Orthopaedic phenotyping of NGLY1 deficiency using an international, family-led disease registry

Abstract

Background: NGLY1 deficiency is a rare autosomal recessive disorder caused by loss in enzymatic function of NGLY1, a peptide N-glycanase that has been shown to play a role in endoplasmic reticulum associated degradation (ERAD). ERAD dysfunction has been implicated in other well-described proteinopathies, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. The classical clinical tetrad includes developmental delay, hypolacrima, transiently elevated transaminases, and hyperkinetic movement disorders. The musculoskeletal system is also commonly affected, but the orthopaedic phenotype has been incompletely characterized. Best practices for orthopaedic clinical care have not been elucidated and considerable variability has resulted from this lack of evidence base. Our study surveyed patients enrolled in an international registry for NGLY1 deficiency in order to characterize the orthopaedic manifestations, sequelae, and management.

Results: Our findings, encompassing the largest cohort for NGLY1 deficiency to date, detail levels of motor milestone achievement; physical exam findings; fracture rates/distribution; frequency of motor skill regression; non-pharmacologic and non-procedural interventions; pharmacologic therapies; and procedural interventions experienced by 29 participants. Regarding the orthopaedic phenotype, at time of survey response, we found that over 40% of patients experienced motor skill regression from their peak. Over 80% of patients had at least one orthopaedic diagnosis, and nearly two-thirds of the total had two or more. More than half of patients older than 6 years had sustained a fracture. Related to orthopaedic non-medical management, we found that 93 and 79% of patients had utilized physical therapy and non-operative orthoses, respectively. In turn, the vast majority took at least one medication (including for bone health and antispasmodic therapy). Finally, nearly half of patients had undergone an invasive procedure. Of those older than 6 years, two-thirds had one or more procedures. Stratification of these analyses by sex revealed distinctive differences in disease natural history and clinical management course.

Conclusions: These findings describing the orthopaedic natural history and standard of care in patients with NGLY1 deficiency can facilitate diagnosis, inform prognosis, and guide treatment recommendations in an evidence-based manner. Furthermore, the methodology is notable for its partnership with a disease-specific advocacy organization and may be generalizable to other rare disease populations. This study fills a void in the existing literature for this population and this methodology offers a precedent upon which future studies for rare diseases can build.

Keywords: Disease advocacy organizations; Disease registry; Evidence-based medicine; NGLY1 deficiency; Natural history; Orthopaedics; Standard of care.

Fig. 1

Level of motor milestone achievement by/at time of survey in patients older than 18 months

Fig. 2

AP pelvis radiograph demonstrating classic signs of neuromuscular hip dysplasia including coxa valga, caput valgum, acetabular dysplasia, and subluxation of the hip joint

Fig. 3

Prevalence of musculoskeletal manifestations in the study cohort

Fig. 4

Frequency of intervention types amongst all patients and within intervention class for physical therapy (PT), occupational therapy (OT), and surgery

Fig. 5

AP pelvis radiograph demonstrating another NGLY-1 deficient patient who has undergone proximal femoral osteotomy to treat neuromuscular hip dysplasia and hip subluxation