ARX-mutation – phenotype and clinical course in two brothers with West Syndrome and developmental delay

Abstract

Background: Mutations in the ARX-gene (Aristaless-Related Homebox Gene) are associated with a different clinical phenotypes; one of which is the X-linked West Syndrome (ISSX, infantile spasm syndrome). In addition to epilepsy, the patients present with psychomotor delay and, rarely, with abnormal movements. The treatment includes anticonvulsive therapy and supportive measures to improve psychomotor development. Patients und methods: Two brothers (3 and 2 years old) from a non-consanguineous Indian family developed infantile spasms each at the age of 4 months. Up to that point the psychomotor development was described as normal. The younger brother was preterm born of the 28th week of gestation and showed, in contrast to his older brother, no hypsarrhythmia but multifocal epileptic activity on electroencephalogram (EEG). The older, now 3-year-old brother, became seizure free as a result of anticonvulsive therapy with sultiam and vigabatrin. However, this didn't improve seizure frequency in the younger brother; therefore we have started the ketogenic diet (KD). Under this treatment, seizure frequency and EEG recordings improved. During clinical follow up, the older boy developed abnormal movements consisting of an awkward gait and a dystonic posture of his hands; in addition he developed a delay in his linguistic development. With the beginning of infantile spasms, the younger brother showed a severe psychomotor decline; by reduction of seizure frequency, slight advancements in his motor development could be observed. Up to date, he suffers from muscular hypotonia, psychomotor delay and he is neither able to turn himself from prone to spine position nor is he able to grasp. His brain magnetic resonance imaging (MRI) disclosed cerebral atrophy whereas the MRI of the older brother is normal. Detailed metabolic work-up disclosed normal laboratory findings in both. Genetic analysis of the ARX gene showed the same pathological mutation (c.464_487dup24; p.Ala155ins) in the brothers and could confirm the diagnosis. A genetic analyses in the mother is pending. Conclusions: Genetic analysis of the ARX-gene should be taken into account in patients presenting with West-Syndrome and developmental delay with/without abnormal movements, especially if X-chromosomal inheritance is assumed. In this patient group the KD can show beneficial effects and presents an important therapeutic option if conventional anticonvulsants failed to be efficient.