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

Cahan and Frick Orphanet Journal of Rare Diseases https://doi.org/10.1186/s13023-019-1131-4 (2019) 14:148 RESEARCH Open Access Orthopaedic phenotyping of NGLY1 deficiency using an international, family-led disease registry Eli M. Cahan1,2* and Steven L. Frick2 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; nonpharmacologic 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: NGLY1 deficiency, Orthopaedics, Natural history, Standard of care, Disease advocacy organizations, Evidence-based medicine, Disease registry * Correspondence: 1 New York University School of Medicine, New York, NY 10010, USA 2 Department of Pediatric Orthopaedics, Stanford University, 300 Pasteur Drive, R107, Palo Alto, CA 94305, USA © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Cahan and Frick Orphanet Journal of Rare Diseases (2019) 14:148 Page 2 of 8 Introduction NGLY1 is a 70 kb gene composed of 12 exons and located on chromosome 3 that is highly conserved between eukaryotic species [1, 2]. The gene product, N-glycanase, is a conserved enzyme localized primarily to the cytoplasm that is involved in endoplasmic reticulum associated degradation (ERAD) [3]. Enzyme induced deglycosylation of misfolded glycoproteins located at the N-termini of polypeptides marks them for transport into the cytosol and proteasomal degradation [4, 5]. Additionally, NGLY1 is required for the transcriptional activity of NFE2L1, a protein with roles in regulating proteotoxic and oxidative stress. These roles are essential to (i) ensure appropriate function for proteins released to the cytosol and (ii) prevent toxic accumulation of malformed proteins within the cell [5, 6]. NGLY1 deficiency (OMIM 610661 and 615,273) is an autosomal recessive disorder that results in a complete or partial loss of N-glycanase activity in the cytosol [7]. There is in vitro evidence that such misfolded products of the endoplasmic reticulum (ER) aggregate within the cell and can cause deleterious effects on multiple subcellular organelles [7, 8]. In this proposed model of pathogenesis, affected organelles include the cytoplasm (which loses functional volume due to protein agglomeration) [8, 9]; endoplasmic reticulum (in which synthetic capability is diminished) [10]; mitochondria [11, 12]; and the proteasome (which incurs defects in functional subunits) [13]. The result may be unregulated cellular necrosis (rather than regulated cellular apoptosis or autophagy): a pathophysiology proposed to resemble other proteinopathies, such as Alzheimer’s disease (due to Tau accumulation) and Huntington’s disease (due to Htt protein accumulation) in animal models [8, 14]. Three cell types shown to have abnormalities in vitro include neurons, myocytes, and fibroblasts. Neurons have demonstrated susceptibility to proteinopathies due to high levels of protein production and low rates of cellular turnover [15]. Myocytes show considerable dependence on mitochondrial function and likewise have high levels of protein production [16]. Fibroblasts also have exhibited high levels of protein production, with extensive energy utilization as a result [8, 10]. Dysfunction and destruction of these cells leads to phenotypic effects across organ systems [17]. In humans, NGLY1 deficiency is a rare disorder with approximately 50 confirmed patients worldwide [17]. The disease classically presents with a clinical tetrad of developmental delay, hypolacrima, transiently elevated transaminases, and hyperkinetic movement disorders [17, 18]. Due to the rarity of the condition, there is a paucity of detailed phenotypic information available in the medical literature [17, 18]. Previously documented symptoms have focused on the neurologic, ophthalmologic, immunologic, and endocrine organ systems [7, 11, 1 (...truncated)