ESPE Abstracts

Background: NGLY1 encodes the enzyme N-glycanase that catalyzes protein deglycosylation in the process of protein degradation. Loss of function mutations in NGLY1 lead to a disorder of N-linked deglycosylation which is a rare multisystemic disease. The typical phenotype includes intellectual disability, liver dysfunction, muscular hypotonia, involuntary movements and decreased or absent tear production. Adrenal insufficiency has been previously reported in only two cases. Micropenis has not been reported yet.

Case report: A 5.6-year-old child was evaluated due to gradual darkening of the skin and more frequent falls. He is a product of pregnancy with intrauterine growth retardation, birth at 38 weeks and birth weight 2,558 grams. He achieved normal milestones until age 1.6 years and then experienced regression in his speech. Myoclonic seizures followed shortly afterward and treatment with sodium valproate and later levetiracetam was started. EEG was compatible with myoclonic epilepsy. MRI showed normal white matter myelinization and brain structure. The parents noticed darkening of the skin and mucous membranes 6 months prior to his referral with more frequent falls. Physical examination revealed general darkening of the skin and mucous membranes. Weight 17.8 kg WSDS -0.69, height 109 cm HSDS -0.6, BMI 15 BMI SDS -0.35, head circumference 50 cm. Normal heart, chest, and abdomen exam. The testes were both in the testicular sac, 3 mL in volume, stretched penile length 3 cm (<3.5SDS), Tanner 1. Cortisol levels were undetectable at baseline and after ACTH stimulation. All other adrenal metabolites were low as well and ACTH levels were very high at baseline. Treatment was started with hydrocortisone and fludrocortisone with gradual improvement in his general condition. A next generation sequencing panel for epilepsy genes revealed a previously unreported homozygous variant c.-17_12del in NGLY1classified as likely pathogenic by Varsome database. Pathogenicity was confirmed by high-resolution mass spectrometry determination of dried blood spot aspartylglycosamine (a diagnostic biomarker for NGLY1-CDDG) revealing a level 5.7 standard deviations above controls.

Conclusion: Mutations in NGLY1 are rare and adrenal insufficiency has been reported only in the minority of the cases. The increased mortality reported in this disorder during intercurrent illness might be attributable to undiagnosed adrenal insufficiency. This is the first report of micropenis in NCLY1-CDDG.