Hyperkinetic Movement Disorders
Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw in Hankey's Clinical Neurology, 2020
Leukodystrophies: Hypomyelination with basal ganglia and cerebellar atrophy syndrome (H-ABC).Pelizaeus–Merzbacher disease (PMzD).POLR3-related leukodystrophy.BCAP31 mutations.Metachromatic leukodystrophy (MLD).Krabbe's disease (KD).Xeroderma pigmentosum (XP).Aicardi–Goutières syndrome (AGS).
Aicardi Syndrome and Klinefelter Syndrome
Dongyou Liu in Handbook of Tumor Syndromes, 2020
Aicardi syndrome is unrelated to Aicardi−Goutières syndrome (AGS), which is an autosomal recessive disorder characterized by early-onset encephalopathy, intellectual and physical handicap, calcification of the basal ganglia (particularly the putamen, globus pallidus, thalamus), leukodystrophy, cerebral atrophy, chronic cerebrospinal fluid (CSF) leukocytosis, and increased concentration of interferon-alpha in the CSF. At the genetic level, AGS is linked to variations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR genes [2].
Controlling Neuroinflammation
Sunit K. Singh, Daniel Růžek in Neuroviral Infections, 2013
The first suspicion that early host innate defense was the culprit in the triggering of neurodegenerative diseases came with the observation that excessive production of type I IFN (a) by astrocytes induces inflammation and neurodegeneration (Akwa et al. 1998; Campbell et al. 1999). In the Aicardi–Goutieres syndrome, there occurs a rare genetic encephalopathy resulting in the chronic production of type I IFN (Aicardi and Goutieres 1984) characterized by chronic lymphocytosis in the CSF and calcifications in the basal ganglia.
Novel RNASET2 Pathogenic Variants in an East Asian Child with Delayed Psychomotor Development
Published in Fetal and Pediatric Pathology, 2018
Yan Sun, Xuyun Hu, Jiqing Song, Yanyan Hu, Caihong Liu, Guimei Li
RNASET2 mutation has high phenotypic heterogeneity. Clinically, it was difficult in our patient to distinguish between CLWM and AGS (Table 1). Our patient had cerebral and cerebellar atrophy which was a characteristic feature of Aicardi-Goutieres syndrome. However, other major distinguishing features of AGS such as skin conditions (e.g. chilblain-like skin lesions and sometimes stigmata of autoimmunity), episodic fever, sleep disturbance or dystonia (8,26), were all absent in our patient. Subcortical cysts were also absent in our patient. Phenotype of multifocal white matter lesions was also not typical in our patient. Whether the atypical white matter alterations will change, and whether the abnormal subcortical white matter will develop into cysts need further follow-up. Mutations in subunits of another RNAse, ribonuclease H2 enzyme complex, cause three subtypes of AGS, types 2–4 (29). Whether CLWM can be classified as a new subtype of Aicardi-Goutieres syndrome needs further discussion.
Designation of orphan conditions in Europe: regulatory observations and considerations after implementation of regulation 141/2000
Published in Expert Opinion on Orphan Drugs, 2020
Segundo Mariz, Kerstin Westermark, Bruno Sepodes
Prevalence of a condition does not appear to be the limiting factor regarding clustering for example in Hemophilia B which has a prevalence below 1 in 10,000 (which some would call an ultra-rare condition) has 18 designations (as of the 16th of August 2019). However low Public awareness linked to low prevalence could however be associated with lower submissions and positive opinions [9]. To illustrate this point, we have highlighted some conditions which have been designated by the COMP for which few additional positive designations have occurred. Adrenoleukodystrophy a metabolic disorder with a prevalence of 0.4 in 10,000 in Europe and first designated in 2012 has had 3 more designations to date. Wolfram Syndrome another very rare metabolic condition with a prevalence in Europe estimated to be 0.2 in 10,000 had its initial designation in 2015 and only one additional designation. Aicardi-Goutieres Syndrome (prevalence reported to be 1 in 10,000) where one center in Europe has submitted two products at the same time for designation in 2015 has had no further submissions. What the limiting factor here is difficult to establish as it can be linked to factors such as limited number of centers working on the condition or limited understanding of the underlying etiology and pathophysiology or limited patient organization interaction [10]. Although a crude measure designation clustering around a new condition can offer some perception into the interest, awareness and trends regarding medicinal research and development activities associated with the specific condition considered.
Novel and emerging treatments for Aicardi-Goutières syndrome
Published in Expert Review of Clinical Immunology, 2020
Davide Tonduti, Elisa Fazzi, Raffaele Badolato, Simona Orcesi
Results were recently published from a single-center, open-label, pilot study in 8 Aicardi-Goutières syndrome patients (ClinicalTrials.gov Identifier NCT02363452) treated for 12 months with a combination of three RTIs (abacavir, lamivudine, and zidovudine). This is the first such study in AGS. Only patients with mutations in the TREX1, RNASEH2A, RNASEH2B, RNASEH2C or SAMHD1 genes were included. The study demonstrated a reduction in IFN signaling without evidence of side effects in 8 patients with mutations in TREX1, RNASEH2A, RNASEH2B and SAMHD1. From a clinical perspective, no changes were observed, but the authors declared that the recruited patients were already in an advanced stage of the disease and presented severe disability, therefore clinical improvements had not been expected and did not constitute an aim of this pilot study. In three patients MRI showed a possible augmentation of resting cerebral blood flow, but larger groups of patients are needed to verify a possible correlation with RTI treatment [12].