How does it manifest itself?

Clinical aspects

AGS typically has onset in the first year of life, usually in the first three months. It follows an uncomplicated pregnancy and delivery and apparently normal early development.
Extreme irritability, disturbed sleep-wake patterns (including difficulty falling asleep and reversal of the sleep-wake cycle), and feeding difficulties are frequent early alarm signals.
Low-grade fevers (38-38.5°C), sometimes recurrent and not apparently linked to any infection, are commonly reported at clinical onset. The presence of these symptoms can initially lead to erroneous diagnoses of meningitis or encephalitis. What these symptoms actually indicate is the onset of an initially sub-acute encephalopathy, which is followed by an increasingly apparent psychomotor delay and/or a loss of early acquired skills, as well as signs of neurological impairment and a slowing of head growth.
After this first phase, which usually lasts a few months, the clinical picture typically stabilises and, according to most authors, no further progression of the disease is detectable.
The stimulus triggering the onset of the disease is not known, and neither is it understood why, after several months, the clinical picture stabilises. In 10-20% of patients, the disease instead manifests itself in the neonatal period. In these cases, the picture — neonatal neurological impairment, microcephaly and calcification (these two features sometimes detected in utero), transitory hepatosplenomegaly, raised transaminases, thrombocytopenia and anaemia — is even more difficult to distinguish from those of congenital viral infections. There have also been reports of cases with an atypical age at onset (after the age of 1 year), in which the disease appears after a more prolonged period of normal psychomotor development.

Neurological signs

During or immediately after the onset phase, the neurological signs typical of AGS progressively appear.
Affected subjects generally develop tetraplegia, poor head control, trunk hypotonia, and pyramidal and extrapyramidal signs, in particular persistence of archaic reflexes and dystonic postures and movements, associated with varying degrees of spasticity and rigidity. They also frequently present abnormal eye movements, nystagmus and poor visual performance.
Another typical finding in affected subjects is the presence of the "startle reaction" in response to even mild sensory stimuli.
The vast majority of affected children present severe motor and cognitive impairment: postural acquisitions are frequently limited to partial head control, while language is severely impaired (indeed absent in most cases), even though some subjects show some awareness of their surroundings and a degree of understanding. As regards the severity of the clinical picture, there exists a certain heterogeneity; indeed, although rare, it is possible to encounter, even within the same family, less severe clinical pictures with preservation of motor and intellectual abilities.
As will be discussed in more detail further on, some affected children, in particular those in whom the SAMHD1 (AGS5) gene is mutated, are at increased risk of developing cerebrovascular disorders; in particular, there have been reports of strokes, due to stenosis of the major cerebral vessels, in some cases reminiscent of Moyamoya syndrome (cerebrovascular disease characterised by stenosis or occlusion of the major brain arteries with the formation of compensatory collateral circulations), or to cerebral aneurysms.
Epileptic seizures are a particularly common symptom in children with AGS. Epilepsy may be defined as a neurological condition characterised by repeated seizures, i.e. paroxysmal events that are the manifestation of a sudden hypersynchronous and simultaneous discharge of a population of neurons in the brain that causes positive or negative symptoms that mimic, in a distorted way, the function normally performed by that same neuronal population.
Different and inconsistent rates of epilepsy have been reported in individuals with AGS, with frequencies ranging from 10-30% to 53-75% in the most recent reports. In general, around 50% of affected children experience epileptic seizures; seizures are more frequent among more severe early-onset cases, in whom they often appear in the first or second month of life; in such cases epilepsy correlates with a worse prognosis and can be particularly severe, manifesting itself from the outset as status epilepticus or with seizures that tend to be poorly controlled by medication. In other cases, epilepsy appears as a symptom of the brain injury and the seizures are well controlled by therapy.
In children affected by AGS it is often difficult to distinguish epileptic seizures from other similar paroxysmal phenomena, such as the "startle reaction" (mentioned earlier) or episodes of paroxysmal dystonia, which can often "mimic" a seizure and are very frequent in these children. Sometimes the correct diagnosis, essential in order to establish the most appropriate therapeutic approach, is reached only after performing polygraphic video-EEG assessments during episodes.

Extraneurological signs

Extraneurological signs are frequent in AGS. The organ most typically affected is the skin, which can present chilblain-like lesions characterised by areas of inflammation and intermittent necrosis. These lesions, reported in around 35% of subjects at least once in their lifetime, are found mainly on the fingers, toes and ears. Although more usual in winter, they can also be present throughout the year. There are also other extraneurological symptoms, reported less frequently in sporadic cases of AGS: in cases with neonatal onset, as well as liver involvement (hepatosplenomegaly and raised transaminases), patients can also present transitory thrombocytopenia.
There have also been reports of congenital glaucoma, neonatal cardiomyopathy, demyelinating peripheral neuropathy, micropenis, transitory antidiuretic hormone deficiency, insulin-dependent diabetes mellitus and hypothyroidism. Polygammaglobulinaemia, haemolytic anaemia and increased levels of autoantibodies have been reported in some subjects.
Furthermore, arthropathy with progressive contractures has also been described, but only in children with mutations in the SAMHD1 gene.
Some of these symptoms, e.g. hypothyroidism, may have an autoimmune origin, in other words, they may be the result of a reaction of the immune system directed erroneously against the patient's own body, and in fact it has recently emerged that there exists a genetic and pathogenetic link between AGS and several autoimmune disorders in which interferon plays a key role (the so-called interferonopathies).