Neurological manifestations and clinical outcomes in pediatric Alexander disease: single-center cohort and identification of novel GFAP variants.

BACKGROUND

We aimed to analyze the prevalence, clinico-radiological and genetic features, and outcomes in children with Alexander disease (AD) with special emphasis on atypical presentations.

METHODS

This cross-sectional study evaluated children with AD seen over the past 10 years. Neuroimaging was evaluated by a trained neuroradiologist. In-silico tools were used to predict the pathogenicity of the novel variants detected by whole-exome sequencing.

RESULTS

N = 12 children (males 58.3 %) with genetically-confirmed AD were evaluated. Disease subtypes were infantile (n = 7, 58.3 %), juvenile (n = 3, 25 %), and neonatal (n = 2, 16.7 %) AD. The clinic-based prevalence of AD was 0.34 cases per 1000 pediatric neurology patients per year, or an average of 1.2 cases per year. Clinical features were developmental delay (n = 9, 75 %), macrocephaly (n = 9, 75 %), spasticity (n = 6, 50 %), and epilepsy (n = 8, 66.7 %); two children with juvenile-onset disease had atypical visual and bulbar manifestations. Pathogenic variations were most common in exons 1 (n = 5, 42 %), and exon 4 (n = 4, 33.3 %). These were missense type (n = 11, 91.6 %) or deletion (n = 1, 8.3 %). Three novel variants were detected: c.251T>G (p.Ile84Ser) in exon 1, c.810_818 deletion (p.Asn271_Glu273del) in exon 5, and c.292G>C (p.Ala98Pro) in exon 1 in the GFAP gene (NM_002055). Majority of children developed spastic paresis (n = 9, 83 %) and mortality rate was 33.3 % (n = 4/12).

CONCLUSION

AD is a rare leukodystrophy with high mortality and progressive spastic paraparesis. Neonatal and juvenile types may present atypically and delay correct diagnosis. Deletions may account for a minor proportion of pathogenic variants. Our study expands the clinico-radiological spectrum of AD in children.