NGLY1 Deficiency: A Rare Newly Described Condition with a Typical Presentation

Abstract

NGLY1 deficiency is the first recognized autosomal recessive disorder of N-linked deglycosylation (NGLY1-CDDG). This severe multisystemic disease is still poorly known and, to date, most cases have been diagnosed through whole exome or genome sequencing. The aim of this study is to provide the clinical, biochemical and molecular description of the first NGLY1-CDDG patient from France along with a literature review. The index case presented with developmental delay, acquired microcephaly, hypotonia, alacrimia, feeding difficulty, and dysmorphic features. Given the complex clinical picture and the multisystemic involvement, a trio-based exome sequencing was conducted and urine oligosaccharides were assessed using mass spectrometry. The exome sequencing revealed a novel variant in the NGLY1 gene in a homozygous state. NGLY1 deficiency was confirmed by the identification of the Neu5Ac1Hex1GlcNAc1-Asn oligosaccharide in the urine of the patient. Literature review revealed the association of some key clinical and biological features such as global developmental delay-hypertransaminasemia, movement disorders, feeding difficulties and alacrima/hypolacrima.

Keywords: NGLY1; NGLY1-CDDG; alacrimia; congenital disorder of deglycosylation; developmental delay; elevated transaminases; hypolacrimia; hypotonia; movement disorder.

Figure 1

(A). Enzymatic and non-enzymatic activities of N-glycanase. ERAD: Endoplasmic Reticulum Associated Degradation, N-ter: N-terminal, C-ter: C-terminal. (B). Molecular variations of thirty-seven described cases including that of the present case (highlighted in a colored background). The number of mutant alleles is indicated between brackets. C-ter: C-terminal domain; N-ter: N-terminal domain.

Figure 2

(A). Photo of the index case presenting dysmorphic features: (left, middle) facial dysmorphism: small mouth, long palpebral fissure, hypertelorism, low-set ears, high-arched palate, corneal opacity. (right) hand abnormality: clasped thumb, clinodactyly. (B). Phenotype summary of the current case and previously reported cases [1,3,4,5,6,7,8,9,10,11,23,25,26,27,28]