SLC39A8-CDG

Excerpt

Clinical characteristics: SLC39A8-CDG is characterized by mild-to-profound developmental delay, intellectual disability, hypotonia, feeding difficulties with poor weight gain and growth deficiency, dystonia, spasticity, epilepsy, ophthalmologic manifestations including cortical blindness and strabismus, and sensorineural hearing impairment.

Diagnosis/testing: The diagnosis of SLC39A8-CDG is established in a proband with characteristic clinical features and suggestive laboratory findings (decreased whole blood manganese, elevated xanthine on urinary purines/pyrimidines, and evidence of altered glycosylation) by identification of biallelic pathogenic variants in SLC39A8 on molecular genetic testing.

Management: Targeted therapy: Manganese supplementation with titration to identify adequate manganese dose prior to adding galactose supplementation.

Supportive care: Developmental and educational support; standard treatments for spasticity, seizures, feeding issues, ophthalmologic involvement, hearing impairment, and musculoskeletal complications; family support and care coordination as needed.

Surveillance: Assess for abnormal glycosylation using mass spectrometry, and measure blood manganese levels as needed to titrate manganese dose; brain MRI every one to two years; assess developmental progress, educational needs, seizures, changes in tone, movement disorders, growth, nutrition, feeding, mobility, self-help skills, clinical evidence of scoliosis, and family needs at each visit; assess visual acuity and for strabismus with frequency per ophthalmologist; annual aspartate transaminase, alanine transaminase, and albumin in those with evidence of liver disease; assess for osteopenia/osteoporosis every one to two years or as needed; DXA scan every three to five years starting in adolescence.

Agents/circumstances to avoid: Fever, hepatotoxic drugs, and drugs contraindicated in mitochondriopathies.

Evaluation of relatives at risk: All at-risk sibs of any age should have molecular genetic testing for the familial SLC39A8 pathogenic variants in order to identify as early as possible those who would benefit from prompt initiation of manganese and galactose supplementation.

Genetic counseling: SLC39A8-CDG is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an SLC39A8 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the SLC39A8 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.