Adrienn Máté

Mutations in B9D1 and MKS1 cause mild Joubert syndrome: expanding the genetic overlap with the lethal ciliopathy Meckel syndrome

Joubert syndrome is a clinically and genetically heterogeneous ciliopathy characterized by a typical cerebellar and brainstem malformation (the “molar tooth sign”), and variable multiorgan involvement. To date, 24 genes have been found mutated in Joubert syndrome, of which 13 also cause Meckel syndrome, a lethal ciliopathy with kidney, liver and skeletal involvement. Here we describe four patients with mild Joubert phenotypes who carry pathogenic mutations in either MKS1 or B9D1, two genes previously implicated only in Meckel syndrome.

EXOSC3 mutations in pontocerebellar hypoplasia type 1: novel mutations and genotype-phenotype correlations

BackgroundPontocerebellar hypoplasia (PCH) represents a group of neurodegenerative disorders with prenatal onset. Eight subtypes have been described thus far (PCH1-8) based on clinical and genetic features. Common characteristics include hypoplasia and atrophy of the cerebellum, variable pontine atrophy, and severe mental and motor impairments. PCH1 is distinctly characterized by the combination with degeneration of spinal motor neurons. Recently, mutations in the exosome component 3 gene (EXOSC3) have been identified in approximately half of the patients with PCH subtype 1.MethodsWe selected a cohort of 99 PCH patients (90 families) tested negative for mutations in the TSEN genes, RARS2, VRK1 and CASK. Patients in this cohort were referred with a tentative diagnose PCH type 1, 2, 4, 7 or unclassified PCH. Genetic analysis of the EXOSC3 gene was performed using Sanger sequencing. Clinical data, MR images and autopsy reports of patients positive for EXOSC3 mutations were analyzed.ResultsEXOSC3 mutations were found in twelve families with PCH subtype 1, and were not found in patients with other PCH subtypes. Identified mutations included a large deletion, nonsense and missense mutations. Examination of clinical data reveals a prolonged disease course in patients with a homozygous p.D132A mutation. MRI shows variable pontine hypoplasia in EXOSC3 mediated PCH, where the pons is largely preserved in patients with a homozygous p.D132A mutation, but attenuated in patients with other mutations. Additionally, bilateral cerebellar cysts were found in patients compound heterozygous for a p.D132A mutation and a nonsense allele.ConclusionsEXOSC3 mediated PCH shows clear genotype-phenotype correlations. A homozygous p.D132A mutation leads to PCH with possible survival into early puberty, and preservation of the pons. Compound heterozygosity for a p.D132A mutation and a nonsense or p.Y109N allele, a homozygous p.G31A mutation or a p.G135E mutation causes a more rapidly progressive course leading to death in infancy and attenuation of the ventral pons.Our findings imply a clear correlation between genetic mutation and clinical outcome in EXOSC3 mediated PCH, including variable involvement of the pons.

Microvascular reactivity in lean, overweight, and obese hypertensive adolescents

The microvascular responses to endothelium-dependent vasodilators (e.g., acetylcholine), endothelium-independent vasodilators (e.g., sodium nitroprusside), and to local heating were studied (for the first time) in adolescents with essential hypertension, grouped according to their body mass index. The forearm microvascular reactivities of thirty-three hypertensive adolescents (ten lean, 13 overweight, and ten obese) and 19 healthy controls were assessed by means of laser Doppler flowmetry. Blood levels of enzymatic and nonenzymatic antioxidants and malondialdehyde were determined. The perfusion increments in response to acetylcholine iontophoresis were not significantly attenuated in the patient groups as compared with the controls. Sodium nitroprusside (SNP) iontophoresis resulted in significantly smaller perfusion increments in the lean and obese hypertensives than in the controls (both p < 0.05). Similar responses to local heating (44°C) performed after either acetylcholine or SNP iontophoresis were observed at the respective measurement sites. As compared with the controls, we found elevated ratios of the whole blood oxidized and reduced glutathione in all the patient groups (all p < 0.001), increased erythrocyte catalase activities in the overweight hypertensives (p < 0.05), and decreased ratios of the plasma alpha-tocopherol and triglycerides in the obese hypertensive group (p < 0.05). Conclusion: The endothelium-dependent microvascular reactivity was not significantly attenuated in the hypertensive adolescents in contrast with the impaired endothelium-independent vasorelaxation in the lean and obese hypertensives.

The Role of Probabilistic Tractography in the Surgical Treatment of Thalamic Gliomas

BACKGROUND: Thalamic gliomas represent a great challenge for neurosurgeons because of the high surgical risk of damaging the surrounding anatomy. Preoperative planning may considerably help the surgeon find the most ideal operative trajectory, avoiding thalamic nuclei and important white matter pathways adjacent to the tumor tissue. Thalamic segmentation is a promising imaging tool based on diffusion tensor magnetic resonance imaging. It provides the possibility to predict the relationship of the tumor to thalamic nuclei. OBJECTIVE: To propose a new tool in thalamic glioma surgery that may help to differentiate between normal thalamus and tumor tissue, making preoperative planning possible and facilitating the choice of the optimal surgical approach and trajectory for neuronavigation-assisted surgery. METHODS: Four patients with thalamic gliomas preoperatively underwent conventional and diffusion-weighted magnetic resonance imaging conducted on 1.5 T. Subsequently, probabilistic tractography and thalamic segmentation were performed with the FSL Software as preoperative planning. We also present a case when thalamic segmentation was applied retrospectively using preoperative images. All patients went through neuronavigation-assisted surgery (1 partial, 4 subtotal resections). RESULTS: Surgery performed based on the output of thalamic segmentation caused no deterioration in the neurological symptoms of our patients. Indeed, we noticed improvement in the neurological condition in 3 cases; furthermore, in 2 patients, a concern-free state was achieved. CONCLUSION: We suggest that thalamic segmentation may be applied successfully and routinely in the surgical treatment of thalamic gliomas. ABBREVIATIONS: DTI, diffusion tensor magnetic resonance imaging DTT, diffusion tensor tractography FLAIR, fluid attenuated inversion recovery FOV, field of view TE, echo time TR, repetition time

Spectrum of neurodevelopmental disabilities: A cohort study in hungary

The spectrum of neurodevelopmental disabilities was studied in a cohort of patients in Hungary. A search for etiologies and assessment of the degree of intellectual disability were carried out. The study included 241 (131 boys) patients. Disability occurred without any prenatal, perinatal, and/or neonatal adverse events in 167 patients. They were classified into the following subgroups: genetic syndromes with recognized etiology, global developmental delay/intellectual disability in association with dysmorphic features but unknown etiology, global developmental delay/intellectual disability without dysmorphic features and recognized etiology, brain malformations, inborn errors of metabolism, leukoencephalopathies, epileptic syndromes, developmental language impairment, and neuromuscular disorders. Adverse events occurred in 74 children classified into subgroups such as cerebral palsy after delivery preterm or at term, and disabilities without cerebral palsy. The etiology was identified in 66.4%, and genetic diagnosis was found in 19.5%. Classification of neurodevelopmental disorders contribute to etiological diagnosis, proper rehabilitation, and genetic counseling.

Co-occurrence of mutations in FOXP1 and PTCH1 in a girl with extreme megalencephaly, callosal dysgenesis and profound intellectual disability

Heterozygous disruptions in FOXP1 are responsible for developmental delay, intellectual disability and speech deficit. Heterozygous germline PTCH1 disease-causing variants cause Gorlin syndrome. We describe a girl with extreme megalencephaly, developmental delay and severe intellectual disability. Dysmorphic features included prominent forehead, frontal hair upsweep, flat, wide nasal bridge, low-set, abnormally modelled ears and post-axial cutaneous appendages on the hands. Brain MRI showed partial agenesis of the corpus callosum and widely separated leaves of the septum pellucidum. Exome sequencing of a gene set representing a total of 4813 genes with known relationships to human diseases revealed an already known heterozygous de novo nonsense disease-causing variant in FOXP1 (c.1573C>T, p.Arg525Ter) and a heterozygous novel de novo frameshift nonsense variant in PTCH1 (c.2834delGinsAGATGTTGTGGACCC, p.Arg945GlnfsTer22). The composite phenotype of the patient seems to be the result of two monogenic diseases, although more severe than described in conditions due to disease-causing variants in either gene.

Connectivity-based segmentation of the brainstem by probabilistic tractography

Diffusion magnetic resonance imaging is a non-invasive tool increasingly used for the investigation of brain connectivity in vivo. In this paper we propose a method that allows segmentation of the brainstem to four subregions (frontopontine, motor, sensory and reticular) based on connections to supratentorial structures, thereby eliminating the need for using anatomical landmarks within the brainstem for the identification of these subregions. The feasibility of connectivity-based brainstem segmentation was investigated in a group of healthy subjects (n = 20). Multifiber probabilistic tractography was performed using the FMRIB Software Library, and connections between a pontomesencephalic seed mask and four supratentorial target regions (anterior and posterior limbs of the internal capsule, sensory and medial thalamus) were used to determine connectivity maps of the brainstem. Results were compared with a neuroanatomy atlas and histological sections, confirming good anatomic correspondence. The four subregions detected by the connectivity-based segmentation showed good intersubject reproducibility. The presented method may be a potential tool to investigate brainstem connectivity in diseases that distort normal anatomy, and quantitative analyses of the diffusion-related parameters may provide additional information on the involvement of brainstem pathways in certain disease states (e.g., traumatic brain injury, demyelinating disorders, brainstem tumors). The potential clinical applicability of the method is demonstrated in two cases of severe traumatic brain injury.

De Novo Interstitial Microdeletion at 1q32.1 in a 10-Year-Old Boy with Developmental Delay and Dysmorphism

A 10-year-old boy was referred with developmental delay and dysmorphism. Genomewide aCGH microarray analysis detected a de novo 3.7 Mb deletion at 1q32.1: arr 1q32.1(199,985,888-203,690,832)x1 dn [build HG19]. This first report of a deletion in this region implies a critical role for dosage-sensitive genes within 1q32.1 in neurological development. This is consistent with previously reported duplications of this region in patients with a similar phenotype.

P105 – 2378: Microcephaly, pontocerebellar hypoplasia and epilepsy in patients with CASK mutations

Objective The CASK protein is a member of the membraneassociated guanylate kinase protein family, and plays a role in neural development and synaptic function. The CASK gene is located on the X-chromosome, its loss-of-function mutations have been shown to cause microcephaly and pontine and cerebellar hypoplasia (MIC-PCH) in females. We report the cases of two girls with MIC-PCH caused by different de novo loss-of function mutations of the CASK gene. Methods Clinical evaluation included neurological examination, developmental assessment, brain MRI, EEG, laboratory tests, audiologic and ophthalmologic examinations, and genetic testing. Sequence analysis of the entire coding region (exons 1–27), and all intron-exon boundaries of the CASK gene was carried out. Results Both patients presented with congenital microcephaly, intellectual disability, delayed motor development in association with therapy-resistant epilepsy beginning around 2 years of age. Brain MRI revealed hypoplasia of the brainstem and cerebellum and the EEG showed bilateral periodic spike-and-wave discharges in both girls. One of them had a very severe phenotype with spastic tetraplegia, visual impairment and hearing loss, while the other patient was able to achieve some motor milestones like rolling and sitting with support. Pathogenic heterozygous deletions in the CASK gene were identified in both girls: deletion of 8 nucleotides (c.20_27delTGTTCGAG p.Leu7ArgfsX35) in one of them and deletion of a single nucleotide (c.1034delG p.Arg345Lysfs*) in the other one. Both deletions result in a frameshift leading to the formation of a premature stop codon. The parents are healthy. Conclusion Mutations of the CASK gene should be considered in female patients with microcephaly, intellectual disability and pontocerebellar hypoplasia. These girls are sporadic cases with de novo mutations. Identification of CASK mutations enables accurate and reassuring genetic counselling.

The clinical manifestations of two novel SPAST mutations

Department of Neurology, Faculty of Medicine, Albert Szent-Gyorgyi Clinical Centre, University of Szeged, Szeged, Hungary Department of Neurosurgery, Faculty of Medicine, Albert Szent-Gyorgyi Clinical Centre, University of Szeged, Szeged, Hungary Department of Pediatrics and Pediatric Health Care Centre, Faculty of Medicine, Albert Szent-Gyorgyi Clinical Centre, University of Szeged, Szeged, Hungary 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary Department of Medical Genetics, Faculty of Medicine, Albert Szent-Gyorgyi Clinical Centre, University of Szeged, Szeged, Hungary MTA-SZTE Neuroscience Research Group, Szeged, Hungary