Abstract
Pathogenic variants in the NGLY1 gene are associated with a Congenital Disorder of Deglycosylation (CDDG) characterized by delays in reaching developmental milestones, complex hyperkinetic movement disorder, transient elevation of transaminases, and alacrima or hypolacrima. To date, only few cases of NGLY1 deficiency have been identified and reported in the literature. This report highlights a first child of non‐consanguineous parents with no relevant family history who presented with hypotonia and poor weight gain since birth. At 2 months, the child developed paroxysmal cervical dystonia, posteriorly resolving spontaneously by age of 3. Subsequently, delays in reaching developmental milestones, ataxia, dyskinesia, visual impairment due to cone rod retinal dystrophy, low triglycerides, and persistently elevated liver transaminases were observed. Extensive etiological investigation was performed, including array‐CGH and metabolic evaluation with no abnormalities to note. Trio whole exome analysis identified a homozygous pathogenic variant of the NGLY1 gene, c.1891del (p.Gln631Serfs*7), consistent with CDDG. Both parents were confirmed to be heterozygous carriers. The authors discuss in this case, the clinical presentation, the diagnostic challenges, and review other relevant NGLY1 deficiency cases previously reported in the literature. This case, along with the previous reported in the literature, indicates that pathogenic variants in NGLY1 cause a recognizable phenotype and should be considered in patients with a typical presentation. It also suggests that decreased sweating is not present universally in these patients.
Highlights
Congenital Disorders of Glycosylation (CDG) are a group of inborn errors of metabolism characterized by abnormalities in biomolecules of glycosylation
According to a database maintained by NGLY1.org, a combination of bi-allelic pathogenic variants in NGLY1 gene coupled with a suggestive clinical phenotype has been identified so far, 63 individuals worldwide, with a total of 21 individuals described in the literature.[2,3,5,6,10,11,12]
Compound heterozygous pathogenic variants in NGLY1 gene were first reported in 2012, in a 3-year-old boy who presented with delay in reaching developmental milestones, multifocal epilepsy, involuntary movements, absent tears, and abnormal liver function.[3]
Summary
Congenital Disorders of Glycosylation (CDG) are a group of inborn errors of metabolism characterized by abnormalities in biomolecules of glycosylation. This article highlights the clinical and molecular findings of another patient with NGLY1 deficiency and reviews the literature describing NGLY1 deficiency in children This case describes an 8-year-old boy, first child of nonconsanguineous parents, born at 38 weeks of gestation (by caesarian delivery) with no known complication during pregnancy. Using the Nijmegen CDG paediatric rating scale[9] to determine the disease progression and severity, he currently shows a moderate impairment with a total score of 27 (6 in section I— Current Function, 2 in section II—Systemic Specific Involvement and 19 in section III—Current Clinical Assessment) He is currently on a regular program of speech therapy and physiotherapy and has individual special education at school. Segregation analysis confirmed that both parents were heterozygous carriers of the pathogenic NGLY1 variant
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