants have been recently linked to isolated brain calcifications in absence of cognitive impairment or other brain malformations. Recently, the phenotypic spectrum associated with PCDH12 deficiency has been expanded including cerebellar and eye abnormalities. Here, we report two female siblings harboring a novel frameshift homozygous variant (c.2169delT, p.(Val724TyrfsTer8)) in PCDH12. In addition to the typical diencephalic-mesencephalic junction dysplasia, brain MRI showed dysmorphic basal ganglia and thalamus that were reminiscent of a tubulin-like phenotype, mild cerebellar vermis hypoplasia and extensive prominence of perivascular spaces in both siblings. The oldest sister developed profound and progressive monocular visual loss and the eye exam revealed exudative vitreoretinopathy. Similar but milder eye changes were also noted in her younger sister. In summary, our report expands the clinical (brain and ocular) spectrum of PCDH12-related disorders and adds a further line of evidence underscoring the important role of PCDH12 in retinal vascular and brain development.

Whole exome sequencing identifies a novel homozygous MECR mutation in a Chinese patient with childhood-onset dystonia and basal ganglia abnormalities, without optic atrophy.

Childhood-onset dystonia with optic atrophy and basal ganglia abnormalities is an extremely rare autosomal recessive mitochondrial disease caused by biallelic mutations in MECR. Using whole-exome sequencing, we identified a novel homozygous MECR mutation (c.910G > T, p.Asp304Tyr) in a Chinese patient with childhood-onset dystonia and basal ganglia abnormalities, without optic atrophy. With lipoic acid treatment, the disease progression was under control, and neither visual impairment nor optic atrophy was observed. To our knowledge, this is the first study about MECR-related mitochondrial disease in a Chinese patient and the first to report that supplementation with lipoic acid is a possible effective therapeutic strategy for this disease.

Basal Ganglia Dysmorphism in Patients With Aicardi Syndrome.

OBJECTIVE: Aiming to detect associations between neuroradiologic and EEG evaluations and long-term clinical outcome in order to detect possible prognostic factors, a detailed clinical and neuroimaging characterization of 67 cases of Aicardi syndrome (AIC), collected through a multicenter collaboration, was performed. METHODS: Only patients who satisfied Sutton diagnostic criteria were included. Clinical outcome was assessed using gross motor function, manual ability, and eating and drinking ability classification systems. Brain imaging studies and statistical analysis were reviewed. RESULTS: Patients presented early-onset epilepsy, which evolved into drug-resistant seizures. AIC has a variable clinical course, leading to permanent disability in most cases; nevertheless, some cases presented residual motor abilities. Chorioretinal lacunae were present in 86.56% of our patients. Statistical analysis revealed correlations between MRI, EEG at onset, and clinical outcome. On brain imaging, 100% of the patients displayed corpus callosum malformations, 98% cortical dysplasia and nodular heterotopias, and 96.36% intracranial cysts (with similar rates of 2b and 2d). As well as demonstrating that posterior fossa abnormalities (found in 63.63% of cases) should also be considered a common feature in AIC, our study highlighted the presence (in 76.36%) of basal ganglia dysmorphisms (never previously reported). CONCLUSION: The AIC neuroradiologic phenotype consists of a complex brain malformation whose presence should be considered central to the diagnosis. Basal ganglia dysmorphisms are frequently associated. Our work underlines the importance of MRI and EEG, both for correct diagnosis and as a factor for predicting long-term outcome. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with AIC, specific MRI abnormalities and EEG at onset are associated with clinical outcomes.

Leigh syndrome in an infant: autopsy and histopathology findings

Leigh syndrome is an inherited neurodegenerative disorder of infancy that typically manifests between 3 and 12 months of age. The common neurological manifestations are developmental delay or regression, progressive cognitive decline, dystonia, ataxia, brainstem dysfunction, epileptic seizures, and respiratory dysfunction. Although the disorder is clinically and genetically heterogeneous, the histopathological and radiological features characteristically show focal and bilaterally symmetrical, necrotic lesions in the basal ganglia and brainstem. The syndrome has a characteristic histopathological signature that helps in clinching the diagnosis. We discuss these unique findings on autopsy and radiology in a young infant who succumbed to a subacute, progressive neurological illness suggestive of Leigh syndrome. Our case highlights that Leigh syndrome should be considered in the differential diagnosis of infantile-onset, subacute neuroregression with dystonia and seizures, a high anion gap metabolic acidosis, normal ketones, elevated lactates in blood, brain, and urine, and bilateral basal ganglia involvement.

Recessive congenital methemoglobinemia type II: Hypoplastic basal ganglia in two siblings with a novel mutation of the cytochrome b5 reductase gene.

Recessive congenital methemoglobinemia type II is a very rare autosomal recessive hematologic disorder due to NADH-cytochrome b5 reductase deficiency, usually caused by full-stop mutations or deletions. This disease classically presents with mild neonatal cyanosis, early onset severe progressive developmental delay, movement disorders, and progressive microcephaly. We report two siblings with recessive congenital methemoglobinemia type II whose evaluation revealed a novel p.Arg92Trp missense mutation of the CYB5R3 gene and a peculiar imaging finding of basal ganglia hypoplasia. Brain magnetic resonance imaging was performed at age 10 months in the older sibling and at age three months in the younger sibling. It revealed similar findings of bilateral small size of the lentiform and caudate nuclei and reduced frontotemporal brain volume. Our patient cases highlight that basal ganglia hypoplasia is an interesting clue to the very rare and frequently unsuspected diagnosis of recessive congenital methemoglobinemia type II, that may explain the associated movement disorders. The novel missense mutation is one of very few identified missense mutations known to cause severe type II recessive congenital methemoglobinemia.

Neurological manifestations of 2q31 microdeletion syndrome.

Microdeletion of 2q31 involving the HOXD gene cluster is a rare syndrome. The deletion of the HOXD gene cluster is thought to result in skeletal anomalies in these patients. HOX genes encode highly conserved transcription factors that control cell fate and the regional identities along the primary body and limb axes. We experienced a new patient with 2q31 microdeletion encompassing the HOXD gene cluster and some neighboring genes including the ZNF385B. The patient showed digital anomalies, growth failure, epileptic seizures, and intellectual disability. Magnetic resonance imaging showed delayed myelination and low signal intensity in the basal ganglia. The ZNF385B is a zinc finger protein expressed in brain. Disruption of ZNF385B was suspected to be responsible for the neurological features of this syndrome.

Association Between Invisible Basal Ganglia and ZNF335 Mutations: A Case Report.

ZNF335 was first reported in 2012 as a causative gene for microcephaly. Because only 1 consanguineous pedigree has ever been reported, the key clinical features associated with ZNF335 mutations remain unknown. In this article, we describe another family harboring ZNF335 mutations. The female proband was the first child of nonconsanguineous Japanese parents. At birth, microcephaly was absent; her head circumference was 32.0 cm (-0.6 SD). At 3 months, microcephaly was noted, (head circumference, 34.0 cm [-4.6 SD]). Brain MRI showed invisible basal ganglia, cerebral atrophy, brainstem hypoplasia, and cerebellar atrophy. At 33 months, (head circumference, 41.0 cm [-5.1 SD]), she had severe psychomotor retardation. After obtaining informed consent from her parents, we performed exome sequencing in the proband and identified 1 novel and 1 known mutation in ZNF335, namely, c.1399T>C (p.C467R) and c.1505A>G (p.Y502C), respectively. The mutations were individually transmitted by her parents, indicating that the proband was compound heterozygous for the mutations. Her brain imaging findings, including invisible basal ganglia, were similar to those observed in the previous case with ZNF335 mutations. We speculate that invisible basal ganglia may be the key feature of ZNF335 mutations. For infants presenting with both microcephaly and invisible basal ganglia, ZNF335 mutations should be considered as a differential diagnosis.

Structural and Functional Brain Abnormalities in Attention-Deficit/Hyperactivity Disorder and Obsessive-Compulsive Disorder: A Comparative Meta-analysis.

IMPORTANCE: Patients with attention-deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD) share impaired inhibitory control. However, it is unknown whether impairments are mediated by shared or disorder-specific neurostructural and neurofunctional abnormalities. OBJECTIVE: To establish shared and disorder-specific structural, functional, and overlapping multimodal abnormalities in these 2 disorders through a voxel-based meta-analytic comparison of whole-brain gray matter volume (GMV) and functional magnetic resonance imaging (fMRI) studies of inhibition in patients with ADHD and OCD. DATA SOURCES: Literature search using PubMed, ScienceDirect, Web of Knowledge, and Scopus up to September 30, 2015. STUDY SELECTION: Whole-brain voxel-based morphometry (VBM) or fMRI studies during inhibitory control comparing children and adults with ADHD or OCD with controls. DATA EXTRACTION AND SYNTHESIS: Voxel-wise meta-analyses of GMV or fMRI differences were performed using Seed-based d-Mapping. Regional structure and function abnormalities were assessed within each patient group and then a quantitative comparison was performed of abnormalities (relative to controls) between ADHD and OCD. MAIN OUTCOMES AND MEASURES: Meta-analytic disorder-specific and shared abnormalities in GMV, in inhibitory fMRI, and in multimodal functional and structural measures. RESULTS: The search revealed 27 ADHD VBM data sets (including 931 patients with ADHD and 822 controls), 30 OCD VBM data sets (928 patients with OCD and 942 controls), 33 ADHD fMRI data sets (489 patients with ADHD and 591 controls), and 18 OCD fMRI data sets (287 patients with OCD and 284 controls). Patients with ADHD showed disorder-contrasting multimodal structural (left z = 1.904, P < .001; right z = 1.738, P < .001) and functional (left z = 1.447, P < .001; right z = 1.229, P < .001) abnormalities in bilateral basal ganglia/insula, which were decreased in GMV and function in patients with ADHD relative to those with OCD (and controls). In OCD patients, they were enhanced relative to controls. Patients with OCD showed disorder-specific reduced function and structure in rostral and dorsal anterior cingulate/medial prefrontal cortex (fMRI z = 2.113, P < .001; VBM z = 1.622, P < .001), whereas patients with ADHD showed disorder-specific underactivation predominantly in the right ventrolateral prefrontal cortex (z = 1.229, P < .001). Ventromedial prefrontal GMV reduction was shared in both disorders relative to controls. CONCLUSIONS AND RELEVANCE: Shared impairments in inhibitory control, rather than representing a transdiagnostic endophenotype in ADHD and OCD, were associated with disorder-differential functional and structural abnormalities. Patients with ADHD showed smaller and underfunctioning ventrolateral prefrontal/insular-striatal regions whereas patients with OCD showed larger and hyperfunctioning insular-striatal regions that may be poorly controlled by smaller and underfunctioning rostro/dorsal medial prefrontal regions.

Reverse asymmetry and changes in brain structural volume of the basal ganglia in ADHD, developmental changes and the impact of stimulant medications.

We discussed the cross section studies and the meta-analysis of published data in children and adolescents with ADHD (both drug naive and receiving stimulant medications), in comparison with healthy children and adolescents of the same age. In children and adolescents with ADHD the deceleration of the maturation dynamics of discrete CNS structures is found, volume reduction and decreased grey matter in prefrontal and occipital regions, which is accompanied by reverse asymmetry of the basal ganglia volume (putamen, nucleus caudate). The above mentioned developmental characteristics are valid only for the ADHD children, who have not been treated by stimulant medications. The stimulant treatment eliminates the mentioned changes into various extend. These developmental changes of CNS structures volume are missing in girls.

Abordajes farmacológicos para mejorar la función cognitiva en el síndrome de Down: estado actual y consideraciones / No disponible

Es creciente, y a veces acuciante, el interés de familias y profesionales relacionados con el síndrome de Down por conocer los posible beneficios que algunos fármacos pueden reportar sobre la cognición y conducta de las personas con síndrome de Down. Los primeros ensayos clínicos que se están realizando en las personas, y los resultados de los cada vez más frecuentes estudios sobre los modelos animales, han creado una atmósfera de esperanza y, por qué no decirlo, también de ansiedad. A principios del presente mes de enero fue publicada una exhaustiva revisión escrita por la investigadora norteamericana Katheleen J. Gardiner, en la que analiza con detalle todos los resultados obtenidos por diversos fármacos en el modelo de ratón más universalmente utilizado, el ratón Ts65Dn, y explica las posibilidades de que algunos de estos fármacos puedan ser probados en la clínica humana. Ofrecemos un muy amplio resumen en español que, esperamos, dé cumplida respuesta a las actuales inquietudes. Quien desee disponer del trabajo original en inglés y la bibliografía, puede solicitarlos a la dirección de la revista

Over the last several years, very promising results have been obtained with a mouse model of Down syndrome, the Ts65Dn. A diverse array of drugs has been shown to rescue, or partially rescue relevant deficits in learning and memory and abnormalities in cellular and electrophysiological features seen in the Ts65Dn. These results suggest that some levels of amelioration or prevention of cognitive deficits in people with Down syndrome may be possible. We review information from the preclinical evaluations on the efficacy of these drugs, and advance possible applications of some of the studied drugs to clinical trials

Behavioral abnormalities and circuit defects in the basal ganglia of a mouse model of 16p11.2 deletion syndrome.

A deletion on human chromosome 16p11.2 is associated with autism spectrum disorders. We deleted the syntenic region on mouse chromosome 7F3. MRI and high-throughput single-cell transcriptomics revealed anatomical and cellular abnormalities, particularly in cortex and striatum of juvenile mutant mice (16p11(+/-)). We found elevated numbers of striatal medium spiny neurons (MSNs) expressing the dopamine D2 receptor (Drd2(+)) and fewer dopamine-sensitive (Drd1(+)) neurons in deep layers of cortex. Electrophysiological recordings of Drd2(+) MSN revealed synaptic defects, suggesting abnormal basal ganglia circuitry function in 16p11(+/-) mice. This is further supported by behavioral experiments showing hyperactivity, circling, and deficits in movement control. Strikingly, 16p11(+/-) mice showed a complete lack of habituation reminiscent of what is observed in some autistic individuals. Our findings unveil a fundamental role of genes affected by the 16p11.2 deletion in establishing the basal ganglia circuitry and provide insights in the pathophysiology of autism.

Cavernous malformation of brainstem, thalamus, and basal ganglia: a series of 176 patients.

BACKGROUND: Cavernous malformations (CMs) in deep locations account for 9% to 35% of brain malformations and are surgically challenging. OBJECTIVE: To study the clinical features and outcomes following surgery for deep CMs and the complication of hypertrophic olivary degeneration (HOD). METHODS: Clinical records, radiological findings, operative details, and complications of 176 patients with deep CMs were reviewed retrospectively. RESULTS: Of 176 patients with 179 CMs, 136 CMs were in the brainstem, 27 in the basal ganglia, and 16 in the thalamus. Cranial nerve deficits (51.1%), hemiparesis (40.9%), numbness (34.7%), and cerebellar symptoms (38.6%) presented most commonly. Hemorrhage presented in 172 patients (70 single, 102 multiple). The annual retrospective hemorrhage rate was 5.1% (assuming CMs are congenital with uniform hemorrhage risk throughout life); the rebleed rate was 31.5%/patient per year. Surgical approach depended on the proximity of the CM to the pial or ependymal surface. Postoperatively, 121 patients (68.8%) had no new neurological deficits. Follow-up occurred in 170 patients. Delayed postoperative HOD developed in 9/134 (6.7%) patients with brainstem CMs. HOD occurred predominantly following surgery for pontine CMs (9/10 patients). Three patients with HOD had palatal myoclonus, nystagmus, and oscillopsia, whereas 1 patient each had limb tremor and hemiballismus. At follow-up, 105 patients (61.8%) improved, 44 (25.9%) were unchanged, and 19 (11.2%) worsened neurologically. Good preoperative modified Rankin Score (98.2% vs 54.5%, P = .001) and single hemorrhage (89% vs 77.3%, P < .05) were predictive of good long-term outcome. CONCLUSION: Symptomatic deep CMs can be resected with acceptable morbidity and outcomes. Good preoperative modified Rankin Score and single hemorrhage are predictors of good long-term outcome.

Location of periventricular nodular heterotopia is related to the malformation phenotype on MRI.

BACKGROUND AND PURPOSE: Periventricular nodular heterotopia are common malformations of cortical development that are associated with many clinical syndromes and with many different neuroimaging phenotypes. The purpose of this study was to determine whether specific malformation phenotypes may be related to location, side, or number of PNH as assessed by MR imaging. MATERIALS AND METHODS: MR images of 200 patients previously diagnosed with PNH were retrospectively analyzed. PNH were classified according to their location along the ventricles (anterior, posterior, or diffuse), side (unilateral or bilateral), and number of nodules (<5, 6-10, or >10). The cerebrum, brain stem and cerebellum were analyzed to assess associated anomalies. Associations between PNH location and the presence of other anomalies were tested by using Fisher exact test and χ2 test. RESULTS: Posterior PNH were significantly associated with malformations of the cerebral cortex, diminished white matter volume, and mid-/hindbrain anomalies. Diffuse PNH were associated with diminished white matter volume, callosal "anomalies," and the presence of megacisterna magna. Unilateral PNH were strongly associated with cortical malformations. CONCLUSIONS: Certain malformation complexes are associated with PNH in specific locations: posterior PNH with cerebral cortical and mid-/hindbrain malformations and diffuse PNH with callosal anomalies and megacisterna magna. Knowledge of these associations should allow more directed analyses of brain MR imaging in patients with PNH. In addition, knowledge of these associations may help to direct studies to elucidate the causes of these malformation complexes.

Bases anatómicas, fisiopatológicas y neuroquímicas de los síndromes rígido-acinéticos / Anatomical, pathophysiological and neurochemical bases of rigid-akinetic syndrome

Introducción. Los síndromes rígido-acinéticos incluyen un grupo heterogéneo de patologías agrupados por una serie de síntomas comunes en las esferas motora, cognitiva y emocional. Desarrollo. Los ganglios basales están constituidos por un grupo de estructuras anatómicamente dispersas que se conectan entre sí y con diversas estructuras formando un entramado de redes funcionales. Las lesiones en estos circuitos producen síntomas en las esferas motora, cognitiva y emocional. En la enfermedad de Parkinson, el síndrome rígido-acinético más conocido y estudiado, actualmente sólo pueden explicarse del conjunto de sus síntomas el temblor y la bradicinesia. Los síndromes rígido-acinéticos se consideran hoy enfermedades neurodegenerativas que afectan a múltiples estructuras y sistemas del sistema nervioso central y periférico. Una gran parte de estos pueden agruparse dentro de las sinucleinopatías y las taupatías, aunque en ocasiones los hallazgos anatomopatológicos entre ambas se solapan. Conclusiones. Es preciso un mayor conocimiento del funcionamiento del sistema nervioso y los procesos de degeneración neuronal para poder obtener nuevas estrategias terapéuticas más eficaces (AU)

Introduction. The rigid-akinetic syndromes include a heterogeneous collection of pathologies grouped by a series of common symptoms that appear in the motor, cognitive and emotional spheres. Development. The basal ganglia are made up of a group of anatomically dispersed structures that are nonetheless connected to each other and with several other structures to form a cluster of functional networks. Lesions in these circuits produce symptoms in the motor, cognitive and emotional spheres. Of all the syndromes that occur in Parkinson's disease, which is the best-known and most widely studied rigid-akinetic syndrome, only tremor and bradykinesia can presently be explained. Rigid-akinetic syndromes are nowadays considered to be neurodegenerative diseases that affect a number of structures and systems within the central and peripheral nervous system. Many of these can be included within the groups of synucleinopathies and tauopathies, although on occasions the pathological findings overlap between the two. Conclusions. Further knowledge of the functioning of the nervous system and the processes involved in neuronal degeneration is needed to be able to produce new, more effective therapeutic strategies (AU)

Neuroimágenes sin evidencia de déficit dopaminérgico (SWEDD) / SWEDDs: scans without evidence of dopaminergic deficit

Introducción. Aproximadamente un 10% de los pacientes diagnosticados inicialmente de Enfermedad de Parkinson (E.P.), no presentan alteraciones en la vía dopaminérgica nigroestriatal en su vertiente presináptica; se engloban bajo el acrónimo SWEDDs (Scans without evidence of dopaminergic deficit) [1]. Objetivo. Revisar aquellos aspectos clínicos que pueden ayudar al diagnóstico diferencial de los SWEDDs, así como las bases del tratamiento. Desarrollo. Las técnicas complementarias empleadas en el diagnóstico de la E.P. como el DAT-SCAN, han favorecido que se establezca un diagnóstico diferencial entre estas dos entidades: E.P. y SWEDDs, cuya evolución, pronóstico y tratamiento será diferente. Conclusiones. El término SWEDDs incluye pacientes con temblor de reposo asimétrico y ausencia de disfunción de la vía dopaminérgica nigroestriatal. En casos dudosos la prueba complementaria a realizar es el DAT-SCAN. La hipótesis de que el temblor en SWEDDs pueda ser una forma de distonía primaria debe ser contrastada en futuros estudios [1]. El tratamiento de los pacientes con SWEDDs se basa en fármacos anticolinérgicos (AU)

Introduction. Approximately 10% of all patients initially diagnosed with Parkinson's disease (PD) do not present any alterations in the presynaptic nigrostriatal dopaminergic pathway; they are classified under the acronym SWEDDs (Scans without evidence of dopaminergic deficit). Aims. Our aim is to review those clinical aspects that can be of use in the differential diagnosis of the SWEDDs, as well as the bases of treatment. Development. The complementary techniques employed in the diagnosis of PD, like DAT-SCAN, have made a valuable contribution to establishing a differential diagnosis between these two conditions, i.e. PD and SWEDDs, whose development, prognosis and treatment will be different. Conclusions. The term SWEDDs includes patients with asymmetrical tremor at rest and absence of dysfunction of the nigrostriatal dopaminergic pathway. In doubtful cases, the complementary test to be conducted is DAT-SCAN. The hypothesis that claims that the tremor in SWEDDs may be a form of primary dystonia must be tested in future studies. The treatment of patients with SWEDDs is based on anticholinergic drugs (AU)

Demencia frontotemporal asociada al cromosoma 17 y otros síndromes parkinsonianos asociados a demencia / Frontotemporal dementia associated to chromosome 17 and other Parkinsonian syndromes linked to dementia

Introducción. Dentro de los síndromes con deterioro cognitivo se hallan múltiples entidades que asocian parkinsonismo como síntoma acompañante a lo largo de su evolución. En ocasiones no se valoran los signos de patología extrapiramidal de forma adecuada, atribuyéndolos a efectos secundarios de la medicación o simplemente obviándolos si son leves y no causan incapacidad notable. Sin embargo, cuando aparecen es conveniente pensar en otras causas que los expliquen, replanteándose el diagnóstico inicial. Objetivo. Realizar un repaso breve de las entidades que presentan demencia como síntoma principal además de síndrome parkinsoniano en diferente medida. Desarrollo. Entre los síndromes con demencia y parkinsonismo asociado se encuentran numerosas patologías muy heterogéneas tanto en frecuencia como en etiología y pronóstico. Algunas son poco frecuentes, como las asociadas a mutaciones del cromosoma 17, y otras son tan comunes como la enfermedad de Alzheimer o la hidrocefalia normotensiva. También se incluyen procesos de diferente etiología: degenerativa, infecciosa, traumática, tóxica o metabólica, vascular, etc... que pueden, entre otros síntomas, presentar demencia y parkinsonismo. Conclusiones. Conocer dichas patologías nos puede ayudar a realizar un diagnóstico correcto, siempre deseable para tratar al paciente adecuadamente e informar de la forma más veraz a la familia sobre la evolución y pronóstico esperables (AU)

Introduction. Among the syndromes with cognitive impairment, there are a number of conditions that associate parkinsonism as an accompanying symptom throughout the whole of its development. On some occasions the signs of extrapyramidal pathology are not appraised properly and are attributed to secondary effects of the medication or are simply ignored if they are mild and do not cause any notable disability. When they do appear, however, it is wise to think about other causes that can explain them, reconsidering the initial diagnosis. Aims. To carry out a brief review of the conditions that present dementia as the main symptom, in addition to Parkinsonian syndrome, although to different extents. Development. Among the syndromes with dementia and parkinsonism associated to them, there are a number of pathologies that are very heterogeneous in terms of both their frequency and their causation and prognosis. Some of them are not very frequent, such as those associated to mutations of chromosome 17, and others are as common as Alzheimer's disease or normotensive hydrocephalus. They also include processes with different aetiologies (which can be degenerative, infectious, traumatic, toxic or metabolic, vascular, and so forth) that can present dementia and parkinsonism, among other symptoms. Conclusions. An understanding of such pathologies can help reach a correct diagnosis, which is fundamental to be able to treat the patient adequately and provide the family with information that is as accurate as possible about the expected development and prognosis (AU)

Anxious, hypoactive phenotype combined with motor deficits in Gtf2ird1 null mouse model relevant to Williams syndrome.

Williams-Beuren syndrome (WBS) is a rare genetic disorder caused by a hemizygous deletion of around 28 genes on the long arm of chromosome 7 (7q11.23), characterized by a unique spectrum of behavioral impairments, including mental retardation, deficits in visuospatial constructive cognition, hypersociability, anxiety and simple phobias. Physical characteristics include dysmorphic faces, short stature, oculomotor deficits, gross and fine coordination impairments, diminished control of balance and mild extrapyramidal signs as well as gait abnormalities resembling gait hypokinesia. Genes near the distal deletion breakpoint appear to contribute most to the WBS cognitive and behavioral profile and include the GTF family of transcription factors: GTF2I, GTF2IRD1, GTF2IRD2. We have previously shown that heterozygous deletions of GTF2IRD1 in humans and homozygous deletion in mice contributes to craniofacial abnormalities. Here we show an important role of this gene in motor coordination and anxiety ascertained from extensive behavioral mouse phenotyping. Gtf2ird1 null mice showed lower body weight, decreased spontaneous and circadian locomotor activity, diminished motor coordination and strength, gait abnormalities, increased anxiety and an elevated endocrinological response to stress. Gtf2ird1 heterozygous mice displayed lower body weight and decreased circadian activity, but only minor motor coordination and anxiety-related behavioral dysfunctions. Our study strongly supports a role for GTF2IRD1 in the motoric and anxiety-related abnormalities seen in Williams-Beuren syndrome, and suggests basal ganglia and potentially cerebellar abnormalities in Gtf2ird1 mice.

Planned two-fraction proton beam stereotactic radiosurgery for high-risk inoperable cerebral arteriovenous malformations.

PURPOSE: To evaluate patients with high-risk cerebral arteriovenous malformations (AVMs), based on eloquent brain location or large size, who underwent planned two-fraction proton stereotactic radiosurgery (PSRS). METHODS AND MATERIALS: From 1991 to 2009, 59 patients with high-risk cerebral AVMs received two-fraction PSRS. Median nidus volume was 23 cc (range, 1.4-58.1 cc), 70% of cases had nidus volume ≥ 14 cc, and 34% were in critical locations (brainstem, basal ganglia). Median AVM score based on age, AVM size, and location was 3.19 (range, 0.9-6.9). Many patients had prior surgery or embolization (40%) or prior PSRS (12%). The most common prescription was 16 Gy radiobiologic equivalent (RBE) in two fractions, prescribed to the 90% isodose. RESULTS: At a median follow-up of 56.1 months, 9 patients (15%) had total and 20 patients (34%) had partial obliteration. Patients with total obliteration received higher total dose than those with partial or no obliteration (mean dose, 17.6 vs. 15.5 Gy (RBE), p = 0.01). Median time to total obliteration was 62 months (range, 23-109 months), and 5-year actuarial rate of partial or total obliteration was 33%. Five-year actuarial rate of hemorrhage was 22% (95% confidence interval, 12.5%-36.8%) and 14% (n = 8) suffered fatal hemorrhage. Lesions with higher AVM scores were more likely to hemorrhage (p = 0.024) and less responsive to radiation (p = 0.026). The most common complication was Grade 1 headache acutely (14%) and long term (12%). One patient developed a Grade 2 generalized seizure disorder, and two had mild neurologic deficits. CONCLUSIONS: High-risk AVMs can be safely treated with two-fraction PSRS, although total obliteration rate is low and patients remain at risk for future hemorrhage. Future studies should include higher doses or a multistaged PSRS approach for lesions more resistant to obliteration with radiation.