JIMD Reports, Volume 22

Bethanny Smith-Packard, Scott M Myers, Marc S Williams, Scott M. Myers, Marc S. Williams, Smith-Packard, Bethanny, Myers, Scott M., Williams, Marc S.

A girl with early onset severe epilepsy, developmental delay, intellectual disability, visual maturation delays, and feeding problems was without a diagnosis despite an extensive genetic and metabolic evaluation. She initially manifested infantile spasms which responded to high-dose ACTH. Seizures seemed to resolve, but then at age 5, she developed complex partial seizures resistant to antiepileptics that responded to a ketogenic diet. Additional features included visual impairment, hypotonia, reflux, and severe feeding problems requiring a G-tube. She was referred to the Geisinger Health System whole-genome sequencing clinical research program. A variant in the X-linked gene ALG13 (c.320A->G p. 107 N->S) was identified. Four additional girls from three published exome sequencing studies were found to have the identical c.320A>G variant in ALG13. All presented with early onset severe epilepsy and intellectual disability. Three of the five exhibited visual impairment and possible developmental regression. A boy with a variant in ALG13 presented with a severe congenital disorder of glycosylation type Is. Glycosylation studies in the case reported here were normal; none of the other girls reported in the literature have had glycosylation studies. X-inactivation studies have not been done. The N107 residue and the surrounding region - MNNHQ - are highly conserved across species and are found in a presumed functional domain of this glycotransferase superfamily. The consistent clinical presentation of a severe phenotype in girls coupled with identical variants in an X-linked gene strongly suggests a critical position effect. Negative glycosylation studies in one individual suggest the possibility of a new mechanism requiring investigation.