Neonatal Alexander Disease : Novel GFAP Mutation and Comparison to Previously Published Cases

Alexander disease (AxD) is a genetic leukodystrophy caused by GFAP mutations leading to astrocyte dysfunction. Neonatal AxD is a rare phenotype with onset in the first month of life. The proband, belonging to a large pedigree with dominantly inherited benign familial neonatal epilepsy (BFNE), had a phenotype distinct from the rest of the family, with hypotonia and macrocephaly in addition to drug-resistant neonatal seizures. The patient deteriorated and passed away at 6 weeks of age. The pathological and neuroimaging data were consistent with the diagnosis of AxD. Genetic analysis of the proband identified a novel de novo GFAP missense mutation and a KCNQ2 splice site mutation segregating with the BFNE phenotype in the family. The GFAP mutation was located in the coil 2B region of GFAP protein, similar to most neonatal-onset AxD cases with an early death. The clinical and neuroradiological features of the previously published neonatal AxD patients are presented. This study further supports the classification of neonatal-onset AxD as a distinct phenotype based on the age of onset.Peer reviewe

Childhood-onset genetic white matter disorders of the brain in Northern Finland

Abstract Genetic white matter disorders (GWMD), leukodystrophies and genetic leukoencephalopathies, are a major cause of neurodevelopmental disorders. Over a hundred related genes are recognised. The recent implementation of next-generation sequencing has facilitated the frequent characterisation of novel disorders seen today. This study was intended to evaluate the current epidemiology, genetic aetiologies, clinical phenotypes, and natural history of childhood-onset GWMDs. Additional aims were to characterise novel and rare phenotypes and to examine the effect of Finnish disease heritage on the distribution of specific disorders. This population-based cohort study consisted of 80 children diagnosed with a genetically defined white matter disorder in Northern Finland between 1990 and 2019. The cumulative childhood incidence was 30/100,000 live births, and it was higher in the later study period. In total, 49 distinct disorders were identified, of which 20% were leukodystrophies and 80% were genetic leukoencephalopathies. Mitochondrial aetiology was noted in 21% of the cases. Disorders belonging to the Finnish disease heritage constituted 10% of the cases. Motor developmental delay (79%), intellectual disability (56%), hypotonia (60%), and spasticity (49%) were the most frequent clinical findings. The study identified 20 disorders that were either recently characterised or not previously associated with white matter abnormalities. These included a novel TAF1C related phenotype. Additionally, a rare neonatal Alexander disease with a novel GFAP variant was described, consolidating the recently proposed neonatal phenotype. These findings provide comprehensive data on the current epidemiology and clinical features of GWMDs, benefitting future clinical trials. In addition to enabling genetic counselling, genetic phenotype data guide clinicians and researchers studying the pathomechanisms of GWMDs.Tiivistelmä Geneettiset valkean aivoaineen sairaudet, leukodystrofiat ja geneettiset leukoenkefalopatiat, ovat merkittäviä neurologisten kehityshäiriöiden aiheuttajia. Taudinaiheuttajageenejä tunnetaan yli sata, ja eksomi- ja genomisekvensoinnin yleistyminen on mahdollistanut uusien tautien löytämisen aiempaa tehokkaammin. Tämän tutkimuksen tavoitteena oli selvittää lapsuusiän geneettisten valkean aivoaineen sairauksien epidemiologiaa, geneettisiä etiologioita, kliinisiä ilmiasuja ja tautien luonnollista kulkua. Lisäksi tavoitteena oli löytää uusia ja harvinaisia fenotyyppejä sekä tarkastella suomalaisen tautiperinnön vaikutusta tautikirjoon. Tämän väestöpohjaisen kohortti-tutkimuksen aineistona oli 80 Pohjois-Suomessa asunutta lasta, joilla diagnosoitiin geneettinen valkean aivoaineen sairaus vuosina 1990–2019. Tautien kumulatiivinen ilmaantuvuus lapsuudessa oli 30/100 000 elävänä syntynyttä lasta, ja insidenssi oli suurempi myöhempinä vuosikymmeninä. Löydetyistä 49 taudista 20 % oli leukodystrofioita ja 80 % geneettisiä enkefalopatioita. Mitokondriaalinen tausta liittyi 21 %:iin tapauksista. Kymmenellä prosentilla oli suomalaiseen tautiperintöön kuuluva sairaus. Yleisimpiä kliinisiä löydöksiä olivat motoriikan kehityshäiriöt (49 %), älyllinen kehitysvammaisuus (56 %), heikko lihasjäntevyys (60 %) ja spastisuus (49 %). Aineistoon kuului 20 viime vuosina löydettyä sairautta tai sairautta, joita ei ole aiemmin pidetty valkean aivoaineen sairauksina. Yksi näistä oli aiemmin kuvaamaton TAF1C-geeniin liittyvä neurologinen sairaus. Toisessa osatyössä kuvattiin uusi GFAP-geenin muutos ja harvinainen Alexanderin taudin vastasyntyneisyyskauden tautimuoto, mikä tukee tämän olemassaoloa muista ikäkausista erillisenä tautimuotona. Tutkimustulokset muodostavat kokonaisvaltaisen kuvauksen geneettisten valkean aivoaineen sairauksien epidemiologiasta ja kliinisistä piirteistä. Löydökset auttavat tulevaisuudessa kliinisten tutkimusten suunnittelua ja perinnöllisyysneuvontaa sekä ohjaavat tautien parissa työskenteleviä kliinikkoja ja tutkijoita

Homozygous TAF1C variants are associated with a novel childhood-onset neurological phenotype

TATA-box binding protein associated factor, RNA polymerase I subunit C (TAF1C) is a component of selectivity factor 1 belonging to RNA polymerase I (Pol I) transcription machinery. We report two unrelated patients with homozygousTAF1Cmissense variants and an early onset neurological phenotype with severe global developmental delay. Clinical features included lack of speech and ambulation and epilepsy. MRI of the brain demonstrated widespread cerebral atrophy and frontal periventricular white matter hyperintensity. The phenotype resembled that of a previously described variant ofUBTF, which encodes another transcription factor of Pol I.TAF1Cvariants were located in two conserved amino acid positions and were predicted to be deleterious. In patient-derived fibroblasts,TAF1CmRNA and protein expression levels were substantially reduced compared with healthy controls. We propose that the variants impairingTAF1Cexpression are likely pathogenic and relate to a novel neurological disease. This study expands the disease spectrum related to Pol I transcription machinery, associating theTAF1Cmissense variants with a severe neurological phenotype for the first time.Peer reviewe

Case report: chemotherapy in conjunction with blood–brain barrier disruption for a patient with germ cell tumor with multiple brain metastases

Clinical practice points Testicular cancer with brain metastases is related to poor prognosis because the penetration of chemotherapeutic agents is decreased by the blood–brain barrier. The standard treatment of brain metastases—whole brain radiation therapy combined with chemotherapy—is related to a limited increase in survival and considerable deleterious cognitive effects. The blood–brain barrier can be transiently disrupted using hyperosmolar intra-arterial mannitol injection. When combined with intra-arterial chemotherapy, therapeutic intratumoral concentrations can be attained. In experienced centers, blood–brain barrier disruption therapy is relatively safe with a low incidence of catheter-related complications. Blood–brain barrier disruption therapy is a promising treatment modality for brain metastases as an alternative to whole brain radiation therapy

Epidemiological, clinical, and genetic characteristics of paediatric genetic white matter disorders in Northern Finland

Abstract Aim: To examine the epidemiological, clinical, and genetic characteristics of paediatric patients with genetic white matter disorders (GWMDs) in Northern Finland. Method: A longitudinal population-based cohort study was conducted in the tertiary catchment area of Oulu University Hospital from 1990 to 2019. Patients were identified retrospectively by International Statistical Classification of Diseases and Related Health Problems codes in hospital records and prospectively by attending physicians. Inclusion criteria were children younger than 18 years with defined GWMDs or genetic disorders associated with white matter abnormalities (WMAs) on brain magnetic resonance imaging. Results: Eighty patients (mean age [SD] at the end of the study 11y [8y 6mo], range 0–35y; 45 males, 35 females) were diagnosed with a defined GWMD. The cumulative childhood incidence was 30 per 100 000 live births. Regarding those patients with 49 distinct GWMDs, 20% had classic leukodystrophies and 80% had genetic leukoencephalopathies. The most common leukodystrophies were cerebral adrenoleukodystrophy, Krabbe disease, and Salla disease. Additionally, 29 patients (36%) had genetic aetiologies not previously associated with brain WMAs or they had recently characterised GWMDs, including SAMD9L- and NHLRC2-related neurological disorders. Aetiology was mitochondrial in 21% of patients. The most common clinical findings were motor developmental delay, intellectual disability, hypotonia, and spasticity. Interpretation: The cumulative childhood incidence of childhood-onset GWMDs was higher than previously described. Comprehensive epidemiological and natural history data are needed before future clinical trials are undertaken