AP1S2-related syndrome presents with a large intraindividual and intrafamilial clinical variability in the frame of a severely disabling non-degenerative condition.
Neurological and Neurodevelopmental disorders:
Hypotonia. Marked hypotonia since postnatal period has been described.
Global developmental delay. Delayed walking with gait abnormalities and progression to major handicap in adulthood was also frequently reported and several patients never walked.
Movement disorders. Progressive limb spasticity, muscular hypotrophy and kyphoscoliosis and athetosis have been reported mainly in syndromic subjects. Stereotypies in all.
Intellectual disability is mostly severe-to-profound following a global developmental delay. Clinical condition remains stable in the adulthood with not obvious neurodegenerative course. In single patient neurological irreversible neurological regression was observed after head trauma.
Verbal communication is extremely poor, with about 40% having no words and the remainder with little speech.
Behavioral disorders. Impulsiveness, compulsiveness, aggressiveness and or dramatic self-injuring behavior is common as part of an autistic spectrum disorders
The face may show progressive dysmorphisms such as coarse facies, long face, synophrys, and thick full lip vermilion.
Eye problems are noted, including ptosis, strabismus, refractive errors, and optic nerve atrophy.
Epilepsy has been reported in a few patients, often not an early problem.
Brain abnormalities. Microcephaly (that is probably acquired), hydrocephalus or enlarged ventricle, periventricular nodular heterotopia, hypoplasia of cerebellar vermis, Dandy-Walker malformation, and basal ganglia calcification. Previous studies suggested that basal ganglia calcification can occur in childhood and progress with age, which would support the hypothesis that this disorder may be a neurodegenerative disease.
Reports of calcium and iron deposition are confusing. The earlier iron deposition in the basal ganglia has not been confirmed, which might be helpful given the convincing images of calcium shown on several brain CT scans. However, both iron and calcium depositions involve regions of the brain where iron levels are higher (basal ganglia and cerebellar dentate nuclei). The assumption is that the neurodegeneration begins with iron deposition, which was seen on both brain pathology and imaging. The calcifications probably follow iron deposition, with onset in childhood most likely between 1 and 9 years. However, this proposed progression needs to be further investigated and confirmed by further studies.
Abnormal CSF neurotransmitter profile: increased biopterin, and 5-hydroxyindolacetic acid and homovanillic acid associated with very low CSF 5-MTHF and elevated CSF protein was described in a single patient. CSF examination has not reported in any other patients with AP1S2 pathogenetic variants.
Most female carriers of a mutation in the AP1S2 gene and tested for X-chromosome inactivation (XCI) have a random pattern of X chromosomal inactivation, normal intelligence and normal phenotypes, even when the whole AP1S2 gene is deleted. Although X-chromosome inactivation has not been tested in the brain, these observations suggest that a proportion of normal cells in a mosaic context is sufficient to prevent these females from being intellectually disabled in the presence of an AP1S2 mutation.
AP1S2