Clinical characteristics: Individuals with NGLY1-related congenital disorder of deglycosylation (NGLY1-CDDG) typically display a clinical tetrad of developmental delay / intellectual disability in the mild to profound range, hypo- or alacrima, elevated liver transaminases that may spontaneously resolve in childhood, and a complex hyperkinetic movement disorder that can include choreiform, athetoid, dystonic, myoclonic, action tremor, and dysmetric movements. About half of affected individuals will develop clinical seizures. Other findings may include obstructive and/or central sleep apnea, oral motor defects that affect feeding ability, auditory neuropathy, constipation, scoliosis, and peripheral neuropathy.
Diagnosis/testing: The diagnosis of NGLY1-CDDG is established in a proband by the identification of biallelic pathogenic variants in NGLY1 on molecular genetic testing. Typical serum screening tests for congenital disorders of glycosylation (i.e., analysis of serum transferrin glycoforms, N and O glycan profiling) will NOT reliably detect NGLY1-CDDG.
Management: Treatment of manifestations: Lubricating eye drops and/or bland ointments for hypolacrima; feeding therapy and/or supplemental tube feeding for those with oromotor deficits and feeding difficulties; adequate access to water and a cool environment (including a cooling vest for those who live in hot climates) for hypohydrosis; vitamin D supplementation for those with vitamin D deficiency; evaluation by a developmental pediatrician and supportive therapies for developmental and cognitive issues; standard treatment for hearing loss, sleep apnea, constipation, scoliosis, and seizure disorder; consideration of referral to a hematologist for abnormal hematologic studies; consideration of referral to a gastroenterologist for elevated liver transaminases.
Surveillance: Annual follow up by a pediatrician/internist, rehabilitation medicine specialist, ophthalmologist, neurologist, and nutritionist is recommended. Periodic evaluation by a developmental pediatrician, gastroenterologist/hepatologist, and audiologist should be considered.
Agents/circumstances to avoid: Hot environment in those with hypohydrosis.
Genetic counseling: NGLY1-CDDG is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has 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. Carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible if the pathogenic variants in the family are known.
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