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We present a transmission spectrum for the warm (500-600 K) sub-Neptune HD 3167c obtained using the Hubble Space Telescope Wide Field Camera 3 infrared spectrograph. We combine these data, which span the 1.125-1.643 μm wavelength range, with broadband transit measurements made using Kepler/K2 (0.6-0.9 μm) and Spitzer/IRAC (4-5 μm). We find evidence for absorption by at least one of H2O, HCN, CO2, and CH4 (Bayes factor 7.4; 2.5σ significance), although the data precision does not allow us to unambiguously discriminate between these molecules. The transmission spectrum rules out cloud-free hydrogen-dominated atmospheres with metallicities ≤100 solar at >5.8σ confidence. In contrast, good agreement with the data is obtained for cloud-free models assuming metallicities >700 solar. However, for retrieval analyses that include the effect of clouds, a much broader range of metallicities (including subsolar) is consistent with the data, due to the degeneracy with cloud-top pressure. Self-consistent chemistry models that account for photochemistry and vertical mixing are presented for the atmosphere of HD 3167c. The predictions of these models are broadly consistent with our abundance constraints, although this is primarily due to the large uncertainties on the latter. Interior structure models suggest that the core mass fraction is >40%, independent of a rock or water core composition, and independent of atmospheric envelope metallicity up to 1000 solar. We also report abundance measurements for 15 elements in the host star, showing that it has a very nearly solar composition.

Alexander disease is a rare neurodegenerative leucoencephalopathy caused by de novo mutations in the GFAP gene. Infantile, juvenile, and adult subtypes have been described and the clinical and radiological phenotypes are broad. Here we report on a single case of juvenile-onset Alexander disease associated with a novel frameshift mutation in the GFAP gene. The 8-year-old male patient had a relatively mild clinical phenotype characterized by dystonia, intermittent episodes of raised intracranial pressure, and characteristic radiological changes. He also presented with the additional and to our knowledge previously unreported, neuroimaging finding of periventricular calcification. We postulate that in children with leucoencephalopathy and periventricular calcification of undetermined aetiology, the diagnosis of Alexander disease should be considered. If the magnetic resonance imaging findings are compatible with Alexander disease, then DNA analysis of the GFAP gene should be performed even if the full criteria for a neuroradiological diagnosis are not met. [ABSTRACT FROM AUTHOR]

Aim To describe a spectrum of intracerebral large artery disease in Aicardi-Goutières syndrome (AGS) associated with mutations in the AGS5 gene SAMHD1. Method We used clinical and radiological description and molecular analysis. Results Five individuals (three males, two females) were identified as having biallelic mutations in SAMHD1 and a cerebral arteriopathy in association with peripheral vessel involvement resulting in chilblains and ischaemic ulceration. The cerebral vasculopathy was primarily occlusive in three patients (with terminal carotid occlusion and basal collaterals reminiscent of moyamoya syndrome) and aneurysmal in two. Three of the five patients experienced intracerebral haemorrhage, which was fatal in two individuals. Post-mortem examination of one patient suggested that the arteriopathy was inflammatory in origin. Interpretation Mutations in SAMHD1 are associated with a cerebral vasculopathy which is likely to have an inflammatory aetiology. A similar disease has not been observed in patients with mutations in AGS1 to AGS4, suggesting a particular role for SAMHD1 in vascular homeostasis. Our report raises important questions about the management of patients with mutations in SAMHD1. [ABSTRACT FROM AUTHOR]

Aicardi-Goutières syndrome (AGS) is a rare, genetically determined encephalopathy whose importance from a clinical viewpoint is magnified because of the risk of misdiagnosis as the sequelae of congenital infection. Recent molecular advances have shown that AGS can be caused by mutations in any one of at least five genes (four of which have so far been identified), most commonly on a recessive basis but occasionally as a dominant trait. Additionally, a recent genotype-phenotype correlation has shown that two clinical presentations can be delineated; an early onset neonatal form highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to RNASEH2B mutations. Evidence is emerging to show that the nucleases defective in AGS are involved in removing endogenous nucleic acid species produced during normal cellular processing, and that a failure of this removal results in inappropriate activation of the innate immune system. This hypothesis explains the phenotypic overlap of AGS with congenital infection and some aspects of systemic lupus erythematosus, where a similar interferon alpha-mediated innate immune response is triggered by viral and host nucleic acids respectively. [ABSTRACT FROM AUTHOR]

1. This study presents the results of the preliminary screening of vigabatrin as add-on therapy in an open, non-controlled multicentre study in children with refractory epilepsy. 2. There were 135 children, with an age range of 2 months-12 years. Main seizure type was partial in 42%, generalized in 29%, Lennox-Gastaut syndrome in 19% and West syndrome in 10%. 3. Vigabatrin was added onto current antiepileptic treatment in an initially recommended dose of 40-80 mg kg-1 day-1. However, the doses were frequently increased when tolerance allowed it, and the final mean dose used was 87 mg kg-1 day-1 (27-600). 4. A 75% to 100% reduction in seizure frequency was observed in 25% of patients (11 patients became seizure free) and 50 to 75% decrease in a further 13%. Efficacy was better in partial seizures, with good to excellent results in 49% of patients. The use of high doses, above 100 mg kg-1 day, was not associated with greater efficacy in this preliminary study. 5. No side effects were reported in 79% of patients. Agitation and insomnia were observed in 8.8% and somnolence in 6%. Other adverse events included ataxia (2.2%), nausea (2.2%) and increased appetite (1%). A moderate and transient decrease in haemoglobin was reported in six patients from the same centre; these patients were all receiving very high doses of vigabatrin (250 to 600 mg kg-1 day-1). 6. Vigabatrin thus appears to be a safe antiepileptic drug that may be effective in the treatment of severe epilepsy in children. [ABSTRACT FROM AUTHOR]

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., Competing Interests: Declaration of competing interest There are no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Intracranial calcification (ICC) occurs in many neurologic disorders both acquired and genetic. In some inherited white matter disorders, it is a common or even invariable feature where the presence and pattern of calcification provides an important pointer to the specific diagnosis. This is particularly the case for the Aicardi-Goutières syndrome (AGS) and for Coats plus (CP) and leukoencephalopathy with calcifications and cysts (LCC), which are discussed in detail in this chapter. AGS is a genetic disorder of type 1 interferon regulation, caused by mutations in any of the nine genes identified to date. In its classic form, AGS has very characteristic clinical and neuroimaging features which will be discussed here. LCC is a purely neurologic disorder caused by mutations in the SNORD118 gene, whereas CP is a multisystem disorder of telomere function that may result from mutations in the CTC1, POT1, or STN genes. In spite of the different pathogenetic basis for LCC and CP, they share remarkably similar neuroimaging and neuropathologic features. Cockayne syndrome, in which ICC is usually present, is discussed elsewhere in this volume. ICC may occur as an occasional feature of many other white matter diseases, including Alexander disease, Krabbe disease, X-ALD, and occulodentodigital dysplasia., (Copyright © 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Planets with radii between that of the Earth and Neptune (hereafter referred to as 'sub-Neptunes') are found in close-in orbits around more than half of all Sun-like stars 1,2 . However, their composition, formation and evolution remain poorly understood 3 . The study of multiplanetary systems offers an opportunity to investigate the outcomes of planet formation and evolution while controlling for initial conditions and environment. Those in resonance (with their orbital periods related by a ratio of small integers) are particularly valuable because they imply a system architecture practically unchanged since its birth. Here we present the observations of six transiting planets around the bright nearby star HD 110067. We find that the planets follow a chain of resonant orbits. A dynamical study of the innermost planet triplet allowed the prediction and later confirmation of the orbits of the rest of the planets in the system. The six planets are found to be sub-Neptunes with radii ranging from 1.94R ⊕ to 2.85R ⊕ . Three of the planets have measured masses, yielding low bulk densities that suggest the presence of large hydrogen-dominated atmospheres., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

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., (Copyright © 2022. Published by Elsevier Ltd.)

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., (© 2022. The Author(s).)

Biallelic mutations in SNORD118, encoding the small nucleolar RNA U8, cause leukoencephalopathy with calcifications and cysts (LCC). Given the difficulty in interpreting the functional consequences of variants in nonprotein encoding genes, and the high allelic polymorphism across SNORD118 in controls, we set out to provide a description of the molecular pathology and clinical spectrum observed in a cohort of patients with LCC. We identified 64 affected individuals from 56 families. Age at presentation varied from 3 weeks to 67 years, with disease onset after age 40 years in eight patients. Ten patients had died. We recorded 44 distinct, likely pathogenic, variants in SNORD118. Fifty two of 56 probands were compound heterozygotes, with parental consanguinity reported in only three families. Forty nine of 56 probands were either heterozygous (46) or homozygous (three) for a mutation involving one of seven nucleotides that facilitate a novel intramolecular interaction between the 5' end and 3' extension of precursor-U8. There was no obvious genotype-phenotype correlation to explain the marked variability in age at onset. Complementing recently published functional analyses in a zebrafish model, these data suggest that LCC most often occurs due to combinatorial severe and milder mutations, with the latter mostly affecting 3' end processing of precursor-U8., (© 2020 Wiley Periodicals LLC.)

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.

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., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

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., Competing Interests: None., (Georg Thieme Verlag KG Stuttgart · New York.)

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., (© 2020 The Authors. Human Mutation published by Wiley Periodicals, Inc.)

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., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (© 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.)

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., (© 2019 Mac Keith Press.)

Excessive type I interferon (IFNα/β) 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 STAT2 R148W in homozygosity (but not heterozygosity) were hypersensitive to IFNα/β, 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 STAT2 R148W to interact with ubiquitin-specific protease 18, a key STAT2-dependent negative regulator of IFNα/β signaling. These observations reveal an essential in vivo function of STAT2 in the regulation of human IFNα/β signaling, providing concrete evidence of the serious pathological consequences of unrestrained IFNα/β activity and supporting efforts to target this pathway therapeutically in IFN-associated disease., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

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., (© 2019 Wiley Periodicals, Inc.)

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., (© 2018 Wiley Periodicals, Inc.)

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., Competing Interests: None., (Georg Thieme Verlag KG Stuttgart · New York.)

Occludin (OCLN) is an important component of the tight junction complex, providing apical intercellular connections between adjacent cells in endothelial and epithelial tissue. In 2010 O'Driscoll et al reported mutations in OCLN to cause band-like calcification with simplified gyration and polymicrogyria (BLC-PMG). BLC-PMG is a rare autosomal recessive syndrome, characterized by early onset seizures, progressive microcephaly, severe developmental delay and deep cortical gray matter and basal ganglia calcification with symmetrical, predominantly fronto-parietal, polymicrogyria. Here we report 4 additional cases of BLC-PMG with novel OCLN mutations, and provide a summary of the published mutational spectrum. More generally, we describe a comprehensive molecular screening strategy taking into account the technical challenges associated with the genetic architecture of OCLN, which include the presence of a pseudo-gene and copy number variants., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1 . The clinicoradiological phenotype encompassed a spectrum of Aicardi-Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64-25.71) compared with controls (median: 0.93, IQR: 0.57-1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context., Competing Interests: Authors' Contributions: J.H.L. and Y.J.C. collated and reviewed all clinical and radiological data. G.I.R. performed quantitative PCR analysis, with assistance from N.K., M.B., T.A.B., A.C.E.B., M.L.C., A.M.C., C.C., R.C.D., F.R.D., N.D., B. De A., V. De G., C.G.E.L. De G., I.D., C De L., A.E., M.C.F., P.F., A.F., E.F., M.P.G., N.R.G., M.H., M.A.K., N.L., J.-P.S.-M.L., M.A.L., S.S.M., R.M., L.M.-S., G.M., M.M., V.N., S.O., J.D.O.-E., B.P.-D., F.P., K.M.R., M.R., F.R., P.R.-P., A.R., T.I.S., M.B.T., A.T., F.U., N.U., A.V., and A.W. provided clinical samples and critically reviewed clinical and immunological patient data. Y.J.C. conceived the study and wrote the initial draft with the assistance of G.I.R. All authors critically reviewed the article and agreed to its publication. Financial Disclosure None of the authors have any financial disclosure to report., (Georg Thieme Verlag KG Stuttgart · New York.)

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., (Georg Thieme Verlag KG Stuttgart · New York.)

Although ribosomes are ubiquitous and essential for life, recent data indicate that monogenic causes of ribosomal dysfunction can confer a remarkable degree of specificity in terms of human disease phenotype. Box C/D small nucleolar RNAs (snoRNAs) are evolutionarily conserved non-protein-coding RNAs involved in ribosome biogenesis. Here we show that biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to late adulthood. These mutations affect U8 expression, processing and protein binding and thus implicate U8 as essential in cerebral vascular homeostasis., Competing Interests: The authors declare that they have no competing financial interests.

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., (Copyright © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Purpose: Spondyloenchondrodysplasia is a rare immuno-osseous dysplasia caused by biallelic mutations in ACP5. We aimed to provide a survey of the skeletal, neurological and immune manifestations of this disease in a cohort of molecularly confirmed cases., Methods: We compiled clinical, genetic and serological data from a total of 26 patients from 18 pedigrees, all with biallelic ACP5 mutations., Results: We observed a variability in skeletal, neurological and immune phenotypes, which was sometimes marked even between affected siblings. In total, 22 of 26 patients manifested autoimmune disease, most frequently autoimmune thrombocytopenia and systemic lupus erythematosus. Four patients were considered to demonstrate no clinical autoimmune disease, although two were positive for autoantibodies. In the majority of patients tested we detected upregulated expression of interferon-stimulated genes (ISGs), in keeping with the autoimmune phenotype and the likely immune-regulatory function of the deficient protein tartrate resistant acid phosphatase (TRAP). Two mutation positive patients did not demonstrate an upregulation of ISGs, including one patient with significant autoimmune disease controlled by immunosuppressive therapy., Conclusions: Our data expand the known phenotype of SPENCD. We propose that the OMIM differentiation between spondyloenchondrodysplasia and spondyloenchondrodysplasia with immune dysregulation is no longer appropriate, since the molecular evidence that we provide suggests that these phenotypes represent a continuum of the same disorder. In addition, the absence of an interferon signature following immunomodulatory treatments in a patient with significant autoimmune disease may indicate a therapeutic response important for the immune manifestations of spondyloenchondrodysplasia.