Critical Comments by Food and Drug Administration Reviewers on Patient-Reported Outcomes in Food and Drug Administration Regulatory Submissions (2018-2021).

OBJECTIVES: This article examined the inclusion of patient-reported outcome (PRO) data in new drug applications (NDAs) submitted to the Food and Drug Administration (FDA) and approved from 2018 to 2021. The importance of assessing PROs, which capture patients' perspectives on the disease and treatment experience, has been underscored by many stakeholders, including regulatory authorities. Despite the increasing inclusion of PRO assessments in registration trials, inclusion of language related to PRO results in approved product labeling varies widely. METHODS: This study examined FDA submission packages for NDAs approved by the FDA from 2018 to 2021 to identify critical reviewer comments related to PROs. Comments were identified and categorized by the type of criticism. Reviewers considered both oncology and nononcology indications. RESULTS: Assessment of PROs was included in 66.2% of the 210 submissions reviewed. Critical comments were identified in 45.3% of these applications; comments most commonly related to statistical analysis considerations, fit for purpose, and study design. Other categories of critical comment included data quality, lack of treatment benefit, administrative considerations, and miscellaneous issues. Differences were observed between oncology and nononcology NDAs with regard to the number and type of comments included in each of these categories. The findings highlight the importance of planning statistical analyses, establishing content validity, carefully considering study design, maximizing data quality, and demonstrating treatment benefit, among other issues. CONCLUSIONS: Overall, this study offers insight into the landscape of PRO data included in recently approved NDAs, along with recommendations for improving the quality and reporting of PROs in clinical trials.

Safety and efficacy of N-acetylmannosamine (ManNAc) in patients with GNE myopathy: an open-label phase 2 study.

PURPOSE: To evaluate the safety and efficacy of N-acetylmannosamine (ManNAc) in GNE myopathy, a genetic muscle disease caused by deficiency of the rate-limiting enzyme in N-acetylneuraminic acid (Neu5Ac) biosynthesis. METHODS: We conducted an open-label, phase 2, single-center (NIH, USA) study to evaluate oral ManNAc in 12 patients with GNE myopathy (ClinicalTrials.gov NCT02346461). Primary endpoints were safety and biochemical efficacy as determined by change in plasma Neu5Ac and sarcolemmal sialylation. Clinical efficacy was evaluated using secondary outcome measures as part of study extensions, and a disease progression model (GNE-DPM) was tested as an efficacy analysis method. RESULTS: Most drug-related adverse events were gastrointestinal, and there were no serious adverse events. Increased plasma Neu5Ac (+2,159 nmol/L, p < 0.0001) and sarcolemmal sialylation (p = 0.0090) were observed at day 90 compared to baseline. A slower rate of decline was observed for upper extremity strength (p = 0.0139), lower extremity strength (p = 0.0006), and the Adult Myopathy Assessment Tool (p = 0.0453), compared to natural history. Decreased disease progression was estimated at 12 (γ = 0.61 [95% CI: 0.09, 1.27]) and 18 months (γ = 0.55 [95% CI: 0.12, 1.02]) using the GNE-DPM. CONCLUSION: ManNAc showed long-term safety, biochemical efficacy consistent with the intended mechanism of action, and preliminary evidence clinical efficacy in patients with GNE myopathy.

Norepinephrine preferentially modulates memory CD8 T cell function inducing inflammatory cytokine production and reducing proliferation in response to activation.

BACKGROUND: Norepinephrine (NE) is one of the primary catecholamines of the sympathetic nervous system released during a stress response and plays an important role in modulating immune function. NE binds to the adrenergic receptors on immune cells, including T cells, resulting in either suppressed or enhanced function depending on the type of cell, activation status of the cell, duration of NE exposure and concentration of NE. Here, we aim to analyze the effects of NE on the functionality of naïve (Tn), central memory (Tcm) and effector memory (Tem) CD8 T cells. METHODS: We isolated CD8 T cell subsets from healthy human adults and treated cells in vitro with NE (1×10(-6)M) for 16h; we then stimulated NE treated and untreated CD8 T cell subsets with antibodies for CD3 and CD28 for 24 and 72h. We assessed the level of beta-2 adrenergic receptor (ADRB2) expression in these cells as well as global gene expression changes in NE treated Tcm cells by microarray analysis. Altered expressed genes after NE treatment were identified and further confirmed by RT-qPCR, and by ELISA for protein changes. We further determined whether the observed NE effects on memory CD8 T cells are mediated by ADRB2 using specific adrenergic receptor agonist and antagonists. Finally, we examined the levels of mRNA and protein of the NE-induced genes in healthy adults with high serum levels of NE (>150pg/mL) compared to low levels (<150pg/mL). RESULTS: We found that memory (Tcm and Tem) CD8 T cells expressed a significantly higher level of ADRB2 compared to naïve cells. Consequently, memory CD8 T cells were significantly more sensitive than naïve cells to NE induced changes in gene expressions in vitro. Global gene expression analysis revealed that NE induced an elevated expression of inflammatory cytokines and chemokines in resting and activated memory CD8 T cells in addition to a reduced expression of growth-related cytokines. The effects of NE on memory CD8 T cells were primarily mediated by ADRB2 as confirmed by the adrenergic receptor agonist and antagonist assays. Finally, individuals with high serum levels of NE had similar elevated gene expressions observed in vitro compared to the low NE group. CONCLUSIONS: Our results demonstrate that NE preferentially modulates the functions of memory CD8 T cells by inducing inflammatory cytokine production and reducing activation-induced memory CD8 T cell expansion.

Qualitative inquiry: a method for validating patient perceptions of palliative care while enrolled on a cancer clinical trial.

BACKGROUND: Palliative care is a vital component of patient-centered care. It has increasingly become central to the management and care of seriously ill patients by integrating physical, psychosocial, and spiritual supportive services. Through qualitative inquiry, this paper examines cancer patients' perceptions of the process and outcomes of the pain and palliative care consultative services they received while enrolled in a clinical trial. METHODS: A qualitative analysis of open-ended questions was conducted from a sub-sample of patients (n = 34) with advanced cancers enrolled in a randomized controlled trial exploring the efficacy of a palliative care consult service. Two open-ended questions focused on patient perceptions of continued participation on their primary cancer clinical trials and their perceptions of interdisciplinary communication. RESULTS: THREE OVERARCHING THEMES EMERGED WHEN ASKED WHETHER RECEIVING PAIN AND PALLIATIVE CARE SERVICES MADE THEM MORE LIKELY TO REMAIN ENROLLED IN THEIR PRIMARY CANCER CLINICAL TRIAL: patients' past experiences with care, self-identified personal characteristics and reasons for participation, and the quality of the partnership. Four themes emerged related to interdisciplinary communication including: the importance of developing relationships, facilitating open communication, having quality communication, and uncertainty about communication between the cancer clinical trial and palliative care teams. CONCLUSIONS: Our findings suggest the importance of qualitative inquiry methods to explore patient perceptions regarding the efficacy of palliative care services for cancer patients enrolled in a cancer clinical trial. Validation of patient perceptions through qualitative inquiry regarding their pain and palliative care needs can provide insight into areas for future implementation research. TRIAL REGISTRATION: NIH Office of Human Subjects Research Protection OHSRP5443 and University of Pennsylvania 813365.

Evaluating Elements of the Care Partner Experience in Individuals Who Care for People with Alzheimer's Disease Across the Severity Spectrum.

INTRODUCTION: Non-professional care partners play an important and often evolving role in the care of persons living with Alzheimer's disease (PLWAD). We investigated two elements of the care partner experience, namely time and strain incurred by care partners providing care to PLWAD across the severity spectrum. METHODS: Data gathered from the Alzheimer's Disease Patient and Caregiver Engagement (AD PACE) What Matters Most (WMM) study series were analyzed to determine how much time care partners spent providing care to PLWAD based on where the care recipients lived. Additionally, quantitative assessments of weekly hours providing care and the strain experienced by care partners were conducted using the UsAgainstAlzheimer's A-LIST Insights Series survey, which included the Modified Caregiver Strain Index (MCSI). Finally, a targeted literature review was conducted to contextualize findings and characterize the existing literature landscape. RESULTS: Care partners in the AD PACE WMM studies (n = 139) spent significantly more hours providing care for recipients who lived with someone (mean ± standard deviation [SD], 57.3 ± 44.3 h/week) than for recipients who lived alone (26.0 ± 12.0 h/week) (P = 0.0096) or lived in assisted living/nursing home (23.6 ± 14.4 h/week) (P = 0.0002). In the A-LIST Insights Series survey, care partners provided an overall mean (± SD) 58.1 ± 53.0 h of direct care each week, with caregiving hours increasing with increasing severity of AD/AD-related dementias (AD/ADRD). Additionally, care partners for recipients with mild (n = 14), moderate (n = 111), and severe AD/ADRD (n = 91) had overall mean MCSI scores of 9.0 ± 3.8 (range 2-14), 13.3 ± 4.8 (range 4-23), and 17.5 ± 5.3 (range 4-26), respectively, with higher scores suggesting greater care partner strain. CONCLUSIONS: Persons living with AD require increasing levels of care along the spectrum of disease, and even individuals with early disease need care from partners. Early interventions that slow progression of AD and programs that improve family function may have beneficial impact on the experiences of care partners for recipients with mild, moderate, or severe AD.

Assessing What Matters to People Affected by Alzheimer's Disease: A Quantitative Analysis.

INTRODUCTION: In this phase of the ongoing What Matters Most study series, designed to evaluate concepts that are meaningful to people affected by Alzheimer's disease (AD), we quantified the importance of symptoms, impacts, and outcomes of AD to people at risk for or with AD and care partners of people with AD. METHODS: We administered a web-based survey to individuals at risk for or with AD (Group 1: unimpaired cognition with evidence of AD pathology; Group 2: AD risk factors and subjective cognitive complaints/mild cognitive impairment; Group 3: mild AD) and to care partners of individuals with moderate AD (Group 4) or severe AD (Group 5). Respondents rated the importance of 42 symptoms, impacts, and outcomes on a scale ranging from 1 ("not at all important") to 5 ("extremely important"). RESULTS: Among the 274 respondents (70.4% female; 63.1% white), over half of patient respondents rated all 42 items as "very important" or "extremely important," while care partners rated fewer items as "very important" or "extremely important." Among the three patient groups, the minimum (maximum) mean importance rating for any item was 3.4 (4.6), indicating that all items were at least moderately to very important. Among care partners of people with moderate or severe AD, the minimum (maximum) mean importance rating was 2.1 (4.4), indicating that most items were rated as at least moderately important. Overall, taking medications correctly, not feeling down or depressed, and staying safe had the highest importance ratings among both patients and care partners, regardless of AD phase. CONCLUSION: Concepts of importance to individuals affected by AD go beyond the common understanding of "cognition" or "function" alone, reflecting a desire to maintain independence, overall physical and mental health, emotional well-being, and safety. Preservation of these attributes may be key to understanding whether interventions deliver clinically meaningful outcomes.

Development of a novel PRO instrument for use in familial chylomicronemia syndrome.

BACKGROUND: Familial chylomicronemia syndrome (FCS), a rare genetic disorder characterized by high levels of circulating triglycerides, negatively impacts multiple organs, including the liver and pancreas. OBJECTIVE: The objective of this study was to develop and support the content validity of a novel patient-reported outcome (PRO) measure addressing FCS symptoms and impacts. To facilitate use in clinical trials of new treatments, evidence supporting the new measure needed to be consistent with regulatory guidance and requirements. METHODS: A pool of items addressing symptoms and impacts of FCS was initially developed based on data from a large burden-of-illness study with patients with FCS as well as a review of available literature and existing PRO measures. Two rounds of qualitative interviews were conducted with patients with FCS (N = 10) to refine the draft items and support the measure's content validity. Each interview began with concept elicitation followed by cognitive debriefing of the draft FCS measure. RESULTS: Patient-reported symptoms and impacts of FCS were generally consistent with those identified by the burden-of-illness study; abdominal pain was particularly prevalent and salient for patients. Suggested changes to the draft item pool were generally minor. Comprehensibility and ease of completion for the final instrument were confirmed during the second set of interviews. CONCLUSION: The content validity of the final 17-item FCS Symptoms and Impacts Scale is strongly supported by patient input gathered through both a large burden-of-illness study and qualitative research. To further support use in clinical trials, psychometric evaluation of the measure is underway.

Qualitative study: burden of menopause-associated vasomotor symptoms (VMS) and validation of PROMIS Sleep Disturbance and Sleep-Related Impairment measures for assessment of VMS impact on sleep.

PURPOSE: We evaluated the impact of menopause-associated vasomotor symptoms (VMS) on sleep. We also sought to establish the content validity of Patient-Reported Outcomes Measurement Information System (PROMIS) short form Sleep-Related Impairment and Sleep Disturbance measures in postmenopausal women with moderate to severe VMS. METHODS: Cross-sectional, in-person, qualitative interviews were conducted in the United States (Texas, Illinois) and European Union (UK, France) with women aged 40-64 years experiencing moderate to severe VMS (≥35/wk). Main outcomes were impact of VMS on sleep based on concept elicitation and content validity of PROMIS Sleep-Related Impairment and Sleep Disturbance short forms via cognitive debriefing. RESULTS: Thirty-two women (US: n = 16; EU: n = 16) participated. A majority (US: 93.8%; EU: 93.8%) said VMS affected sleep; specifically, they had sleep interrupted by sweating or overheating and had difficulty returning to sleep. Sleep disturbance was the most bothersome aspect of VMS (US: 75%; EU: 50%). VMS-associated sleep disturbance affected next-day work productivity, mood, relationships, daily activities, concentration, social activities, and physical health. Participants found both PROMIS sleep measures relevant and easy to answer; the Sleep Disturbance measure was considered the most relevant. Participants had no difficulty remembering their experiences over the 7-day recall period and found the response options to be distinct. CONCLUSION: VMS associated with menopause significantly interferes with sleep and next-day functioning (e.g., work productivity), supporting assessment of sleep outcomes in studies evaluating treatment of VMS. Women with moderate to severe VMS found that the PROMIS Sleep-Related Impairment and Sleep Disturbance short forms assessed constructs important to understanding sleep in the context of menopause-associated VMS.

Development of a Patient-Reported Outcome Measure for Non-Alcoholic Steatohepatitis (NASH-CHECK): Results of a Qualitative Study.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease characterized by excessive liver fat accumulation, inflammation, cell injury, and fibrosis. It is viewed as largely asymptomatic in its earlier (non-cirrhotic) stages, and information on the patient-perceived impact of NASH is scarce. OBJECTIVE: This study aimed to develop a NASH-specific patient-reported outcome (PRO) measure (NASH-CHECK) for use as a trial endpoint, using methods compliant with regulatory expectations. METHODS: A NASH conceptual model was developed based on the literature and clinical/patient expert review. The model guided concept elicitation (CE) interviews in patients with non-cirrhotic NASH recruited via a US tertiary care center. NASH-CHECK content was generated via thematic analysis of CE data and review by clinical/patient experts. Cognitive debriefing (CD) interviews with US patients evaluated content validity. RESULTS: The literature review confirmed that NASH impacts on functioning and health-related quality of life (HRQoL). Overall, 23 CE and 20 CD interviews were conducted. Key symptoms reported in CE interviews included pain in the upper-right abdomen (n = 14), fatigue (n = 18), poor sleep quality (n = 12), impaired memory (n = 13), and reduced focus (n = 11); key HRQoL impacts included impaired physical functioning, reduced ability to conduct daily living tasks, reduced quality of relationships, low mood, anxiety, and self-consciousness. The 52-item first-draft NASH-CHECK was reduced to 31 items based on patient feedback on item relevance, acceptability, and comprehension. CONCLUSIONS: The interviews revealed key symptoms and broad HRQoL impacts of NASH. As a disease-specific PRO measure assessing symptoms and HRQoL, the NASH-CHECK is relevant, comprehensive, and acceptable to patients and clinicians.

Exploring the Impact of Fatigue in Progressive Multiple Sclerosis: A Mixed-Methods Analysis.

BACKGROUND: Patient-focused literature on fatigue in progressive forms of multiple sclerosis (MS) is sparse. This study aimed to explore progressive MS patients' experiences of fatigue. METHODS: Adult patients in the United States with primary progressive MS (n=21) and secondary progressive MS (n=23), recruited from research panels, completed the following PRO measures: Patient Global Impression of Severity (Fatigue) (PGI-F); Fatigue Scale of Motor and Cognitive Functions (FSMC); Modified Fatigue Impact Scale (MFIS); Patient Health Questionnaire, two-item version (PHQ-2); and Patient Determined Disease Steps (PDDS). Patients subsequently participated in a 45-minute semistructured telephone interview and were asked to describe their MS symptoms and to comment on how MS affected their day-to-day lives. More detailed questions followed on the nature of their fatigue, including symptoms, impacts, frequency, and bothersomeness. RESULTS: Patients' mean age was 52.5 years, mean time since diagnosis was 14.7 years, and 81.8% were female. 79.5% of patients were unemployed and/or receiving disability benefits. Of all spontaneously reported MS symptoms, fatigue was the most common (n=38, 86.4%), followed by ambulation problems (n=31, 70.5%) and muscle weakness (n=25, 56.8%). Patients used the words "tired," "exhausted," "wiped out," and having "little or no energy" to describe their fatigue. More patients rated fatigue as their "most troubling symptom" (n=17, 38.6%) compared with other MS-related symptoms. Half of patients reported feeling constantly fatigued, and more than 90% reported experiencing fatigue at least daily. The top three most frequently reported negative impacts of fatigue were social functioning, emotional well-being, and cognitive functioning (all >80%). Patients described themselves as "homebodies," as fatigue limited their social interactions with friends and family and impacted the types of activities they could participate in. Patients attributed their inability to think clearly or focus for long periods of time to their fatigue. Patients also reported experiencing depression and anxiety because of their fatigue, which would often have further negative effects on their relationships with friends and family. On the fatigue PRO measures, mean (standard deviation) scores were 75.2 (14.7) on the FSMC and 55.0 (15.2) on the MFIS. Most participants scored in the "high" fatigue category on the FSMC (84.1%) and above the clinically significant fatigue threshold (86.4%). MFIS and FSMC total scores correlated with PGI-F (polyserial correlations r=0.74 and r=0.62, both p<0.01) and PHQ-2 (r=0.56 and r=0.57, both p<0.01), but not with PDDS (r=0.09 and r=0.02, both p>0.05). CONCLUSIONS: Fatigue is a common, troublesome, and disabling symptom which has a profound impact on patients' daily lives, as evidenced by qualitative analyses and high scores on established fatigue measures observed in this sample. These findings provide insights into the burden of fatigue and can inform its measurement in both clinical and research settings. Treatments that improve the symptoms of fatigue or prevent exacerbations are needed for patients with progressive MS.

Assessing what matters most to patients with or at risk for Alzheimer's and care partners: a qualitative study evaluating symptoms, impacts, and outcomes.

BACKGROUND: The What Matters Most (WMM) study was initiated to evaluate symptoms, AD-related impacts, treatment-related needs, preferences, and priorities among individuals with or at risk for Alzheimer's disease (AD) and their care partners. The objective of this qualitative study phase was to identify a comprehensive set of concepts of interest that are meaningful to individuals across the AD continuum. METHODS: Interviews were conducted with 60 clinically referred individuals and care partners across 5 AD stages (n = 12 each): group 1 (non-clinically impaired individuals with AD pathology), group 2 (individuals with mild cognitive impairment and AD pathology), group 3 (individuals with mild AD), group 4 (individuals with moderate AD and their care partners), and group 5 (care partners of individuals with severe AD). Interviews were conducted by experienced interviewers, audio-recorded, and transcribed. Dominant trends were identified in each interview and compared across subsequent interviews to generate themes or patterns in descriptions of AD symptoms, impacts, and desired treatment outcomes. RESULTS: All participants endorsed current issues related to memory; nearly all participants (n = 55; 92%) across the five groups endorsed symptoms related to communication and language. Groups 1-3 reported an impact on mood/emotions (n = 23; 64%) and a decrease in social activities or outgoingness (n = 17; 47%). Current and future concerns reported by the overall sample included memory (n = 48; 80%), dependence (n = 40; 67%), and "other" concerns (n = 33; 55.0%) (e.g., uncertainty about the future, burdening others). The most desired AD treatment outcomes were improvement or restoration of memory (n = 40; 67%) and stopping AD progression (n = 35; 58.3%). Group-level differences were observed in the symptoms, impacts, and desired treatment outcomes among patients and care partners across the AD continuum. CONCLUSIONS: Cognitive functioning issues-particularly in memory and communication-are present even in preclinical and early-stage AD, including among those without a formal AD diagnosis. While the impacts of AD vary across the disease-severity spectrum, improved memory and disease modification were treatment outcomes considered most important to participants across all 5 AD stages. Neuropsychological assessments traditionally used in AD clinical trials may not evaluate the often-subtle concepts that are important to patients and care partners. Results from this study will inform the second phase of the WMM project-a quantitative study to elicit the relative importance of these concepts of interest to people at risk for and living with AD and their care partners.

Patient reported outcomes in GNE myopathy: incorporating a valid assessment of physical function in a rare disease.

BACKGROUND: The aim of this analysis was to evaluate the psychometric properties of three patient reported outcome (PRO) measures characterizing physical function in GNE myopathy: the Human Activity Profile, the Inclusion Body Myositis Functional Rating Scale, and the Activities-specific Balance Confidence scale. METHODS: This analysis used data from 35 GNE myopathy subjects participating in a natural history study. For construct validity, correlational and known-group analyses were between the PROs and physical assessments. Reliability of the PROs between baseline and 6 months was evaluated using the intra-class correlation coefficient model; internal consistency was tested with Cronbach's alpha. RESULTS: The hypothesized moderate positive correlations for construct validity were supported; the strongest correlation was between the human activity profile adjusted activity score and the adult myopathy assessment endurance subscale score (r = 0.81; p < 0.0001). The PROs were able to discriminate between known high and low functioning groups for the adult myopathy assessment tool. Internal consistency of the PROs was high (α > 0.8) and there was strong reliability (ICC >0.62). CONCLUSION: The PROs are valid and reliable measures of physical function in GNE myopathy and should be incorporated in investigations to better understand the impact of progressive muscle weakness on physical function in this rare disease population. Implications for Rehabilitation GNE myopathy is a rare muscle disease that results in slow progressive muscle atrophy and weakness, ultimately leading to wheelchair use and dependence on a caregiver. There is limited knowledge on the impact of this disease on the health-related quality of life, specifically physical function, of this rare disease population. Three patient reported outcomes have been shown to be valid and reliable in GNE myopathy subjects and should be incorporated in future investigations to better understand how progressive muscle weakness impacts physical functions in this rare disease population. The patient reported outcome scores of GNE myopathy patients indicate a high risk for falls and impaired physical functioning, so it is important clinicians assess and provide interventions for these subjects to maintain their functional capacity.

Identification of an Alu element-mediated deletion in the promoter region of GNE in siblings with GNE myopathy.

BACKGROUND: GNE myopathy is a rare genetic disease characterized by progressive muscle atrophy and weakness. It is caused by biallelic mutations in the GNE gene that encodes for the bifunctional enzyme, uridine diphosphate (UDP)-N-acetylglucosamine (GlcNAc) 2-epimerase/N-acetylmannosamine (ManNAc) kinase. Typical characteristics of GNE myopathy include progressive myopathy, first involving anterior tibialis muscle and sparing the quadriceps, and rimmed vacuoles on muscle biopsy. Identifying biallelic mutations by sequencing of the GNE gene confirms the diagnosis of GNE myopathy. In a subset of patients, diagnostic confirmation is challenged by the identification of mutations in only one allele, suggesting mutations in deep intronic regions or regulatory regions. METHODS: We performed targeted sequencing and copy number variant (CNV) analysis of GNE in two siblings who clinically presented with GNE myopathy. Further molecular and biochemical studies were done to characterize the effect of a previously uncharacterized GNE mutation. RESULTS: We report two siblings of Indian descent with characteristic features of GNE myopathy, including progressive skeletal muscle weakness initially involving the anterior tibialis, and rimmed vacuoles on muscle biopsy, in which a heterozygous mutation, p.Val727Met, was identified in both affected siblings, but no other deleterious variants in either coding region or exon-intron boundaries of the gene. Subsequent insertion/deletion analysis identified a novel 11.3-kb deletion (Chr9 [GRCh37]: g.36257583_36268910del) encompassing the GNE promoter region, with breakpoints residing in Alu repeats. Gene expression analysis revealed reduced GNE mRNA and protein levels, confirming decreased expression of the deleted allele harboring the deletion. CONCLUSIONS: We have identified GNE as one of the genes susceptible to Alu-mediated recombination. Our findings suggest that the deletion may encompass the promoter or another region necessary for GNE expression. In patients with typical manifestations of GNE myopathy and a single GNE variant identified, copy number variant (CNV) analysis may be useful in arriving at the diagnosis.