Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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Aicardi-Goutieres syndrome is a rare, genetically determined progressive encephalopathy. The main features of the earliest described, also the most common form, are progressive microcephaly associated with basal ganglia and white matter calcifications, leukodystrophy, cerebral atrophy, and variable increase of lymphocyte count in the cerebrospinal fluid. The cytokine interferon alpha usually present in viral infections is elevated in cerebrospinal fluid and blood without presence of infective agents. There are 2 main clinical presentations: an early-onset neonatal form highly reminiscent of congenital infection (pseudo-TORCH) and a later-onset presentation, occurring several months after apparently normal development. Recessive mutations in any of 7 genes involved in the removal of redundant endogenous or exogenous DNA, RNA, or DNA/RNA hybrids can cause Aicardi-Goutieres syndrome. Progress started with the pioneering work of Pierre Lebon, who discovered the increased interferon alpha in the cerebrospinal fluid of the patients. The last 2 decades have witnessed the discovery of 7 genes associated with Aicardi-Goutieres syndrome and the discovery of the basic pathogenic role of alpha-interferon by Yannick Crow, Gillian Rice, and many others.
• Aicardi-Goutieres syndrome (AGS) is a progressive genetic encephalopathy, mimicking congenital infections like TORCH and congenital HIV.
• Mutations in any of 7 genes involved in removal of endogenous or infectious nucleic acids cause Aicardi-Goutieres syndrome (AGS 1-7). Most, but not all, causative mutations are recessive.
• Failure to remove intracellular remnants of nucleic acid leads to stimulation of the innate and adaptive immune responses by the cytokine interferon alpha. The resulting inflammation, predominantly in the central nervous system, causes its symptoms.
• Increase of interferon alpha in the CSF in the absence of demonstrable infection is the principal laboratory finding linking the whole clinical spectrum and all known disease causing mutations in Aicardi-Goutieres syndrome.
• Other phenotypes or shared expressions include disseminated lupus erythematodes, childhood chilblain lupus, and leukodystrophy and retinopathy.
In 1984, Jean Aicardi and Francoise Goutieres reported 8 infants from 5 families who suffered from an early onset familial encephalopathy with chronic CSF lymphocytosis and basal ganglia calcifications mimicking an intrauterine infectious process but with negative TORCH (toxoplasmosis, rubella, cytomegalovirus, and herpes) investigations (03). Clinically, the patients showed bilateral spasticity, dystonia, ocular jerks, and acquired progressive microcephaly with a rapid course toward profound deterioration and death. In addition, CT scan showed diffuse and progressive brain atrophy, deep white matter hypodensities, and bilateral symmetric calcifications of the basal ganglia including the thalamus.
The authors suggested a probable genetic condition with autosomal recessive inheritance. In the literature, they identified 9 previously reported, possibly similar cases of unclassified leukodystrophy with calcifications. However, none of them had CT scan, and information on CSF was insufficient. Following the publication by Aicardi and Goutieres, and prior to the finding of its associated gene defects, similar cases were reported (83; 80; 38; 58; 43; 44; 64).
Barth and colleagues reported widespread cerebral microangiopathy and infarctions in an autopsied case (07). This finding was confirmed by Rasmussen and associates (64).
In 1988 the chronic CSF lymphocytosis and cerebral calcifications mimicking a congenital infection led Lebon and colleagues to search for interferon alpha, a cytokine previously shown to be elevated in congenital rubella (46), acquired herpetic encephalitis and other viral diseases of the CNS (31). The finding of elevated interferon alpha in patients reported by Lebon and associates in the absence of overt viral disease was the first evidence of an autoimmune process and introduced a valuable marker in clinical diagnosis that can be easily applied to CSF samples (45). In retrospect, this was a seminal paper because interferon alpha in later studies proved to be not an epiphenomenon, but a triggering factor in the whole disease process of Aicardi-Goutieres syndrome.
Similar cases with prenatal onset with microcephaly, increased cell count in the cerebrospinal fluid, increase of interferon alpha, absence of all known intrauterine infections and with cerebral calcifications manifest at birth, collectively known aspseudo-TORCH, also belong to the Aicardi-Goutieres syndrome complex (65; 75).
In 1988, the disorder was listed as Aicardi-Goutieres syndrome, an autosomal recessive disorder (OMIM 225750).
Thereafter, the clinical spectrum of the syndrome appeared broader than previously thought. Since the initial publication on 8 children (03), an update of the clinical and radiological presentation and results of interferon alpha studies was published by Goutieres and colleagues, who reviewed 27 cases from 19 families (32), and by Lanzi and colleagues, who reviewed 21 cases (43). In 2004 more than 100 cases, including patients from new studies, were registered by Lebon and colleagues (47).
Crow’s group in the UK identified the first gene associated with Aicardi-Goutieres syndrome, the 3’-5’ exonuclease encoding TREX1 (18). This and subsequent studies so far identified mutations in 7 genes causing Aicardi-Goutieres syndrome. Overlap was also reported with disseminated lupus erythematosus (23). A most telling story is provided by Cree encephalitis, an apparent infectious disease present in Cree Indian families (09), subsequently proved to be genetic and allelic to AGS1, making Aicardi-Goutieres syndrome the ultimate diagnosis (19).
The course and presentation of typical Aicardi-Goutieres syndrome can be divided into 2 types (21; 57).
The neonatal form (most often found in TREX1 mutations), presenting as pseudo-TORCH, is characterized by jitteriness, poor feeding, and seizures in the neonatal period, hepatosplenomegaly with elevated liver enzymes, and thrombocytopenia with anemia, which requires transfusion. These findings tend to resolve after the first few weeks of life. This clinical picture, together with a typical pattern of calcifications, best demonstrated on CT scanning, mimics congenital infections (32; 38).
Patients with the more common later-onset form present after several months from birth with a subacute onset of severe encephalopathy characterized by extreme irritability, intermittent episodes of fever, slowing of head growth, and loss of acquired milestones. In this later-onset form initial results from CT or MRI scanning may fail to show the typical calcifications. CSF sampling usually, but not always, reveals lymphocytosis, which may lead to a false presumptive diagnosis of viral encephalitis.
Weight and head circumference at birth are within the normal range. Vomiting, feeding difficulties, jitteriness, irritability, ocular jerks, and lack of progress in motor and social skills are the main symptoms. Bouts of mild fever (38°C to 38.5°C) especially when combined with elevated lymphocyte count in the CSF may lead to the erroneous diagnosis of meningitis or encephalitis (32), but the subacute course of the inflammatory CSF response and the absence of demonstrable infections should arouse suspicion of Aicardi-Goutieres syndrome. A high degree of suspicion is warranted because the characteristic cerebral calcifications may not be present at this early stage. Therefore, any subacute “sterile meningo-encephalitis” in the first 6 months must be suspected until proven otherwise. A few infants show a still later onset, between 6 and 12 months of age, marked by loss of previously acquired psychomotor skills (03; 88; 32; 58).
Typically affected infants show diffuse neurologic signs with truncal hypotonia, dystonia, pyramidal tract signs, and cortical blindness. Fundi are normal or show mildly pale papillae, without retinopathy. Progressive microcephaly develops between 3 and 12 months of age. Death occurred in one fourth of the reported patients between 9 months and 17 years of age (83; 32).
Epilepsy is not a major feature. In most of the patients with a "startle response" to sensory stimuli, electroencephalographic recordings exclude an epileptic origin of this phenomenon (66). Occasional seizures develop in about 25% of children (eg, tonic-clonic generalized or massive myoclonic jerks) (83); the EEG is usually not informative. The reported frequency of epilepsy in Aicardi-Goutieres syndrome ranges from 25% to 53% (66).
The following nonneurologic signs are present in a minority, but are highly suspicious for the diagnosis: vascular necrotic cutaneous lesions of the acra looking like chilblains with acrocyanosis (80; 32), erythematous periungual skin, puffy hands and feet, or cold feet (32). These lesions are reported in around 40% of subjects at least once in their lifetime (66). Cutaneous lesions consisting of the discrete, bluish-red, nonblanching macules and papules known as “blueberry muffin rash” are an important diagnostic clue, occurring even in the neonatal period (12). Also, liver involvement with transient hepatomegaly and increased levels of hepatic transaminases and transient thrombocytopenia are found in cases with neonatal onset (32). Also, patients have been reported with 1 or more of the following symptoms: congenital glaucoma, raised levels of autoantibodies, hypothyroidism, insulin-dependent diabetes mellitus, hemolytic anemia, polygammaglobulinemia, neonatal cardiomyopathy, demyelinating peripheral neuropathy, micropenis, and transitory antidiuretic hormone deficiency (22; 66; 21). Patients with RNASEH2B mutations present at a later age (67).
Routine laboratory investigations give normal results for blood calcium, phosphorus, amino acid, organic acid chromatographies, immunoglobulins, and lysosomal enzyme activities. Virological research in blood and CSF for TORCH agents, Epstein-Barr virus, BV varicella, entero-adenoviruses, human T-cell leukemia virus type I and II, and human immunodeficiency virus type 1 and 2 are negative with tissue culture or serology (32; 47). Elevated phospholipid antibodies were reported by Rasmussen and colleagues (64). Elevated levels of the cytokine interferon alpha are found in CSF and blood. Electromyography, motor and sensory nerve conduction velocities (with rare exceptions), and electroretinogram are normal. Visual evoked potentials are absent, decreased in amplitude, or delayed (32; 38); brainstem evoked potentials may show a prolonged I-V interval (38).
Aicardi-Goutieres syndrome tends to stabilize after a period of progression. Spontaneous regression of symptoms and leukoencephalopathy were reported in an atypical case caused by a compound heterozygous mutation of RNASEH2B with both mutations having been previously associated with Aicardi-Goutieres syndrome (40).
Neuropathological studies in 4 children failed to show significant inflammatory changes (83; 32). Instead, they showed severe brain atrophy with reduced brain weight, widespread neuronal loss in the basal ganglia and cortex, and focal areas of necrosis suggestive of a vascular process. Calcific deposits predominated in infarcted areas around small vessels. White matter showed demyelination and gliosis without breakdown products. Cerebellar hypoplasia was present in 2 cases (83). Peripheral nerve and muscle histology were normal (88), as were muscle and liver biopsies (88; 32). A microangiopathy with calcific deposits in the tunica media of small arteries and arterioles is emphasized (07; 64; 39).
Long-term prognosis is poor in typical cases. Most of the children are in a vegetative state with little or no awareness of their surroundings. About 25% are less severely impaired and able to understand simple situations and manifest pleasure or discomfort. A few patients with RNASEH2B mutations have relatively preserved cognitive function with good comprehension and some retained communication (67). One exceptional 19-year-old patient with nonprogressive spastic diplegia and language appropriate for age is on record (52). The severity of encephalopathy may vary within the same sibship. Cases with early onset are more severely disabled. Most patients have acquired microcephaly, but head circumference is normal in patients with preserved intellect. In the vast majority of the patients hearing is reported to be normal, and there are no retinal changes. Visual functions vary from normal to cortical blindness. Absence of hearing loss and retinal changes are useful clinical clues to differentiate Aicardi-Goutieres syndrome from congenital infections.
RNASEH2B mutations are associated with a lower mortality rate (10%) compared to mutations in TREX1, RNASEH2A, and RNASEH2C (34%) (67; 21). Biallelic RNASEH2B mutations may result in static encephalopathy from infancy, spastic quadriplegia, preserved intellect, and increased iron signal in the basal ganglia, rather than calcifications and leukoencephalopathy (78).
There is no disease progression beyond the encephalopathic period, and death usually occurs secondary to consequences of neurologic damage.
Patients with a pseudo-TORCH presentation are severely affected from birth.
The patient, a 2-month-old girl, was born following a normal pregnancy and delivery.
She was the second child of healthy, nonconsanguineous parents. The parents had received favorable genetic counseling after the birth of the elder sister, then 5 years of age, who was affected by a congenital encephalopathy with basal ganglia calcification and CSF lymphocytosis diagnosed as "viral fetopathy." The patient was normal at birth (weight 3200 g; cranial perimeter 34 cm), but from 2 weeks of age, she vomited, fed poorly, and did not progress. At 2 months, she had ocular jerks but did not follow visual cues, and she had no social smile. She was jittery with limb hypertonia, pyramidal tract signs, and extensor plantar responses. Head control was poor, and she had truncal hypotonia. CSF analysis showed 26 WBC/mm3 and 0.47 g/l protein. CT scan showed frontal and occipital white matter hypodensities but no calcification (these were present in the basal ganglia and dentate nuclei of her sister). She progressively developed microcephaly and neurologic deterioration. By 12 months of age, she was in a vegetative state with rigidity in flexion, cortical blindness, and occasional convulsive seizures. At 4 years 10 months of age, CSF showed 7 lymphocytes/mm3 and 8 IU/ml of interferon alpha (normal value less than 2). At 11 years 8 months of age, CT scan showed extreme brain atrophy and punctuate calcification in the basal ganglia and dentate nuclei.
She died at the age of 13 years 4 months.
Central to the understanding of Aicardi-Goutieres syndrome is the role of the cytokine interferon alpha, which belongs to the type 1 interferons, which has a central role in innate immune response to nuclei acid remnants, the common reactants to viral infections. The understanding of the role of interferon alpha (IFN alpha) has progressed from a crucial diagnostic (32; 47) to its present central role in the pathogenesis of Aicardi-Goutieres syndrome. Interferon is a cytokine that triggers transcription of numerous genes (29) and has the ability to protect cells against a wide range of DNA and RNA viruses (89). Its cellular expression is induced after nucleic acid fingerprints from viruses or excess of host nucleic acids interact with Toll-like receptors (59). It is currently considered basic to the diagnosis as well as to the pathomechanism of the disease (16).
Aicardi-Goutieres syndrome is a genetically heterogenous disorder caused by mutations in any of 7 genes. Homozygosity mapping revealed a first locus on chromosome 3p21 in half of the affected families analyzed by Crow and colleagues (19). A second locus was found at 13q14-q21 in 7 families (04), confirming the existence of more than 1 causative gene defect. By 2014, 7 genes involved in Aicardi-Goutieres syndrome are known. Subtypes representing different associated genes are referred to as AGS1 through 7.
TREX1. Mutations in TREX1, the gene encoding 3’-->5’ DNA exonuclease, cause AGS1. TREX1 is the first gene associated with AGS1 that was discovered (18). Mutations result in 4 different phenotypes: (1) typical Aicardi Goutieres syndrome (if the exonuclease function is disabled), which is usually due to compound heterozygous or homozygous missense mutations, rarely dominant. An early-onset neonatal form highly reminiscent of congenital infection is seen particularly with TREX1 mutations (74); (2) familial chilblain lupus, in a dominant familial form; (3) systemic lupus erythematosus (SLE), due to TREX1 mutations in 0% to 2% of all cases of SLE; and (4) retinal vasculopathy with cerebral leukodystrophy, so far described in 10 families (72). Inflammatory myopathy has been described in a single case report, but might be more prevalent on examination of further cases (84).
TREX1 protein eliminates redundant single-stranded DNA. First regarded to have a proofreading function in DNA replication, its induced absence in knock-down mice unexpectedly resulted in inflammatory changes similar to the picture in humans. Although the affected tissue in knockout mice was myocardium, the conclusion was the first experimental evidence that TREX1 deficiency caused an autoimmune process similar to humans with Aicardi-Goutieres syndrome (54; 08).
RNASEH2. Mutations have been identified in the 3 nonallelic components of the ribonuclease H2 protein complex (RNASEH2 A, B, and C) (20; 67). RNASEH2 eliminates excess RNA-DNA hybrids. Such hybrids may arise from viral infections but may also arise from Okazaki fragments during lagging strand DNA replication. Excess of RNA-DNA duplexes may stimulate interferon alpha (20). RNASEH2 mutations A, B, and C cause AGS 2, 3, and 4, respectively.
Onset of the disease is significantly earlier with TREX1, RNASEH2A, and RNASEH2C mutations than with RNASEH2B defects; clinical course as outcome is less severe with RNASEH2B. A mild case with regressive symptoms, minimal calcifications, and leukoencephalopathy, due to compound RNASEH2B mutations, was reported (40).
SAMHD1. Autosomal-recessive mutations in SAMHD1, encoding deoxynucleoside triphosphate triphosphohydrolase, were the cause of Aicardi-Goutieres syndrome in 8 families identified by gene mapping (68). SAMHD1 encodes a protein involved in the removal of nuclear debris. The new locus was named AGS5. SAMHD1 mutations may cause lupus erythematosus beside Aicardi-Goutieres syndrome according to an epidemiologic study in Japan (01).
Atypical Aicardi-Goutieres syndrome with peculiar findings so far not reported in other types of Aicardi-Goutieres syndrome were found in some families with SAMHD1 mutations. In patients with Aicardi-Goutieres syndrome carrying mutations in SAMHD1, cerebral arterial stenoses, stroke, and cerebral vasculopathy occur as a part of the neurologic picture (63; 79; 91). Large artery disease is not described in association with other known mutations responsible for Aicardi-Goutieres syndrome, and SAMHD1 may have a particular role in blood vessel integrity and homeostasis (30).
In a family with autosomal recessive degenerative disorder with white matter destruction and calcifications presenting in utero, multiple mtDNA deletions were found (49). Muscle biopsy was normal and did not show any evidence of respiratory chain dysfunction. Southern blot analysis of tissue from a living child and affected fetuses showed multiple mtDNA deletions without any mutations of the genes involved in mtDNA synthesis and function. A large homozygous deletion in the SAMHD1 gene causing Aicardi-Goutieres syndrome with multiple mtDNA deletions in this family further expands the clinical and laboratory spectrum. These additional findings may add information regarding the involvement of mitochondria in the self-activation of innate immunity by cell intrinsic components (49). In a 12-year-old boy with SAMHD1 mutation who presented with neonatal-onset encephalopathy, thrombocytopenia, hepatomegaly, and hypotonia, systemic lupus erythematosus was diagnosed at the age of 6 years, during the course of the disease (62).
ADAR1 (adenosine deaminase acting on RNA). Dominant and recessive mutations were reported to cause Aicardi-Goutieres syndrome (70). ADARs catalyze hydrolytic deamination of adenosine to inosine in double-stranded RNA. Deficiency caused by ADAR1 mutation causes upregulation of interferon. A second phenotype associated with ADAR1 reported by La Piana and colleagues and Livingston and associates is bilateral striatal necrosis, unlike Aicardi-Goutieres syndrome mimicking juvenile bilateral striatal necrosis (41; 50). Forty-six patients with ADAR1-related neurologic disease were studied by Rice and colleagues, revealing peculiarities in ADAR1-related gene defects (71). Biallelic homozygous mutations were found in 28 of 37 families examined. Others were symptomatic with only 1 allele affected. These included de novo mutations, mono-allelic deleterious mutations of either paternal or maternal origin, with the affected parent in some cases symptomatic. Besides typical Aicardi-Goutieres syndrome, variants were described with isolated bilateral striatal necrosis, spastic paraparesis with normal brain imaging, progressive mixed spasticity and dystonia, and adult-onset psychologic disturbance with intracranial calcification. In 34 patients, blood samples revealed an upregulation of interferon type 1 stimulated gene transcripts. Special immune sensors, known as PKR and MDA5, are required to detect RNA, leading to IFN production. ADAR1 is required to prevent the activation of these immune sensors (PKR and MDA5) against host RNA. ADAR1, thus, regulates sensing of self RNA versus nonself RNA, thereby preventing self-destructive RNA loss (13).
IFIH1. IFIH1, (interferon induced with helicase C domain), encodes a cytoplasmic sensor protein that activates a cascade leading to upregulation of type 1 interferons on sensing of double-stranded RNA (dsRNA). Heterozygous gain of function mutations in IFIH1 were found to cause Aicardi-Goutieres syndrome by Rice and associates and by Oda and colleagues, codified as AGS7 (56; 69).
AGS, FCL, RVCL, SLE
AGS, FCL, NSP
AGS, BSN, NSP
AGS, NSP, other immunopathologies
Percentages adapted from (15; 17)
Between brackets: percentages with autosomal dominant inheritance.
Abbreviations: FCL: familial chilblain lupus, RVCL: retinal vasculopathy with cerebral leukodystrophy, SLE: systemic lupus erythematosus, BSN: bilateral striatal necrosis, NSP: nonsyndromic spastic paraparesis
The existence of various inherited disorders characterized by autoimmunity and the upgrading of type 1 interferon led Crow to propose a separate group of genetic autoimmune disorders as type 1 interferonopathies (14). This has become an established new field of clinical genetics and neurogenetic disorders (15).
Autosomal-recessive deficiency of USP18 causes pseudo-TORCH syndrome, observed by Meuwissen and colleagues (53). USP18 is a negative regulator of type 1 interferon signaling. This finding extends the spectrum of interferonopathies that may cause pseudo-TORCH syndrome.
Isolated spastic paraplegia, associated with type I interferonopathies. Whole exome sequencing in families with nonsyndromic spastic paraplegia identified pathogenic mutations in ADAR1, IFIH1, and RNASE2B in 5 patients from 4 families. Measurement of RNA’s expressed by interferon-stimulated genes showed significant increases only in ADAR1 and IFIH1 mutations (25). In a separate report, in a patient manifesting early onset systemic lupus erythematosus, IgA deficiency, and lower limb spasticity, a de novo gain of function mutation of IFIH1 was found (86).
The pathogenic role of interferon alpha. The discovery of raised interferon alpha in the CSF of patients by Lebon and associates in Aicardi-Goutieres syndrome in the absence of any of the known viral infections is the key to the pathomechanism of the disease (45). Unprocessed viral nucleic acids as well as unprocessed nucleic acids from the host that enter the cell are sensed by transmembrane receptors collectively known as Toll-like receptors (TLR) (Perry by et al 2005). Different Toll-like receptors recognize different classes of nucleic acids, including single-stranded DNA and single-stranded and double-stranded RNA (ssRNA, dsRNA). The binding of nucleic acids by TLRs initiates a cascade ending with the induction of type 1 interferon. Type 1 interferons are regulated at the transcriptional level. The resulting type 1 interferons, which include interferon alpha, induce innate as well as adaptive immune responses. In the case of TREX1 it has been shown that TREX1 protein can recognize reverse-transcribed DNA produced by retroviruses and single-stranded DNA derived from endogenous retroelements (the latter an ancient noncoding but large portion of the genome) and regulate the resulting interferon response. Interferon alpha accumulates in TREX1-deficient cells (76). Failure of the removal of excess DNA or RNA breakdown products may trigger an inappropriate viral-like innate immune response. DsRNA and dsDNA are known activators of innate immunity and stimulate type I interferon production (36). Mutations in any of the genes associated with Aicardi-Goutieres syndrome result in sustained overproduction of type 1 interferon triggered by nucleic acids and may lead to a state of autoimmunity. Type 1 interferons (IFN-α, IFN-β) have pronounced immune stimulatory effects that promote the loss of B cell and T cell tolerance, dendritic cell activation, and autoantibody production (48).
The presence of specific autoantibodies has been the object of several studies. In 2 patients, Rasmussen and colleagues reported antiphospholipid antibodies (64) similar to lupus erythematosus. Although lupus erythematosus and Aicardi-Goutieres syndrome show overlapping clinical features, and indeed genetic overlap in the case of TREX1 mutations, the involvement of the brain in the Aicardi-Goutieres syndrome is largely unexplained. Cuadrado and colleagues assessed the spectrum of serum autoantibodies to brain epitopes in 56 genetically confirmed patients with Aicardi-Goutieres syndrome (26). Also, the affinity of sera against brain epitopes was tested in brain sections of deceased patients. Aicardi-Goutieres syndrome patients produced a broad spectrum of autoantibodies, some targeting endothelial cells and astrocytes, which probably explains the brain specificity of the syndrome. Pulliero and colleagues evaluated the expression of 957 microRNAs in lymphocytes from Aicardi-Goutieres syndrome patients and controls and demonstrated microRNA overload in patients with Aicardi-Goutieres syndrome (60).
Explaining the specific role of the central nervous system in the pathogenesis of Aicardi-Goutieres syndrome. Although induced mutations in mice have reproduced some features of Aicardi-Goutieres syndrome, none of these models showed the typical encephalitis of this syndrome. Van Heteren and colleagues tested the innate immune response in the CSF of patients with Aicardi-Goutieres syndrome and in patients with several viral disorders (87). Besides interferon alpha, the cytokines CXCL10 and CCL2 were expressed in both Aicardi-Goutieres syndrome and viral infections. However, high levels of IL-6 and CXCL8 found in viral disorders were absent in Aicardi-Goutieres syndrome. Importantly, postmortem immune-histochemical staining of brain sections in Aicardi-Goutieres syndrome showed that astrocytes were responsible for the production of cytokines and not the infiltrating leukocytes. The role of interferon alpha in the characteristic widespread calcifying microangiopathy of Aicardi-Goutieres syndrome was demonstrated by Klok and colleagues, who showed increased permeation of calcium in cultured smooth muscle cells by adding interferon alpha at a concentration similar to a patient’s CSF (39).
Reporting of Aicardi-Goutieres syndrome is worldwide. Increased local incidence may be expected in regions with high inbreeding due to autosomal recessive inheritance. Cree Indian “encephalitis” due to a recessive TREX1 mutation is a classic example.
Autosomal recessive inheritance present in the majority entails a risk of 25% for subsequent siblings in affected families. Antenatal diagnosis has become possible on the basis of identification of mutated genes. Autosomal dominant inheritance is present in a small minority of patients with TREX1 or ADAR1 or IFHI1 mutations.
As a result of the lymphocytosis and calcifications, Aicardi-Goutieres syndrome can be mistaken for congenital or neonatal encephalitis due to rubella, herpes virus, varicella-zoster virus, cytomegalovirus, toxoplasmosis, or HIV (37; 57). However, the predominant localization of calcifications in the basal ganglia, negative TORCH investigations, visceral involvement, and a lack of retinopathy, hearing loss, microcephaly, or hydrocephaly at birth are all distinguishing features of Aicardi-Goutieres syndrome.
Cockayne syndrome, a familial leukodystrophy with striocerebellar calcifications caused by defective repair of transcriptionally active DNA (55), differs from Aicardi-Goutieres syndrome by special facial features, dwarfism, microcephaly, nerve deafness, retinitis pigmentosa, cataract, and skin photosensitivity (OMIM 216400).
Familial encephalopathy with intracerebral calcifications, white matter lesions, growth hormone deficiency, and retinal degeneration can be differentiated from Aicardi-Goutieres syndrome by the associated features (10) (OMIM 225755).
Normal interferon levels in these patients, even at a young age, may point to a separate entity. In some cases, static nonprogressive encephalopathy associated with basal ganglia calcification of the CSF is normal (02).
There is a phenotypic overlap between Aicardi-Goutieres syndrome with neonatal onset multisystem inflammatory disease (NOMID) or chronic infantile neurologic cutaneous and articular (CINCA) syndrome (27). The latter is an autoinflammatory disorder characterized by recurrent fever, skin rash, arthropathy, central nervous system abnormalities, and absence of autoantibodies. Arthropathy of NOMID/CINCA is characterized by bony overgrowth without significant joint effusion. The gene CIAS1/NLRPS is found mutated in almost half of the patients. Familial forms of hemophagocytic lymphohistiocytosis (or macrophage activation syndrome) can present with young-onset encephalopathy, hepatosplenomegaly and hematological abnormalities, and MRI lesions similar to acute disseminated encephalomyelitis or cerebral vasculitis (27).
The study of larger groups of patients with pediatric age onset encephalopathies with calcifications by whole genome sequencing reveals that at this stage only a minority can be assigned to a specific entity (82).
Loss-of-function mutations in the gene encoding the RNASET2 glycoprotein lead to an autosomal recessive disorder with an indistinguishable clinical and neuroradiological phenotype from congenital cytomegalovirus infection and Aicardi-Goutieres syndrome (34). Three of the 5 families described were of Turkish origin, and the affected individuals were asymptomatic at birth and showed a static encephalopathy with normocephaly or microcephaly and psychomotor impairment within the first year of life. A diagnostic pattern of neuroimaging (CT, MRI) included intracranial calcifications in some, anterior temporal cystic lesions, enlarged inferior horns, and multifocal white matter alterations. The RNASET2 gene encodes the glycoprotein RNASET2, which is the only human member of the Rh/T2/S family of RNases. Clinical overlap between this disease, presenting as encephalopathy with bilateral anterior temporal subcortical cysts and Aicardi-Goutieres syndrome, was emphasized by Tonduti and colleagues (81).
Autosomal-recessive deficiency of USP18 causes pseudo-TORCH syndrome, observed by Meuwissen and colleagues (53). USP18 is a negative regulator of type 1 interferon signaling. This finding extends the spectrum of interferonopathies linked to pseudo-TORCH syndrome.
There are more than 50 acquired or familial conditions with bilateral calcification in the brain parenchyma (06). In children, differential diagnosis includes intrauterine infections, intrauterine or early postnatal hemorrhage, or neoplasia. Appearance of multiple affected individuals in a single family assures an underlying genetic disorder. In an exhaustive review of causes of intracranial calcifications in childhood, Livingston and colleagues listed 24 reports on different familial and nonfamilial cases with intracranial calcification of unknown etiology (51).
MRI has now largely replaced CT scanning in diagnosis in the pediatric age group. This entails the risk of missing the presence of calcifications. Vanderver and colleagues reviewed an MRI series of patients with proven Aicardi-Goutieres syndrome and scored a panel of radiologic predictors (85). Characteristic predictors were temporal lobe swelling followed by atrophy, global cerebral atrophy, and calcifications. Temporal lobe swelling has to be differentiated from several known disorders including vanishing white matter disease, megalencephalic leukoencephalopathy with cysts, rubella, and cytomegaly. A large multicenter neuroradiological study performed by La Piana and colleagues described patterns of neuroradiological abnormalities in 121 patients with Aicardi-Goutieres syndrome (La Piana et al 2016). The most common abnormality was leukoencephalopathy (99%), followed by cerebral atrophy (92%) and calcification (91%). Other, less common findings were white matter rarefication (50%), deep white matter cysts associated with TREX1 mutations, and delayed myelination associated with RNASEH2B mutation and early age at onset.
The 3 main characteristics of Aicardi-Goutieres syndrome as originally defined are CSF lymphocytosis, presence of interferon alpha in CSF, and basal ganglia calcifications.
CSF white cells, interferon alpha, and pterins. Chronic CSF lymphocytosis (> 35 cells/mm3) was originally described as a primary diagnostic feature in Aicardi-Goutieres syndrome. It is now well recognized that the level of both white cells and interferon alpha in the CSF of patients fall to normal over the first few years of life (21). In a series, normal CSF white cell count was documented in the presence of elevated CSF interferon alpha titers as 10% in the first year of life. Most of all CSF samples contained 8 or more white blood cells in the first 12 months of life (between 10 and 50 in most samples). Although lymphocytosis decreases with age, it persisted beyond the age of 2 years in 2 patients (32). One child still had 8 white blood cells at 9 years of age (52); 1 familial case had no cell when studied at 12 months, pleocytosis being present in his sibling (58). In 2 cases related to the locus AGS1 and in a case of Cree encephalitis, lymphocytosis was absent in spite of the presence of interferon in CSF (19; 16). CSF protein level is normal (usually lower than 0.5 g/l), with normal electrophoresis or mild blood-CSF barrier disturbances without oligoclonal pattern. Elevated level of interferon alpha in CSF is currently considered a marker for the syndrome (45; 32; 43; 47; 16). Generally, values are higher in CSF than in serum. They varied from 3 to 300 UI/ml (normal less than 2) in 77 children aged 4 years 10 months or less (32; Lebon and al 2002). Values are higher at birth and decrease with age; however, interferon alpha is still present in 2 children at 5 years (45). If we consider the level of interferon alpha in CSF and blood according to the onset of the disease, the averages of interferon levels appear to be high in patients with early onset, although they are lower when the disease began after 3 months. In the early onset form, the interferon alpha levels in blood seem to decrease less rapidly as the level in CSF (Lebon and al 2002). Tubuloreticular inclusions associated with the presence of interferon alpha have been observed in the skin, muscle, and lymphocytes (45; 32) and were first described by Rich in lupus erythematosus (73).
The number of normal CSF white cell and interferon alpha examinations in mutation-positive patients with Aicardi-Goutieres syndrome is documented in Table 2 (Rice at al 2007a). This underlines the importance of evaluation of CSF data in the diagnostic workup of the patients because a normal number of white cells in the CSF does not rule out the diagnosis of Aicardi-Goutieres syndrome even in the acute phase.
Elevated neopterin levels in the CSF are well correlated with a raised number of white blood cells and interferon alpha levels (67). A phenocopy of Aicardi-Goutieres syndrome with a pattern of calcifications strikingly reminiscent of Aicardi-Goutieres syndrome, high levels of CSF pterins, and decreased 5-methyltetrahydrofolate, amenable to treatment, has been described (11). Interferon alpha and lymphocyte counts in the CSF were normal. There has been no follow-up on this publication. Examination of 5-MTHF in similar cases is advisable in view of reported therapeutic success of suppletion (61). CSF neopterin analysis of patients with mutation-positive Aicardi-Goutieres syndrome showed consistently increased levels. Pterin analysis is available as a part of a neurotransmitter screen, and the data show that the level of neopterin tends to normalize over time (66).
Dale and colleagues reported elevated neopterin in CSF as a useful marker of inflammation in a broad range of acute and chronic CNS disorders (28). In patients with a milder phenotype, in spite of overproduction of pterins, CSF IFNa and pleocytosis can be normal (90). Evaluation of CSF pterins besides IFNa, which is a reliable marker during the active stage of the disease, will increase the number of patients recognized with Aicardi-Goutieres syndrome.
Age range (years)
WCC ≤5/mm3 (total recordings)
IFN-A ≤2 IU/l (total recordings)
Neonatal screening for inborn errors of metabolism in neonatal blood spots may result in cases with elevated C26:0 lyso PC, falsely suggesting X-linked adrenoleukodystrophy or other peroxisomal disorders resulting in elevated C26:0 very long-chain fatty acids. Preliminary studies point to accidental elevation of C26:0 lyso PC in presymptomatic Aicardi-Goutieres syndrome (05).
Neuroimaging features (basal ganglia calcifications, white matter changes, and cerebral atrophy). Basal ganglia calcifications involving thalami, basal ganglia, and patchy areas of white matter are the hallmark of Aicardi-Goutieres syndrome. However, because Aicardi-Goutieres syndrome is a progressive disease, they may be absent in the early case and detected later in its course. Mineralization may be suspected by MRI as hypointense areas on T2 or gradient echo images, but definite proof often requires a CT scan performed without contrast. Intracranial calcification develops over a prolonged period of time (57). The aspect varies from punctiform to massive, even in the same sibship (32; 58) and the degree is not correlated with the severity of the status.
They were lacking on the first CT scan in 2 children at 7 weeks and 10 months (03; 32) and at 12 months in a patient of Ostergaard and colleagues (58). In addition to calcifications, CT scan shows white matter hypodensities located mainly around the ventricles. They appear as hyperintense on MRI T2 sequences; they are not constant, and a diffuse leukodystrophic aspect is uncommon (32).
Thinning and, as in 1 case, complete absence of corpus callosum can be observed (Rice and al 2007b). Signs of severe and progressive brain atrophy with enlarged ventricles and sulci increasing on successive examinations are a constant finding on CT and MRI, and they confirm the destructive nature of the disorder. In fact, the combination of calcifications in the mentioned places, together with signs of cortical, subcortical, and brainstem atrophy should raise suspicion of Aicardi-Goutieres syndrome.
MRI has now largely replaced CT scanning in diagnosis in the pediatric age group. This entails the risk of missing calcifications. Vanderver and colleagues reviewed an MRI series of patients with proven Aicardi-Goutieres syndrome and scored a panel of radiologic predictors (85). Characteristic predictors were temporal lobe swelling followed by atrophy, global cerebral atrophy, and calcifications. Temporal lobe swelling has to be differentiated from several known disorders including vanishing white matter disease, megalencephalic leukoencephalopathy with cysts, rubella, and cytomegaly. The study by La Piana and colleagues presents the largest study so far encompassing findings in 121 subjects (La Piana et al 2016).
No specific therapy is available yet. General management relates to seizures, feeding problems, and development of scoliosis. Seizures may be treated with standard antiepileptic drugs. Physiotherapy may delay the occurrence of limb contractures.
Recurrent bouts of fever (hyperpyrexia) without demonstrable infection may be amenable to treatment with cimetidine, as described in a single case of Aicardi-Goutieres syndrome in an infant with de novo IFIH1 mutation and systemic signs of autoinflammation (77).
Tube-feeding or gastrostomy is indicated in case of feeding difficulties. Glaucoma should be considered in patients with the neonatal form of the disease (22). Necrotic and chilblain lesions that may develop during the course of the disease usually do not respond to immunosuppressor and vasodilator therapies. The central role of interferon alpha has attracted attention resulting in experimental treatment protocols. Because lupus erythematosus is an allied disorder in which interferon alpha blocking by antibodies is presently in the preliminary stage, the results are highly relevant for Aicardi-Goutieres syndrome (24). Determination of methylene tetrahydrofolic acid (5-MTHF) in CSF is warranted to detect brain folate deficiency due to complicating folate receptor antibodies attached to the plasma side of choroid plexus epithelial cells, blocking MTHF transport across the choroid plexus, in which case treatment should be considered (11; 61).
Treatment of cerebral vasculopathy due to SAMHD1 mutation in a single patient by infusion therapy with tocilizumab was reported by Henrickson and Wang (35). Prior to treatment the juvenile patient had skin lesions and arthropathy as well as multiple cerebral arterial stenoses with collateralization, resulting in signs of Moyamoya disease. Intravenous treatment with the IL-6 antagonist tocilizumab resulted in regression of the arteriopathy after corticosteroid and subcutaneous adalimumab had resulted in stabilization.
No specific hazards exist with respect to medical treatments or special procedures.
Aicardi-Goutieres syndrome may be complicated by other acquired immune-related disorders as has been shown in the case of a patient with neuromyelitis optica complicating Aicardi-Goutieres syndrome, confirmed by the presence of aquaporin (AqP4) antibodies (33).
Most patients with Aicardi-Goutieres syndrome are not likely to become pregnant in view of the severity of the disease. An exception may exist for milder expressions such as hereditary spastic paraparesis. No data are available on specific risks for this group, but genetic risks involved should be considered.
No anesthetic risks are known, but the usual precautions should be taken in case of manifest epilepsy.
Peter G Barth MD PhD
Dr. Barth of the University of Amsterdam has no relevant financial relationships to disclose.See Profile
Joseph R Siebert PhD
Dr. Siebert of the University of Washington has no relevant financial relationships to disclose.See Profile
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