RESUMEN
OBJECTIVES: We aimed to study the risks of relapse and long term disability in children with non-MS acquired demyelinating syndromes (ADS). METHODS: In this prospective, multi-centre study, from the 14 UK pediatric neurology centres, children (<16 years) experiencing a first episode of ADS were recruited from 2010 to 2014. Case report forms were collected prospectively. RESULTS: A total of 269 children were recruited and followed up for a median of 7.2 years. Median age at onset was 9y (IQR 9.5-14.5, 126 females). At last follow-up, 46 (18 %) had MS, 4 AQP4-Ab NMOSD and 206 (80 %) had other ADS, of which 27 (13 %) relapsed. Relapsing MOGAD was the diagnosis in 12/27, 6 were seronegative and 9 did not have antibodies tested. Frequency of relapse differed according to first presentation in non-MS ADS, being least likely in transverse myelitis (p = 0.025). In the non-MS group, MOG-Ab was predictive of relapse (HR = 8.42; p < 0.001) occurring 8 times as often decreasing over time. Long-term difficulties did not differ between children with monophasic vs relapsing diseases. CONCLUSION: The risk of relapse in non-MS ADS depends on initial diagnosis, and MOG-Ab positivity. Long-term difficulties are observed regardless of relapses and are determined by presenting phenotype.
RESUMEN
BACKGROUND: Negative regulator of reactive oxygen species (NRROS) related microgliopathy, a rare and recently recognized neurodegenerative condition, is caused by pathogenic variants in the NRROS gene, which plays a major role in the regulation of transforming growth factor-beta 1. METHODS: We report a child presenting with infantile spasms syndrome (ISS) with subsequent progressive neurodegeneration who was identified to harbour a novel likely pathogenic NRROS variant (c.1359del; p.Ser454Alafs*11). The previously published reports of patients with this disorder were also reviewed systematically. RESULTS: Including our index patient, 11 children (6 girls) were identified in total. Early development was normal in seven of these eleven children. All had a history of drug-resistant epilepsy, with 3 having epileptic spasms. The median age at seizure onset and developmental regression was 12 months, and the median age at death was 36 months. Intracranial calcifications were described in eight of eleven children. Neuroimaging revealed progressive cerebral atrophy and white matter loss in all children. The most common reported genetic variation was c.1981delC; (p.Leu661Serfs*97) observed in two families (likely due to a founder effect). CONCLUSIONS: Pathogenic variants in NRROS should be suspected in children with neuro-regression and drug-resistant epilepsy including ISS with onset in the first two years of life. Punctate or serpiginous calcifications at the grey-white matter junction and acquired microcephaly are further clues towards the diagnosis.
Asunto(s)
Calcinosis , Epilepsia , Enfermedades Neurodegenerativas , Espasmos Infantiles , Calcinosis/complicaciones , Epilepsia/diagnóstico , Humanos , Enfermedades Neurodegenerativas/complicaciones , Neuroimagen , Fenotipo , Convulsiones/complicaciones , Espasmos Infantiles/diagnósticoRESUMEN
Leukodystrophies are a heterogenous group of genetic disorders, characterised by abnormal development of cerebral white matter. Pelizaeus-Merzbacher disease is caused by mutations in PLP1, encoding major myelin-resident protein required for myelin sheath assembly. We report a missense variant p.(Ala109Asp) in MAL as causative for a rare, hypomyelinating leukodystrophy similar to Pelizaeus-Merzbacher disease. MAL encodes a membrane proteolipid that directly interacts with PLP1, ensuring correct distribution during myelin assembly. In contrast to wild-type MAL, mutant MAL was retained in the endoplasmic reticulum but was released following treatment with 4-phenylbutyrate. Proximity-dependent identification of wild-type MAL interactants implicated post-Golgi vesicle-mediated protein transport and protein localisation to membranes, whereas mutant MAL interactants suggested unfolded protein responses. Our results suggest that mislocalisation of MAL affects PLP1 distribution, consistent with known pathomechanisms for hypomyelinating leukodystrophies.
Asunto(s)
Enfermedades Neurodegenerativas , Enfermedad de Pelizaeus-Merzbacher , Humanos , Mutación , Mutación Missense , Proteína Proteolipídica de la Mielina/genética , Proteína Proteolipídica de la Mielina/metabolismo , Enfermedad de Pelizaeus-Merzbacher/genética , Transporte de ProteínasRESUMEN
Inappropriate stimulation or defective negative regulation of the type I interferon response can lead to autoinflammation. In genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome, we identified biallelic mutations in LSM11 and RNU7-1, which encode components of the replication-dependent histone pre-mRNA-processing complex. Mutations were associated with the misprocessing of canonical histone transcripts and a disturbance of linker histone stoichiometry. Additionally, we observed an altered distribution of nuclear cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) and enhanced interferon signaling mediated by the cGAS-stimulator of interferon genes (STING) pathway in patient-derived fibroblasts. Finally, we established that chromatin without linker histone stimulates cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) production in vitro more efficiently. We conclude that nuclear histones, as key constituents of chromatin, are essential in suppressing the immunogenicity of self-DNA.
Asunto(s)
Cromatina/metabolismo , Histonas/metabolismo , Interferón Tipo I/biosíntesis , Precursores del ARN/metabolismo , Proteínas de Unión al ARN/genética , Ribonucleoproteína Nuclear Pequeña U7/genética , Enfermedades Autoinmunes del Sistema Nervioso/genética , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Línea Celular , ADN/inmunología , Regulación de la Expresión Génica/genética , Regulación de la Expresión Génica/inmunología , Células HCT116 , Células HEK293 , Enfermedades Autoinflamatorias Hereditarias/genética , Enfermedades Autoinflamatorias Hereditarias/inmunología , Humanos , Proteínas de la Membrana/metabolismo , Malformaciones del Sistema Nervioso/genética , Malformaciones del Sistema Nervioso/inmunología , Nucleótidos Cíclicos/biosíntesis , Nucleotidiltransferasas/metabolismoRESUMEN
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.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Displasia Cleidocraneal/genética , Displasia Ectodérmica/genética , Flavoproteínas/genética , Predisposición Genética a la Enfermedad , Deformidades Congénitas de las Extremidades/genética , Micrognatismo/genética , Monoéster Fosfórico Hidrolasas/genética , Edad de Inicio , Enfermedad de Charcot-Marie-Tooth/complicaciones , Enfermedad de Charcot-Marie-Tooth/patología , Niño , Preescolar , Displasia Cleidocraneal/complicaciones , Displasia Cleidocraneal/patología , Distonía/complicaciones , Distonía/genética , Distonía/patología , Displasia Ectodérmica/complicaciones , Displasia Ectodérmica/patología , Femenino , Genotipo , Humanos , Deformidades Congénitas de las Extremidades/complicaciones , Deformidades Congénitas de las Extremidades/patología , Masculino , Micrognatismo/complicaciones , Micrognatismo/patología , Hipotonía Muscular/complicaciones , Hipotonía Muscular/genética , Hipotonía Muscular/patología , Mutación/genética , Linaje , FenotipoRESUMEN
We report the clinical and molecular characterization of a novel biallelic mutation in the CSF1R gene leading to an autosomal recessive form of childhood onset leukoencephalopathy in a consanguineous family. The female child experienced acute encephalopathy at the age of 2 years, followed by spasticity and loss of all achieved milestones over 6 months. Her elder brother presented with encephalopathy at 4 years of age, with a subsequent loss of all achieved milestones over 8 months. Brain imaging in both children revealed multiple well-defined areas of calcification in the parietal and frontal regions and the occipital horns of both lateral ventricles. Clinical exome trio analysis showed homozygosity for a p.T833M mutation in CSF1R in the girl. Heterozygous family members, including both parents, were asymptomatic, with the eldest being 68 years of age. Total CSF1R protein expression levels were normal as compared with wild-type allele, but CSF1 ligand dependent autophosphorylation was consistent with a hypomorphic allele.
Asunto(s)
Leucoencefalopatías , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Preescolar , Consanguinidad , Resultado Fatal , Femenino , Humanos , Leucoencefalopatías/genética , Leucoencefalopatías/patología , Leucoencefalopatías/fisiopatología , Masculino , LinajeRESUMEN
Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by a combination of neurological, psychiatric, and cognitive decline associated with calcium deposition on brain imaging. To date, mutations in five genes have been linked to PFBC. However, more than 50% of individuals affected by PFBC have no molecular diagnosis. We report four unrelated families presenting with initial learning difficulties and seizures and later psychiatric symptoms, cerebellar ataxia, extrapyramidal signs, and extensive calcifications on brain imaging. Through a combination of homozygosity mapping and exome sequencing, we mapped this phenotype to chromosome 21q21.3 and identified bi-allelic variants in JAM2. JAM2 encodes for the junctional-adhesion-molecule-2, a key tight-junction protein in blood-brain-barrier permeability. We show that JAM2 variants lead to reduction of JAM2 mRNA expression and absence of JAM2 protein in patient's fibroblasts, consistent with a loss-of-function mechanism. We show that the human phenotype is replicated in the jam2 complete knockout mouse (jam2 KO). Furthermore, neuropathology of jam2 KO mouse showed prominent vacuolation in the cerebral cortex, thalamus, and cerebellum and particularly widespread vacuolation in the midbrain with reactive astrogliosis and neuronal density reduction. The regions of the human brain affected on neuroimaging are similar to the affected brain areas in the myorg PFBC null mouse. Along with JAM3 and OCLN, JAM2 is the third tight-junction gene in which bi-allelic variants are associated with brain calcification, suggesting that defective cell-to-cell adhesion and dysfunction of the movement of solutes through the paracellular spaces in the neurovascular unit is a key mechanism in CNS calcification.
Asunto(s)
Edad de Inicio , Alelos , Encefalopatías/genética , Calcinosis/genética , Moléculas de Adhesión Celular/genética , Genes Recesivos , Adolescente , Adulto , Animales , Encefalopatías/diagnóstico por imagen , Calcinosis/diagnóstico por imagen , Niño , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , LinajeAsunto(s)
Encéfalo/patología , Proteínas de Unión a TGF-beta Latente/genética , Mutación/genética , Edad de Inicio , Alelos , Animales , Femenino , Humanos , Masculino , Ratones Noqueados , LinajeRESUMEN
IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi-Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate.
Asunto(s)
Mutación con Ganancia de Función , Estudios de Asociación Genética , Genotipo , Helicasa Inducida por Interferón IFIH1/genética , Fenotipo , Alelos , Enfermedades Autoinmunes del Sistema Nervioso/diagnóstico , Enfermedades Autoinmunes del Sistema Nervioso/genética , Análisis Mutacional de ADN , Femenino , Estudios de Asociación Genética/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Helicasa Inducida por Interferón IFIH1/química , Masculino , Modelos Moleculares , Malformaciones del Sistema Nervioso/diagnóstico , Malformaciones del Sistema Nervioso/genética , Conformación Proteica , Relación Estructura-ActividadRESUMEN
BACKGROUND: A homozygous founder mutation in MTPAP/TENT6, encoding mitochondrial poly(A) polymerase (MTPAP), was first reported in six individuals of Old Order Amish descent demonstrating an early-onset, progressive spastic ataxia with optic atrophy and learning difficulties. MTPAP contributes to the regulation of mitochondrial gene expression through the polyadenylation of mitochondrially encoded mRNAs. Mitochondrial mRNAs with severely truncated poly(A) tails were observed in affected individuals, and mitochondrial protein expression was altered. OBJECTIVE: To determine the genetic basis of a perinatal encephalopathy associated with stereotyped neuroimaging and infantile death in three patients from two unrelated families. METHODS: Whole-exome sequencing was performed in two unrelated patients and the unaffected parents of one of these individuals. Variants and familial segregation were confirmed by Sanger sequencing. Polyadenylation of mitochondrial transcripts and de novo synthesis of mitochondrial proteins were assessed in patient's fibroblasts. RESULTS: Compound heterozygous p.Ile428Thr and p.Arg523Trp substitutions in MTPAP were recorded in two affected siblings from one family, and a homozygous p.Ile385Phe missense variant identified in a further affected child from a second sibship. Mitochondrial poly(A) tail analysis demonstrated shorter posttranscriptional additions to the mitochondrial transcripts, as well as an altered expression of mitochondrial proteins in the fibroblasts of the two siblings compared with healthy controls. CONCLUSION: Mutations in MTPAP likely cause an autosomal recessive perinatal encephalopathy with lethality in the first year of life.
Asunto(s)
Encefalopatías/genética , Encefalopatías/metabolismo , ARN Polimerasas Dirigidas por ADN/genética , Fibroblastos/metabolismo , Proteínas Mitocondriales/metabolismo , Femenino , Humanos , Lactante , Muerte del Lactante , Masculino , Proteínas Mitocondriales/genética , Linaje , Secuenciación del ExomaRESUMEN
OBJECTIVE: Biallelic variants in RARS1, encoding the cytoplasmic tRNA synthetase for arginine (ArgRS), cause a hypomyelinating leukodystrophy. This study aimed to investigate clinical, neuroradiological and genetic features of patients with RARS1-related disease, and to identify possible genotype-phenotype relationships. METHODS: We performed a multinational cross-sectional survey among 20 patients with biallelic RARS1 variants identified by next-generation sequencing techniques. Clinical data, brain MRI findings and genetic results were analyzed. Additionally, ArgRS activity was measured in fibroblasts of four patients, and translation of long and short ArgRS isoforms was quantified by western blot. RESULTS: Clinical presentation ranged from severe (onset in the first 3 months, usually with refractory epilepsy and early brain atrophy), to intermediate (onset in the first year with nystagmus and spasticity), and mild (onset around or after 12 months with minimal cognitive impairment and preserved independent walking). The most frequent RARS1 variant, c.5A>G, led to mild or intermediate phenotypes, whereas truncating variants and variants affecting amino acids close to the ArgRS active centre led to severe phenotypes. ArgRS activity was significantly reduced in three patients with intermediate and severe phenotypes; in a fourth patient with intermediate to severe presentation, we measured normal ArgRS activity, but found translation mainly of the short instead of the long ArgRS isoform. INTERPRETATION: Variants in RARS1 impair ArgRS activity and do not only lead to a classic hypomyelination presentation with nystagmus and spasticity, but to a wide spectrum, ranging from severe, early-onset epileptic encephalopathy with brain atrophy to mild disease with relatively preserved myelination.
Asunto(s)
Arginino-ARNt Ligasa/genética , Estudios de Asociación Genética , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/genética , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/patología , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/fisiopatología , Adolescente , Adulto , Edad de Inicio , Niño , Preescolar , Estudios Transversales , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/diagnóstico por imagen , Humanos , Lactante , Imagen por Resonancia Magnética , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
Comprehensive reviews of the clinical characteristics and pathogenesis of Aicardi-Goutières syndrome (AGS), particularly its contextualization within a putative type I interferonopathy framework, already exist. However, recent reports of attempts at treatment suggest that an assessment of the field from a therapeutic perspective is warranted at this time. Here, we briefly summarize the neurological phenotypes associated with mutations in the seven genes so far associated with AGS, rehearse current knowledge of the pathology as it relates to possible treatment approaches, critically appraise the potential utility of therapies, and discuss the challenges in assessing clinical efficacy. WHAT THIS PAPER ADDS: Progress in understanding AGS disease pathogenesis has led to the first attempts at targeted treatment. Further rational therapies are expected to become available in the short- to medium-term.
Asunto(s)
Enfermedades Autoinmunes del Sistema Nervioso/terapia , Malformaciones del Sistema Nervioso/terapia , Enfermedades Autoinmunes del Sistema Nervioso/etiología , Enfermedades Autoinmunes del Sistema Nervioso/genética , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Humanos , Malformaciones del Sistema Nervioso/etiología , Malformaciones del Sistema Nervioso/genética , Malformaciones del Sistema Nervioso/inmunologíaRESUMEN
Excessive type I interferon (IFNα/ß) activity is implicated in a spectrum of human disease, yet its direct role remains to be conclusively proven. We investigated two siblings with severe early-onset autoinflammatory disease and an elevated IFN signature. Whole-exome sequencing revealed a shared homozygous missense Arg148Trp variant in STAT2, a transcription factor that functions exclusively downstream of innate IFNs. Cells bearing STAT2R148W in homozygosity (but not heterozygosity) were hypersensitive to IFNα/ß, which manifest as prolonged Janus kinase-signal transducers and activators of transcription (STAT) signaling and transcriptional activation. We show that this gain of IFN activity results from the failure of mutant STAT2R148W to interact with ubiquitin-specific protease 18, a key STAT2-dependent negative regulator of IFNα/ß signaling. These observations reveal an essential in vivo function of STAT2 in the regulation of human IFNα/ß signaling, providing concrete evidence of the serious pathological consequences of unrestrained IFNα/ß activity and supporting efforts to target this pathway therapeutically in IFN-associated disease.
Asunto(s)
Enfermedades del Sistema Inmune/genética , Interferón Tipo I/inmunología , Factor de Transcripción STAT2/genética , Mutación de Línea Germinal , Humanos , Enfermedades del Sistema Inmune/inmunología , Lactante , Masculino , Transducción de SeñalRESUMEN
The lipid phosphatase gene FIG4 is responsible for Yunis-Varón syndrome and Charcot-Marie-Tooth disease Type 4J, a peripheral neuropathy. We now describe four families with FIG4 variants and prominent abnormalities of central nervous system (CNS) white matter (leukoencephalopathy), with onset in early childhood, ranging from severe hypomyelination to mild undermyelination, in addition to peripheral neuropathy. Affected individuals inherited biallelic FIG4 variants from heterozygous parents. Cultured fibroblasts exhibit enlarged vacuoles characteristic of FIG4 dysfunction. Two unrelated families segregate the same G > A variant in the +1 position of intron 21 in the homozygous state in one family and compound heterozygous in the other. This mutation in the splice donor site of exon 21 results in read-through from exon 20 into intron 20 and truncation of the final 115 C-terminal amino acids of FIG4, with retention of partial function. The observed CNS white matter disorder in these families is consistent with the myelination defects in the FIG4 null mouse and the known role of FIG4 in oligodendrocyte maturation. The families described here the expanded clinical spectrum of FIG4 deficiency to include leukoencephalopathy.
Asunto(s)
Alelos , Enfermedades Desmielinizantes/diagnóstico , Enfermedades Desmielinizantes/genética , Flavoproteínas/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Mutación , Monoéster Fosfórico Hidrolasas/genética , Niño , Preescolar , Análisis Mutacional de ADN , Enfermedades Desmielinizantes/metabolismo , Fibroblastos/metabolismo , Genotipo , Humanos , Patrón de Herencia , Imagen por Resonancia Magnética , Masculino , Neuroimagen , Linaje , FenotipoRESUMEN
We describe progressive spastic paraparesis in two male siblings and the daughter of one of these individuals. Onset of disease occurred within the first decade, with stiffness and gait difficulties. Brisk deep tendon reflexes and extensor plantar responses were present, in the absence of intellectual disability or dermatological manifestations. Cerebral imaging identified intracranial calcification in all symptomatic family members. A marked upregulation of interferon-stimulated gene transcripts was recorded in all three affected individuals and in two clinically unaffected relatives. A heterozygous IFIH1 c.2544T>G missense variant (p.Asp848Glu) segregated with interferon status. Although not highly conserved (CADD score 10.08 vs. MSC-CADD score of 19.33) and predicted as benign by in silico algorithms, this variant is not present on publically available databases of control alleles, and expression of the D848E construct in HEK293T cells indicated that it confers a gain-of-function. This report illustrates, for the first time, the occurrence of autosomal-dominant spastic paraplegia with intracranial calcifications due to an IFIH1-related type 1 interferonopathy.
Asunto(s)
Helicasa Inducida por Interferón IFIH1/genética , Paraparesia Espástica/genética , Algoritmos , Encefalopatías/genética , Calcinosis/genética , Femenino , Mutación con Ganancia de Función/genética , Células HEK293 , Heterocigoto , Humanos , Masculino , Mutación Missense/genética , LinajeRESUMEN
Alexander disease (AD) is a leukodystrophy caused by heterozygous mutations in the gene encoding the glial fibrillary acidic protein (GFAP). Currently, de novo heterozygous missense mutations in the GFAP gene are identified in over 95% of patients with AD. However, patients with biopsy-proven AD have been reported in whom no GFAP mutation has been identified. We report identical twin boys presenting in infancy with seizures and developmental delay in whom MR appearances were suggestive of AD with the exception of an unusual, bilateral, arc of calcification at the frontal white-gray junction. Initial mutation screening of the GFAP gene did not identify a mutation. Whole exome sequencing in both brothers revealed a de novo heterozygous in-frame deletion of the whole of exon 5 of the GFAP gene. Mutations in the GFAP gene are thought to result in a toxic effect of mutant GFAP disrupting the formation of the normal intermediate filament network and resulting in Rosenthal fiber formation, which has hitherto not been linked to exonic scale copy number variants in GFAP. Further studies on mutation negative AD patients are warranted to determine whether a similar mechanism underlies their disease.
Asunto(s)
Enfermedad de Alexander/genética , Exones/genética , Eliminación de Gen , Proteína Ácida Fibrilar de la Glía/genética , Enfermedad de Alexander/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Niño , Preescolar , Análisis Mutacional de ADN , Estudios de Seguimiento , Humanos , Imagen por Resonancia Magnética , Masculino , Tomógrafos Computarizados por Rayos XRESUMEN
The Aicardi-Goutières syndrome (AGS) was first described in 1984, and over the following years was defined by the clinical and radiological features of an early onset, severe, neurologic disorder with intracranial calcification, leukoencephalopathy, and cerebral atrophy, usually associated with a cerebrospinal fluid (CSF) pleocytosis and elevated CSF interferon α activity. It is now recognized that mutations in any of the following seven genes may result in the classical AGS phenotype: TREX1 (AGS1), RNASEH2A (AGS2), RNASEH2B (AGS3), RNASEH2C (AGS4), SAMHD1 (AGS5), ADAR1 (AGS6), and IFIH1 (AGS7). All of these genes encode proteins involved in nucleotide metabolism and/or sensing. Mutations in these genes result in the induction of type 1 interferon production and an upregulation of interferon stimulated genes. As more patients harboring mutations in these genes have been described, in particular facilitated by the advent of whole exome sequencing, a remarkably broad spectrum of associated neurologic phenotypes has been revealed, which we summarize here. We propose that the term AGS has continued clinical utility in the designation of a characteristic phenotype, which suggests relevant diagnostic investigations and can inform outcome predictions. However, we also suggest that the use of the term "type 1 interferonopathy" is appropriate for the wider spectrum of disease consequent upon dysfunction of these genes and proteins since it implies the possibility of a common "anti-interferon" approach to therapy as such treatments become available.
Asunto(s)
Enfermedades Autoinmunes del Sistema Nervioso/genética , Mutación/genética , Malformaciones del Sistema Nervioso/genética , Adenosina Desaminasa/genética , Enfermedades Autoinmunes del Sistema Nervioso/líquido cefalorraquídeo , Enfermedades Autoinmunes del Sistema Nervioso/diagnóstico por imagen , Exodesoxirribonucleasas/genética , Estudios de Asociación Genética , Humanos , Helicasa Inducida por Interferón IFIH1/genética , Interferones/líquido cefalorraquídeo , Imagen por Resonancia Magnética , Proteínas de Unión al GTP Monoméricas/genética , Malformaciones del Sistema Nervioso/líquido cefalorraquídeo , Malformaciones del Sistema Nervioso/diagnóstico por imagen , Fosfoproteínas/genética , Proteínas de Unión al ARN/genética , Ribonucleasa H/genética , Proteína 1 que Contiene Dominios SAM y HDRESUMEN
BACKGROUND: Cystic leukoencephalopathy without megalencephaly is a disorder related in some cases to RNASET2 mutations and characterized by bilateral anterior temporal subcortical cysts and multifocal lobar white matter lesions with sparing of central white matter structures. This phenotype significantly overlaps with the sequelae of in utero cytomegalovirus (CMV) infection, including the presence of intracranial calcification in some cases. Aicardi-Goutières syndrome (AGS) is another inherited leukodystrophy with cerebral calcification mimicking congenital infection. Clinical, radiological and biochemical criteria for the diagnosis of AGS have been established, although the breadth of phenotype associated with mutations in the AGS-related genes is much greater than previously envisaged. PATIENTS AND METHODS: We describe the clinical, biochemical and radiological findings of five patients demonstrating a phenotype reminiscent of AGS. RESULTS: All patients were found to carry biallelic mutations of RNASET2. CONCLUSIONS: Our patients illustrate the clinical and radiological overlap that can be seen between RNASET2-related leukodystrophy and AGS in some cases. Our data highlight the need to include both disorders in the same differential diagnosis, and hint at possible shared pathomechanisms related to auto-inflammation which are worthy of further investigation.