Targeted long-read sequencing identifies missing disease-causing variation.

Despite widespread clinical genetic testing, many individuals with suspected genetic conditions lack a precise diagnosis, limiting their opportunity to take advantage of state-of-the-art treatments. In some cases, testing reveals difficult-to-evaluate structural differences, candidate variants that do not fully explain the phenotype, single pathogenic variants in recessive disorders, or no variants in genes of interest. Thus, there is a need for better tools to identify a precise genetic diagnosis in individuals when conventional testing approaches have been exhausted. We performed targeted long-read sequencing (T-LRS) using adaptive sampling on the Oxford Nanopore platform on 40 individuals, 10 of whom lacked a complete molecular diagnosis. We computationally targeted up to 151 Mbp of sequence per individual and searched for pathogenic substitutions, structural variants, and methylation differences using a single data source. We detected all genomic aberrations-including single-nucleotide variants, copy number changes, repeat expansions, and methylation differences-identified by prior clinical testing. In 8/8 individuals with complex structural rearrangements, T-LRS enabled more precise resolution of the mutation, leading to changes in clinical management in one case. In ten individuals with suspected Mendelian conditions lacking a precise genetic diagnosis, T-LRS identified pathogenic or likely pathogenic variants in six and variants of uncertain significance in two others. T-LRS accurately identifies pathogenic structural variants, resolves complex rearrangements, and identifies Mendelian variants not detected by other technologies. T-LRS represents an efficient and cost-effective strategy to evaluate high-priority genes and regions or complex clinical testing results.

How tyrannical leadership relates to workplace bullying and turnover intention over time: The role of coworker support.

INTRODUCTION: In light of the deleterious consequences associated with workplace bullying, it is important to identify the work-related factors that can contribute to the presence of bullying behaviors over time. Up to now, most research on the topic has investigated job characteristics (presence of job demands, absence of job resources) as contributing factors of workplace bullying. Given the key role leadership plays in shaping employees' work environment, this study aims to better understand how harmful forms of leadership relate to bullying behaviors over time and, subsequently, to employee functioning. METHODS: More specifically, this longitudinal study (two data collections over a 3-month period) conducted among a sample of Canadian employees (T1 n = 600, T2 n = 422) assesses the temporal relationship between tyrannical leadership, exposure to bullying behaviors, and turnover intention, as well as the moderating role of perceived coworker support in the relationship between tyrannical leadership and bullying behaviors. RESULTS: Results from cross-lagged analyses show that, controlling for baseline effects, T1 tyrannical leadership positively predicts T2 exposure to bullying behaviors and that T1 bullying behaviors positively predict T2 turnover intention. T1 coworker support did not significantly buffer the relationship between T1 tyrannical leadership and T2 exposure to bullying behaviors, although it did significantly predict, negatively so, T2 turnover intention. CONCLUSION: The present study provides valuable insight into the social contextual determinants of bullying behaviors and highlights the destructive nature of tyrannical leadership. Furthermore, this study illustrates the importance of fostering supportive behaviors between colleagues, as this important social resource can play a key role in reducing turnover intention over time.

Diagnosis and management of glycogen storage disease type IV, including adult polyglucosan body disease: A clinical practice resource.

Glycogen storage disease type IV (GSD IV) is an ultra-rare autosomal recessive disorder caused by pathogenic variants in GBE1 which results in reduced or deficient glycogen branching enzyme activity. Consequently, glycogen synthesis is impaired and leads to accumulation of poorly branched glycogen known as polyglucosan. GSD IV is characterized by a remarkable degree of phenotypic heterogeneity with presentations in utero, during infancy, early childhood, adolescence, or middle to late adulthood. The clinical continuum encompasses hepatic, cardiac, muscular, and neurologic manifestations that range in severity. The adult-onset form of GSD IV, referred to as adult polyglucosan body disease (APBD), is a neurodegenerative disease characterized by neurogenic bladder, spastic paraparesis, and peripheral neuropathy. There are currently no consensus guidelines for the diagnosis and management of these patients, resulting in high rates of misdiagnosis, delayed diagnosis, and lack of standardized clinical care. To address this, a group of experts from the United States developed a set of recommendations for the diagnosis and management of all clinical phenotypes of GSD IV, including APBD, to support clinicians and caregivers who provide long-term care for individuals with GSD IV. The educational resource includes practical steps to confirm a GSD IV diagnosis and best practices for medical management, including (a) imaging of the liver, heart, skeletal muscle, brain, and spine, (b) functional and neuromusculoskeletal assessments, (c) laboratory investigations, (d) liver and heart transplantation, and (e) long-term follow-up care. Remaining knowledge gaps are detailed to emphasize areas for improvement and future research.

Physical therapy assessment and whole-body magnetic resonance imaging findings in children with glycogen storage disease type IIIa: A clinical study and review of the literature.

INTRODUCTION: Early recognized manifestations of GSD III include hypoglycemia, hepatomegaly, and elevated liver enzymes. Motor symptoms such as fatigue, muscle weakness, functional impairments, and muscle wasting are typically reported in the 3rd to 4th decade of life. OBJECTIVE: In this study, we investigated the early musculoskeletal findings in children with GSD IIIa, compared to a cohort of adults with GSD IIIa. METHODS: We utilized a comprehensive number of physical therapy outcome measures to cross-sectionally assess strength and gross motor function including the modified Medical Research Council (mMRC) scale, grip and lateral/key pinch, Gross Motor Function Measure (GMFM), Gait, Stairs, Gowers, Chair (GSGC) test, 6 Minute Walk Test (6MWT), and Bruininks-Oseretsky Test of Motor Proficiency Ed. 2 (BOT-2). We also assessed laboratory biomarkers (AST, ALT, CK and urine Glc4) and conducted whole-body magnetic resonance imaging (WBMRI) to evaluate for proton density fat fraction (PDFF) in children with GSD IIIa. Nerve Conduction Studies and Electromyography results were analyzed where available and a thorough literature review was conducted. RESULTS: There were a total of 22 individuals with GSD IIIa evaluated in our study, 17 pediatric patients and 5 adult patients. These pediatric patients demonstrated weakness on manual muscle testing, decreased grip and lateral/key pinch strength, and decreased functional ability compared to non-disease peers on the GMFM, 6MWT, BOT-2, and GSGC. Additionally, all laboratory biomarkers analyzed and PDFF obtained from WBMRI were increased in comparison to non-diseased peers. In comparison to the pediatric cohort, adults demonstrated worse overall performance on functional assessments demonstrating the expected progression of disease phenotype with age. CONCLUSION: These results demonstrate the presence of early musculoskeletal involvement in children with GSD IIIa, most evident on physical therapy assessments, in addition to the more commonly reported hepatic symptoms. Muscular weakness in both children and adults was most significant in proximal and trunk musculature, and intrinsic musculature of the hands. These findings indicate the importance of early assessment of patients with GSD IIIa for detection of muscular weakness and development of treatment approaches that target both the liver and muscle.

When workload predicts exposure to bullying behaviours in nurses: The protective role of social support and job recognition.

AIMS: This study examined the moderating role of two resources (social support and recognition) in the longitudinal relationship between workload and bullying behaviours in nurses. DESIGN: A two-wave (12-month) longitudinal study was conducted. METHOD: French-Canadian nurses (n = 279) completed an online survey (October 2014 and October 2015) assessing their perceptions of job characteristics within the work environment (workload, social support, job recognition) as well as exposure to negative behaviours at work. RESULTS: Workload positively predicted exposure to bullying behaviours over time, but only when job recognition and social support were low. Workload was unrelated to bullying when social support was high and was negatively related to bullying when job recognition was high. CONCLUSION: This study aligns with the work environment hypothesis, showing that poorly designed and stressful job environments provide fertile ground for bullying behaviours. IMPACT: Bullying is a growing concern in the nursing profession that not only undermines nurses' well-being but also compromises patient safety and care. It is thus important to identify work-related factors that can contribute to the presence of bullying behaviours in nurses in the hopes of reducing their occurrence and repercussions. This study contributes to this endeavour and identifies two key social coping resources that can help manage the stress associated with workload, resulting in less perceived bullying behaviour among nurses.

Workaholism, presenteeism, work-family conflicts and personal and work outcomes: Testing a moderated mediation model.

AIMS AND OBJECTIVES: While research suggests that nurses who experience work-family conflicts (WFC) are less satisfied and perform less well, these negative outcomes may be more important for some nurses. This study proposes a mediated moderation model wherein the interaction between two individual characteristics, workaholism and presenteeism, relates to family life satisfaction and work performance with WFC mediating these relationships. BACKGROUND: Because a limited number of nursing studies have examined the potential outcomes of workaholism and presenteeism, we extend past research to address the question of how workaholism and presenteeism affect nurses' functioning. DESIGN: We used a cross-sectional questionnaire survey design to test our hypotheses. STROBE guidelines for cross-sectional research were followed in designing and reporting this study. METHODS: A total of 419 nurses completed measures of workaholism, presenteeism, WFC, family life satisfaction and work performance. RESULTS: Results revealed that the relationships between workaholism and outcomes (family life satisfaction and work performance) through WFC were stronger among nurses characterised by high levels of presenteeism. CONCLUSIONS: These results revealed that high presenteeism may exacerbate the negative relationships of workaholism to family life satisfaction and work performance through WFC. RELEVANCE TO CLINICAL PRACTICE: Healthcare organisations and managers should consider addressing work environment factors in their efforts to reduce the negative outcomes (e.g., low family satisfaction and work performance) of nurses' workaholism, presenteeism and WFC.

Predicting nurses' occupational commitment and turnover intention: The role of autonomous motivation and supervisor and coworker behaviours.

AIM: To examine whether supportive supervisor (transformational leadership) and coworker (autonomy-supportive) behaviours predict occupational commitment and turnover intention over time through autonomous motivation. BACKGROUND: Nurse turnover is a serious issue in several countries, straining the efficiency of the healthcare system and compromising both the quality and accessibility of healthcare. METHOD: Longitudinal data were collected over 12 months from 387 French-Canadian registered nurses. Structural equation modeling was used to test the hypothesized model. RESULTS: The relationships between predictors at Time 1 (supervisor and coworker behaviours) and occupational commitment and turnover intention at Time 2 are mediated by autonomous motivation at Time 1. CONCLUSION: In times of global scarcity, the present findings provide insights into how the healthcare work environment acts on nurses' occupational turnover and commitment. IMPLICATIONS FOR NURSING MANAGEMENT: Healthcare organizations are advised to foster supportive work environments and promote autonomous motivation to sustain the nursing workforce.

Whole-body magnetic resonance imaging in late-onset Pompe disease: Clinical utility and correlation with functional measures.

Whole-body magnetic resonance imaging (WBMRI) has clinical utility in measuring the amount of fatty infiltration in late-onset Pompe disease (LOPD). Muscle strength and function testing also provide valuable insight to the progression of myopathy seen in these patients. The main purpose of this study was to determine how closely muscle strength and functional testing correlate to the amount of fatty infiltration seen on WBMRI. LOPD patients were followed longitudinally and WBMRI, muscle strength testing using the modified Medical Research Council (mMRC) scale, muscle function testing using the Gait, Stairs, Gowers, Chair (GSGC) score, and labs including urinary glucose tetrasaccharide (Glc4) were performed at each visit. The amount of fat seen on WBMRI was quantified using proton density fat fraction (PDFF) and correlated to appropriate muscle strength and functional tests. Nineteen patients with LOPD aged 10 to 67 years were followed for a 1 to 2 year duration. There was a small increase of 1.26% (±2.57%) in overall PDFF per year in patients on ERT. Muscle strength (mMRC) and functional testing (GSGC) correlated highly with PDFF (r = -.7596, P < .0001 and r = .8267, P < .0001, respectively). Time to carry out individual tasks of the GSGC also correlated highly with PDFF of the muscles involved. Glc4 levels were normal on most visits (27/39) despite varying severity of muscle weakness in patients. Muscle strength and GSGC scores correlate highly with PDFF values from WBMRI. They may be used in assessing severity of muscle disease and to follow LOPD patients over time.

Fatigue in new registered nurses: A 12-month cross-lagged analysis of its association with work motivation, engagement, sickness absence and turnover intention.

AIM: This longitudinal study examines the motivational factors that explain why and how fatigue acts on new nurses' affective (work engagement), attitudinal (intention to leave the occupation) and behavioural (sickness absence) work outcomes. BACKGROUND: Growing nurse shortage makes it crucial to understand how and why fatigue can cut short the career of nurses. METHODS: This two-wave longitudinal study (baseline, 12-month follow-up) was conducted among 630 French-speaking new registered nurses from Canada. The proposed cross-lagged model was analysed using the EQS statistical software package for structural equation modelling (SEM). RESULTS: Time 1 fatigue was positively related to time 2 controlled motivation (working under internal or external pressure). Taking into account the cross-lagged effects of T1 fatigue on T2 outcomes, T1 controlled motivation was positively associated with T2 sickness absence, whereas T1 autonomous motivation (working because the activity is valued or inherently interesting) was related to all T2 outcomes. CONCLUSION: These findings provide insights into the motivational processes that affect nurses' early career functioning, revealing that distinct forms of motivation explain how fatigue relates to work outcomes. IMPLICATIONS FOR NURSING MANAGEMENT: Organisational efforts to strengthen autonomous over controlled motivation constitute a promising strategy to improve new nurses' well-being and retention in the occupation.

Neutropenia in glycogen storage disease Ib: outcomes for patients treated with granulocyte colony-stimulating factor.

PURPOSE OF REVIEW: Glycogen storage disease Ib (GSD Ib) is characterized by hepatomegaly, hypoglycemia, neutropenia, enterocolitis and recurrent bacterial infections. It is attributable to mutations in G6PT1, the gene for the glucose-6-phosphate transporter responsible for transport of glucose into the endoplasmic reticulum. Neutropenia in GSD Ib is now frequently treated with granulocyte colony-stimulating factor (G-CSF). We formed a cooperative group to review outcomes of the long-term treatment of GSD Ib patients treated with G-CSF. RECENT FINDINGS: The study enrolled 103 patients (48 men and 55 women), including 47 currently adult patients. All of these patients were treated with G-CSF, starting at a median age of 3.8 years (range 0.04-33.9 years) with a median dose of 3.0 mcg/kg/day (range 0.01-93.1 mcg/kg/day) for a median of 10.3 years (range 0.01-29.3 years). Neutrophils increased in response to G-CSF in all patients (median values before G-CSF 0.2 × 10/l, on G-CSF 1.20 x 10/l). Treatment increased spleen size (before G-CSF, 47%, on treatment on G-CSF 76%), and splenomegaly was the dose-limiting adverse effect of treatment (pain and early satiety). Clinical observations and records attest to reduce frequency of infectious events and the severity of inflammatory bowel symptoms, but fever and recurrent infections remain a significant problem. In the cohort of patients followed carefully through the Severe Chronic Neutropenia International Registry, four patients have developed myelodysplasia or acute myeloid leukemia and we are aware of four other cases, (altogether seven on G-CSF, one never treated with G-CSF). Liver transplantation in five patients did not correct neutropenia. Four patients had hematopoietic stem cell transplantation; two adults and two children were transplanted; one adult and one child survived. SUMMARY: GSD Ib is a complex disorder of glucose metabolism causing severe chronic neutropenia. G-CSF is effective to raise blood neutrophil counts and reduce fevers and infections in most patients. In conjunction with other therapies (salicylates, mesalamine sulfasalazine and prednisone), G-CSF ameliorates inflammatory bowel symptoms, but doses must be limited because it increases spleen size associated with abdominal pain.

Liver fibrosis during clinical ascertainment of glycogen storage disease type III: a need for improved and systematic monitoring.

PURPOSE: In glycogen storage disease type III (GSD III), liver aminotransferases tend to normalize with age giving an impression that hepatic manifestations improve with age. However, despite dietary treatment, long-term liver complications emerge. We present a GSD III liver natural history study in children to better understand changes in hepatic parameters with age. METHODS: We reviewed clinical, biochemical, histological, and radiological data in pediatric patients with GSD III, and performed a literature review of GSD III hepatic findings. RESULTS: Twenty-six patients (median age 12.5 years, range 2-22) with GSD IIIa (n = 23) and IIIb (n = 3) were enrolled in the study. Six of seven pediatric patients showed severe fibrosis on liver biopsy (median [range] age: 1.25 [0.75-7] years). Markers of liver injury (aminotransferases), dysfunction (cholesterol, triglycerides), and glycogen storage (glucose tetrasaccharide, Glc4) were elevated at an early age, and decreased significantly thereafter (p < 0.001). Creatine phosphokinase was also elevated with no significant correlation with age (p = 0.4). CONCLUSION: Liver fibrosis can occur at an early age, and may explain the decrease in aminotransferases and Glc4 with age. Our data outlines the need for systematic follow-up and specific biochemical and radiological tools to monitor the silent course of the liver disease process.

Diagnosis and management of glycogen storage diseases type VI and IX: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG).

PURPOSE: Glycogen storage disease (GSD) types VI and IX are rare diseases of variable clinical severity affecting primarily the liver. GSD VI is caused by deficient activity of hepatic glycogen phosphorylase, an enzyme encoded by the PYGL gene. GSD IX is caused by deficient activity of phosphorylase kinase (PhK), the enzyme subunits of which are encoded by various genes: ɑ (PHKA1, PHKA2), ß (PHKB), É£ (PHKG1, PHKG2), and δ (CALM1, CALM2, CALM3). Glycogen storage disease types VI and IX have a wide spectrum of clinical manifestations and often cannot be distinguished from each other, or from other liver GSDs, on clinical presentation alone. Individuals with GSDs VI and IX can present with hepatomegaly with elevated serum transaminases, ketotic hypoglycemia, hyperlipidemia, and poor growth. This guideline for the management of GSDs VI and IX was developed as an educational resource for health-care providers to facilitate prompt and accurate diagnosis and appropriate management of patients. METHODS: A national group of experts in various aspects of GSDs VI and IX met to review the limited evidence base from the scientific literature and provided their expert opinions. Consensus was developed in each area of diagnosis, treatment, and management. Evidence bases for these rare disorders are largely based on expert opinion, particularly when targeted therapeutics that have to clear the US Food and Drug Administration (FDA) remain unavailable. RESULTS: This management guideline specifically addresses evaluation and diagnosis across multiple organ systems involved in GSDs VI and IX. Conditions to consider in a differential diagnosis stemming from presenting features and diagnostic algorithms are discussed. Aspects of diagnostic evaluation and nutritional and medical management, including care coordination, genetic counseling, and prenatal diagnosis are addressed. CONCLUSION: A guideline that will facilitate the accurate diagnosis and optimal management of patients with GSDs VI and IX was developed. This guideline will help health-care providers recognize patients with GSDs VI and IX, expedite diagnosis, and minimize adverse sequelae from delayed diagnosis and inappropriate management. It will also help identify gaps in scientific knowledge that exist today and suggest future studies.

Early-onset of symptoms and clinical course of Pompe disease associated with the c.-32-13 T > G variant.

BACKGROUND: Individuals with late-onset Pompe disease (LOPD) and the common c.-32-13 T > G variant are widely thought to have milder, adult-onset disease. This belief, and the consequent low suspicion of clinical involvement in children, has led to delays in diagnosis and treatment initiation in patients with early onset of symptoms. Previous reports of LOPD in children do not include description of the early-onset phenotype. This description of signs and symptoms, some of which are subtle and less known, is important to facilitate prompt identification and appropriate treatment in symptomatic children. METHODS: Retrospective chart review of a cohort of 84 LOPD patients with the c.-32-13 T > G variant was conducted to identify patients diagnosed clinically (as opposed to through newborn screening) who had clinically documented symptom-onset within the first two years of life. RESULTS: Four patients had early onset of symptoms, with age at onset ranging from 10 days to 20 months. Initial symptoms included delay in achievement of gross motor milestones, signs of proximal muscle weakness, swallow and feeding difficulties, and sleep apnea. Early and characteristic alterations in posture and movement were identified in all patients. Age at diagnosis ranged from 10 months to 26 months. Median age at enzyme replacement therapy (ERT) initiation was 23.5 months. Despite ERT, progression of musculoskeletal involvement and residual muscle weakness was evident in all patients, as evidenced by ptosis, myopathic facies, scoliosis, lumbar lordosis, scapular winging, and trunk and lower extremity weakness. Standardized functional assessments showed gross motor function below age level as measured by the Alberta Infant Motor Scales, the Peabody Developmental Motor Scales-2, the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, and the six-minute walk test. CONCLUSIONS: Onset of symptoms including delay in achievement of gross motor milestones, signs of proximal muscle weakness, swallow and feeding difficulties, and sleep apnea in the first two years of life is not uncommon in individuals with LOPD and the c.-32-13 T > G variant. Patients with early-onset disease appear to have a more, rapid and severe progression of disease with persistent residual muscle deficits which partially improve with higher doses of ERT. Careful evaluation for specific and characteristic patterns of posture and movement in patients with this variant is necessary to identify those who have early onset of disease. Increased awareness of the early-onset signs and symptoms may also enable early identification of disease onset in children who are diagnosed through newborn screening.

Neuroimaging findings in infantile Pompe patients treated with enzyme replacement therapy.

BACKGROUND: Recombinant human acid α-glucosidase (rhGAA) enzyme replacement therapy (ERT) has prolonged survival in infantile Pompe disease (IPD), but has unmasked central nervous system (CNS) changes. METHODS: Brain imaging, consisting of computed tomography (CT) and/or magnetic resonance imaging (MRI), was performed on 23 patients with IPD (17 CRIM-positive, 6 CRIM-negative) aged 2-38months. Most patients had baseline neuroimaging performed prior to the initiation of ERT. Follow-up neuroimaging was performed in eight. RESULTS: Sixteen patients (70%) had neuroimaging abnormalities consisting of ventricular enlargement (VE) and/or extra-axial cerebrospinal fluid accumulation (EACSF) at baseline, with delayed myelination in two. Follow-up neuroimaging (n=8) after 6-153months showed marked improvement, with normalization of VE and EACSF in seven patients. Two of three patients imaged after age 10years demonstrated white matter changes, with one noted to have a basilar artery aneurysm. CONCLUSIONS: Mild abnormalities on brain imaging in untreated or newly treated patients with IPD tend to resolve with time, in conjunction with ERT. However, white matter changes are emerging as seen in Patients 1 and 3 which included abnormal periventricular white matter changes with subtle signal abnormalities in the basal ganglia and minimal, symmetric signal abnormalities involving the deep frontoparietal cerebral white matter, respectively. The role of neuroimaging as part of the clinical evaluation of IPD needs to be considered to assess for white matter changes and cerebral aneurysms.

Cognitive and academic outcomes in long-term survivors of infantile-onset Pompe disease: A longitudinal follow-up.

This study examines the long-term cognitive and academic outcomes of 11 individuals with infantile onset Pompe disease (IOPD) (median age=11years, 1month, range=5years, 6months through 17years of age) treated with enzyme replacement therapy from an early age. All participants (7 males, 4 females) were administered individual intelligence tests (Wechsler or Leiter scales or both), a measure of their academic skill levels (Woodcock-Johnson Tests of Achievement), and a screening measure of visual-motor integration ability (Beery-Buktenica). Consistent with our earlier findings, median IQ scores for the entire group on the Wechsler (median=84) and Leiter (median=92) scales continue to fall at the lower end of the average range compared to same-aged peers. The median scores for the group on a measure of visual-motor integration (median=76), visual perception (median=74) and motor coordination (median=60) were below average. Two distinct subgroups emerged based on participants' average or below average performance on the majority of academic subtests. Those participants with below average academic skills (n=6) demonstrated average nonverbal cognitive abilities on the Leiter, but had weaknesses in speech and language skills and greater medical involvement. Their profiles were more consistent with a learning disability diagnosis than an intellectual disability. Two of these participants showed a significant decline (15 and 23 points, respectively) on repeated Wechsler scales, but one continued to earn average scores on the Leiter scales where the verbal and motor demands are minimal. Participants with average academic skills (n=5) demonstrated average cognitive abilities (verbal and nonverbal) on the Wechsler scales and less medical involvement. Their speech and language skills appeared to be more intact. However, both groups earned below average median scores on the Beery-Buktenica motor coordination task. This study highlights the importance of using appropriate tests to capture both verbal and nonverbal abilities, considering each individual's motor skills, speech and language abilities, hearing status and native language. This will allow for a more accurate assessment of whether there is a learning disability or an intellectual disability. Long-term outcomes may be related to the stability of an individual's expressive and/or receptive language abilities over time. Changes in the speech and language domain may account for the decline in IQ observed in some IOPD long-term survivors, reflecting a learning disability rather than a decline in overall cognition or an intellectual disability. These observations, in conjunction with neuroimaging, will further our understanding of the neurocognitive profile of long-term IOPD survivors.

Alglucosidase alfa enzyme replacement therapy as a therapeutic approach for a patient presenting with a PRKAG2 mutation.

OBJECTIVE: PRKAG2 syndrome, an autosomal dominant disorder, is characterized by severe infantile hypertrophic cardiomyopathy and heart rhythm disturbances to cases with a later presentation and a spectrum of manifestations including cardiac manifestations, myopathy and seizures. The cardiac features of PRKAG2 resemble the cardiac manifestations of Pompe disease. We present a patient who was initially diagnosed with Pompe disease and treated with alglucosidase-alfa enzyme replacement therapy (ERT); however, he was eventually diagnosed to carrying a PRKAG2 pathogenic gene mutation; he did not have Pompe disease instead he was a carrier for the common adult leaky splice site mutation in the GAA gene. CASE REPORT: At 2.5months, the patient had hypotonia/generalized muscle weakness, a diagnosis of non-classic infantile Pompe disease was made based on low acid alpha-glucosidase activity and the patient started on ERT at 11months. However, 1month later, the patient began to have seizures. As the patient's medical history was somewhat unusual for infantile Pompe disease, further evaluation was initiated and included a glycogen storage disease sequencing panel which showed that the patient had a pathogenic mutation in PRKAG2 which had been reported previously. ERT was discontinued and patient had a progression of motor deficits. ERT was reinitiated by the treating physician, and a clinical benefit was noted. CONCLUSION: This report outlines the benefits of ERT with alglucosidase alfa in a patient with PRKAG2 syndrome, the decline in his condition when the ERT infusions were discontinued, and the significant positive response when ERT was reinitiated.

The emerging phenotype of late-onset Pompe disease: A systematic literature review.

BACKGROUND: Pompe disease is an autosomal recessive disorder caused by deficiency of the lysosomal glycogen-hydrolyzing enzyme acid α-glucosidase (GAA). The adult-onset form, late-onset Pompe disease (LOPD), has been characterized by glycogen accumulation primarily in skeletal, cardiac, and smooth muscles, causing weakness of the proximal limb girdle and respiratory muscles. However, increased scientific study of LOPD continues to enhance understanding of an evolving phenotype. PURPOSE: To expand our understanding of the evolving phenotype of LOPD since the approval of enzyme replacement therapy (ERT) with alglucosidase alfa (Myozyme™/Lumizyme™) in 2006. METHODS: All articles were included in the review that provided data on the charactertistics of LOPD identified via the PubMed database published since the approval of ERT in 2006. All signs and symptoms of the disease that were reported in the literature were identified and included in the review. RESULTS: We provide a comprehensive review of the evolving phenotype of LOPD. Our findings support and extend the knowledge of the multisystemic nature of the disease. CONCLUSIONS: With the advent of ERT and the concurrent increase in the scientific study of LOPD, the condition once primarily conceptualized as a limb-girdle muscle disease with prominent respiratory involvement is increasingly recognized to be a condition that results in signs and symptoms across body systems and structures.

Three cases of multi-generational Pompe disease: Are current practices missing diagnostic and treatment opportunities?

Pompe disease (Glycogen storage disease type II, GSDII, or acid maltase deficiency) is an autosomal recessive metabolic myopathy with a broad clinical spectrum, ranging from infantile to late-onset presentations. In 2015, Pompe disease was added as a core condition to the Recommended Uniform Screening Panel for state newborn screening (NBS). The clinical importance of Pompe disease is evolving with the use of NBS, increasing awareness of the disease, and higher than previously reported disease prevalence; however, current practices miss additional diagnostic and potential treatment opportunities in close relatives of the family proband. In this report, we describe three families with multiple individuals in multiple generations affected by both infantile and late-onset clinical presentations of Pompe disease. The presence of multi-generational disease within these families highlights the importance of subsequent risk assessment through medical history and physical examination, with a low threshold for the screening of a proband's family members. We recommend enzymology (GAA activity assay) as the first screening method, as opposed to targeted mutation analysis, for at-risk family members. Given that the initial symptoms of the slowly progressive late-onset presentation of Pompe disease may be mild or non-specific, enzymatic testing of all parents of affected infants should be considered.

PRKAG2 mutations presenting in infancy.

PRKAG2 encodes the γ2 subunit of AMP-activated protein kinase (AMPK), which is an important regulator of cardiac metabolism. Mutations in PRKAG2 cause a cardiac syndrome comprising ventricular hypertrophy, pre-excitation, and progressive conduction-system disease, which is typically not diagnosed until adolescence or young adulthood. However, significant variability exists in the presentation and outcomes of patients with PRKAG2 mutations, with presentation in infancy being underrecognized. The diagnosis of PRKAG2 can be challenging in infants, and we describe our experience with three patients who were initially suspected to have Pompe disease yet ultimately diagnosed with mutations in PRKAG2. A disease-causing PRKAG2 mutation was identified in each case, with a novel missense mutation described in one patient. We highlight the potential for patients with PRKAG2 mutations to mimic Pompe disease in infancy and the need for confirmatory testing when diagnosing Pompe disease.

Motivational pathways of occupational and organizational turnover intention among newly registered nurses in Canada.

BACKGROUND: Staff turnover is a major issue for health care systems. In a time of labor shortage, it is critical to understand the motivational factors that underlie turnover intention in newly licensed nurses. PURPOSE: To examine whether different forms of motivation (the reasons for which nurses engage in their work) predict intention to quit the occupation and organization through distinct forms (affective and continuance) and targets (occupation and organization) of commitment. METHODS: Cross-sectional data were collected from a sample of 572 French-Canadian newly registered nurses working in public health care in the province of Quebec, Canada. The hypothesized model was tested by structural equation modeling. FINDINGS: Autonomous motivation (nurses accomplish their work primarily out of a sense of pleasure and satisfaction or because they personally endorse the importance or value of their work) negatively predicts intention to quit the profession and organization through target-specific affective commitment. However, although controlled motivation (nurses accomplish their work mainly because of internal or external pressure) is positively associated with continuance commitment to the occupation and organization, it directly predicts, positively so, intention to quit the occupation and organization. CONCLUSION: These results highlight the complexity of the motivational processes at play in the turnover intention of novice nurses, revealing distinct forms of commitment that explain how motivation quality is related simultaneously to intention to quit the occupation and organization. Health care organizations are advised to promote autonomous over controlled motivation to retain newly recruited nurses and sustain the future of the nursing workforce.