NGLY1 deficiency: a prospective natural history study

Abstract

N-glycanase 1 (NGLY1) deficiency is a debilitating, ultra-rare autosomal recessive disorder caused by loss of function of NGLY1, a cytosolic enzyme that deglycosylates other proteins. It is characterized by severe global developmental delay and/or intellectual disability, hyperkinetic movement disorder, transient elevation of transaminases, (hypo)alacrima and progressive, diffuse, length-dependent sensorimotor polyneuropathy. A prospective natural history study (NHS) was conducted to elucidate clinical features and disease course. Twenty-nine participants were enrolled (15 onsite, 14 remotely) and followed for up to 32 months, representing ~29% of the ~100 patients identified worldwide. Participants exhibited profound developmental delays, with almost all developmental quotients below 20 on the Mullen Scales of Early Learning, well below the normative score of 100. Increased difficulties with sitting and standing suggested decline in motor function over time. Most patients presented with (hypo)alacrima and reduced sweat response. Pediatric quality of life was poor except for emotional function. Language/communication and motor skill problems including hand use were reported by caregivers as the most bothersome symptoms. Levels of the substrate biomarker, GlcNAc-Asn (aspartylglucosamine; GNA), were consistently elevated in all participants over time, independent of age. Liver enzymes were elevated for some participants but improved especially in younger patients and did not reach levels indicating severe liver disease. Three participants died during the study period. Data from this NHS informs selection of endpoints and assessments for future clinical trials for NGLY1 deficiency interventions. Potential endpoints include GNA biomarker levels, neurocognitive assessments, autonomic and motor function (particularly hand use), (hypo)alacrima and quality of life.

Figure 1

NGLY1 deficiency clinical features and summary of study protocol. Core clinical features of NGLY1 deficiency (1–3) are shown above. The study protocol is summarized below.

Figure 2

Scatter plot of Mullen-DQ vs chronological age. Individual participant DQ scores over time are shown. The normative value is 100 ± 15. Black symbols are female and gray symbols are male subjects.

Figure 3

Vineland ABC. Individual participant Vineland ABC scores over time are shown. The normative value is 100 ± 15 (shaded area). Black symbols are female and gray symbols are male subjects.

Figure 4

PDMS-2 gross motor (A) and fine motor (B) function. Individual participant PDMS-2 gross motor (A) and fine motor (B) function scores over time are shown. The normative values are 100 ±15. Black symbols are female and gray symbols are male subjects.

Figure 5

Motor function: Standing ability. Individual participant standing ability over time is shown. Black symbols are female and gray symbols are male subjects.

Figure 6

Schirmer’s lacrimation test. Results from left eye. Wetting of ≤5 mm per 5 min is considered a strong positive test for (hypo)alacrima (17). Greater than 10 mm is considered normal (gray line).

Figure 7

PedsQL (total score) vs. visit. Black symbols are female and gray symbols are male subjects.

Figure 8

Plasma GNA concentration vs. age at collection for participants as measured over time. Age at sample collection and GNA concentration were compared to determine whether there was a significant relationship. The line is the trend line with statistical correlation shown. Each point represents a measurement, and points connected by short black lines are consecutive measurements for the same participant.

Figure 9

ALT (units per liter [U/L]) vs. chronological age. Legend: If participants had multiple laboratory measurements at the same visit, the highest value was selected for analysis.

Figure 10

AST (U/L) vs chronological age. Legend: If participants had multiple laboratory measurements at the same visit, the highest value was selected for analysis.