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At a glance

A rapidly progressive, familial encephalopathy with calcifications of the basal ganglia, cerebral white matter abnormalities, cerebral atrophy, progressive microcephaly, chronic cerebrospinal fluid (CSF) lymphocytosis, and elevated levels of interferon-α in CSF and serum. This syndrome may progress fast into a vegetative state and early death.

Synonym

Familial Infantile Encephalopathy with Calcification of Basal Ganglia.

Incidence

Approximately 400 cases have been described to date, but the incidence is unknown.

Genetic inheritance

Depending on the gene carrying the causative mutation, seven subtypes of AGS can be distinguished.

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Type Inheritance Frequency (%) Gene Location
AGS 1 AD, AR 22-25 TREX1 3p21.31
AGS 2 AR 36-40 RNASEH2B 13q14.3
AGS 3 AR 12-14 RNASEH2C 11q13.1
AGS 4 AR 4-5 RNASEH2A 19p13.2
AGS 5 AR 13 SAMHD1 20q11.23
AGS 6 AR 7 ADAR 1q21.3
AGS 7 AD 3% IFIH1 2q24

The abbreviations included in this table are defined as follow: AD, autosomal dominant; AR, autosomal recessive; TREX1, 3-Prime Repair Exonuclease 1; RNASEH2A/B/C, Ribonuclease H2, subunit A/B/C; SAMHD1, Sam Domain- and HD Domain-Containing Protein 1; ADAR, Adenosine Deaminase, RNA-specific; IFIH1, Interferon-Induced Helicase C Domain-Containing Protein 1.

The largest survey to date of 374 patients with AGS found that the most common mutations occurred in RNASEH2B. The clinical features and course vary somewhat by genotype. In AGS 1 with mutations in the TREX1-gene the mortality is rather high, whereas in AGS 2 with RNASEH2B mutations the neurological deficiencies are slightly milder and the life expectancy longer. Incomplete penetrance of the same underlying mutations can result in very different neurological and developmental outcomes in different patients, even within affected families.

History

First described in 1984 by the French pediatric neurologists Jean François Marie Aicardi (1926-2015) and Françoise Goutiéres.

Diagnosis

Initially rather unspecific symptoms like irritability, feeding and sleeping difficulties, and unexplained low-grade fevers. Chilblain-like skin lesions on fingers, toes, and ears may appear. The diagnosis is later based on the clinical presentation of early-onset, progressive encephalopathy with psychomotor delay, spasticity, extrapyramidal signs, abnormal eye movements, and microcephaly (becoming obvious in the first year of life). It is associated with chronic CSF lymphocytosis (pleocytosis) and elevated serum- and CSF-levels of interferon-α. The CSF-levels of neopterin and biopterin are elevated and 5-methyltetrahydrofolate is reduced. A CT- or MRI-scan of the brain shows cerebral atrophy (mainly white matter), hydrocephalus, leukoencephalopathy, delayed myelination, cysts in the temporal and frontal lobes and calcifications in the basal ganglia (putamen, globus pallidus, caudate nucleus), the dentate nuclei, thalamus, lobar white matter, and cerebellum. The heterogeneity of the neuroradiologic findings is partly explained by the timing of the disease onset. This medical condition resembles the neurological sequelae of congenital infections, thus positive TORCH (T...

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