bims-glecem 2024-01-14 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2024‒01‒14
six papers selected by
Dipsikha Biswas, Københavns Universitet

Report of an Iranian child with chronic abdominal pain and constipation diagnosed as glycogen storage disease type IX: a case report.
A novel PHKA2 variant in a Chinese boy with glycogen storage diseases type IXa.
Repurposing empagliflozin in individuals with glycogen storage disease Ib: A value-based healthcare approach and systematic benefit-risk assessment.
Glycogen storage disease type III: a mixed-methods study to assess the burden of disease.
Severe CNS involvement in a subset of long-term treated children with infantile-onset Pompe disease.
Exercise-based interventions for cancer cachexia: A systematic review of randomised and non-randomised controlled trials.

J Med Case Rep. 2024 Jan 12. 18(1): 14

Report of an Iranian child with chronic abdominal pain and constipation diagnosed as glycogen storage disease type IX: a case report.

Daniel Zamanfar, Seyed MohammadBagher Hashemi-Soteh, Mobin Ghazaiean, Elham Keyhanian.

  BACKGROUND: Glycogen storage disease type IX is a rare disorder that can cause a wide variety of symptoms depending on the specific deficiency of the phosphorylase kinase enzyme and the organs it affects.CASE PRESENTATION: A 4-and-a-half-year-old Caucasian girl was referred to our clinic with a liver biopsy report indicating a diagnosis of glycogen storage disease. Prior to being referred to our clinic, the patient had been under the care of pediatric gastroenterologists. The patient's initial symptoms included chronic abdominal pain, constipation, and elevated liver transaminase. With the help of the pediatric gastroenterologists, cholestasis, Wilson disease, and autoimmune hepatitis were ruled out. Given that glycogen storage diseases type I and type III are the most common, we initially managed the patient with frequent feedings and a diet that included complex carbohydrates such as a corn starch supplement and a lactose restriction. Following an unfavorable growth velocity and hepatomegaly during the follow-up period, genetic analysis was conducted, which revealed a novel mutation of the phosphorylase kinase regulatory subunit beta gene- a c.C412T (P.Q138x) mutation. As the diagnosis of glycogen storage disease type IX was confirmed, the treatment regimen was altered to a high protein diet (more than 2 g/kg/day) and a low fat diet.
CONCLUSION: Given the mild and varied clinical manifestations of glycogen storage disease type IX, it is possible for the diagnosis to be overlooked. It is important to consider glycogen storage disease type IX in children who present with unexplained hepatomegaly and elevated transaminase levels. Furthermore, due to the distinct management of glycogen storage disease type IX compared with glycogen storage disease type I and glycogen storage disease type III, genetic analysis is essential for an accurate diagnosis.

Keywords:  Glycogen storage disease type IX; Hepatomegaly; Liver; PHKB; Poor growth

DOI:  https://doi.org/10.1186/s13256-023-04295-0
Front Endocrinol (Lausanne). 2023 ;14 1332450

A novel PHKA2 variant in a Chinese boy with glycogen storage diseases type IXa.

Hongdan Zhu, Tao Zhang, Hua Yuan, Yan Chen, Jinlong Ding, Haigang Ding, Xiaoliang Shi, Dalei Gu, Yingying Ma.

  Background: Glycogen storage diseases (GSDs) are a group of heterogeneous inherited metabolic disorders with an incidence of 4%-5%. There are 19 types of GSDs, making diagnosis one of the greatest challenges.Methods: The proband and his parents were referred to our hospital for genetic diagnosis. Ultrasound screening suggested hepatomegaly. A novel insertion variant NM_000292 c.1155_1156insT (p. 386N>*) in PHKA2 gene was identified using trio whole exome sequencing (Trio-WES), which resulted in the codon of amino acid 386 from asparagine to termination (p. 386N>*). The 3D mutant protein structure was predicted using AlphaFold, and the results showed that the truncated PHKA2 protein contained 385 of the 1,235 amino acids of the mature protein.
Conclusion: We describe a previously unreported case of a GSDs IXa type Chinese boy caused by a novel PHKA2 variant. This clinical case contributes to the understanding of the characteristics of GSDs type IXa and expands the variants spectrum of genes related to GSDs type IXa. Our findings demonstrated the significance of genetic testing in the diagnosis of GSDs.

Keywords:  3D structure; PHKA2 gene; X-chromosome recessive genetic diseases; glycogen storage disease; whole exome sequencing

DOI:  https://doi.org/10.3389/fendo.2023.1332450
J Inherit Metab Dis. 2024 Jan 07.

Repurposing empagliflozin in individuals with glycogen storage disease Ib: A value-based healthcare approach and systematic benefit-risk assessment.

Terry G J Derks, Annieke Venema, Clara Köller, Eline Bos, Ruben J Overduin, Nina N Stolwijk, Peter Hofbauer, Mathieu S Bolhuis, Fred van Eenennaam, Henk Groen, Carla E M Hollak, Saskia B Wortmann.

  Off-label repurposing of empagliflozin allows pathomechanism-based treatment of neutropenia/neutrophil-dysfunction in glycogen storage disease type Ib (GSDIb). From a value-based healthcare (VBHC) perspective, we here retrospectively studied patient-reported, clinical and pharmacoeconomic outcomes in 11 GSDIb individuals before and under empagliflozin at two centers (the Netherlands [NL], Austria [AT]), including a budget impact analysis, sensitivity-analysis, and systematic benefit-risk assessment. Under empagliflozin, all GSDIb individuals reported improved quality-of-life-scores. Neutrophil dysfunction related symptoms allowed either granulocyte colony-stimulating factor cessation or tapering. Calculated cost savings per patient per year ranged between € 6482-14 190 (NL) and € 1281-41 231 (AT). The budget impact analysis estimated annual total cost savings ranging between € 75 062-225 716 (NL) and € 37 697-231 790 (AT), based on conservative assumptions. The systematic benefit-risk assessment was favorable. From a VBHC perspective, empagliflozin treatment in GSDIb improved personal and clinical outcomes while saving costs, thereby creating value at multiple pillars. We emphasize the importance to reimburse empagliflozin for GSDIb individuals, further supported by the favorable systematic benefit-risk assessment. These observations in similar directions in two countries/health care systems strongly suggest that our findings can be extrapolated to other geographical areas and health care systems.

Keywords:  drug repurposing; glycogen storage disease type Ib; inborn metabolic diseases; off-label treatment; rare diseases; value-based health care

DOI:  https://doi.org/10.1002/jimd.12714
Ther Adv Endocrinol Metab. 2024 ;15 20420188231224233

Glycogen storage disease type III: a mixed-methods study to assess the burden of disease.

Ayla Evins, Jill Mayhew, Tricia Cimms, Julie Whyte, Kathy Vong, Elizabeth Hribal, Christopher J Evans, Andrew Grimm.

  Background: Glycogen storage disease type III (GSD III) is a rare inherited disorder that results from a glycogen debranching enzyme deficiency.Objectives: The purpose of this research was to collect data on the signs, symptoms, and impacts of GSD III from the perspective of adult patients and caregivers of individuals with GSD III.
Design: Online survey and qualitative interviews.
Methods: Following institutional review board approval, adult patients and caregivers of children with GSD III were recruited through advocacy networks and clinical sites. If eligible, participants were consented, screened, and sent a survey and/or participated in a 60-min interview. The survey and interview included questions about family history, diagnosis, signs and symptoms, impacts, and management of GSD III. Conceptual models were developed following the analysis of results.
Results: In all, 29 adults and 46 caregivers completed the online survey and/or the interviews with 73 survey and 19 interview respondents. Adults and caregivers reported digestive, musculoskeletal, growth and physical appearance, and cardiac signs and symptoms. Liver conditions were reported by most respondents (83%). Adults and caregivers frequently reported impacts such as difficulty keeping up with peers (77%) and difficulty exercising/difficulty with physical activity (53%). Hypoglycemia was frequently reported in both adults and children, with more than half reporting hospitalizations due to hypoglycemia. Caregivers focused on hypoglycemia when reporting signs/symptoms that most interfere with their child's life and prevention of hypoglycemia as a desired outcome for an effective therapy. Adults most often reported muscle weakness as a top interfering symptom and the most important goal of a potential therapy. Impacts were also reported in activities of daily living, cognitive, emotional, work/school, and sleep domains.
Conclusion: Individuals with GSD III experience a broad spectrum of symptoms and disease impacts. There is an unmet need for therapies that improve metabolic control, reduce the burden of dietary management, reduce fatigue and liver problems, and improve muscle strength and function.

Keywords:  conceptual model; glycogen storage disease type III; mixed methods; qualitative research; rare disease

DOI:  https://doi.org/10.1177/20420188231224233
Mol Genet Metab. 2023 Dec 22. pii: S1096-7192(23)00749-7. [Epub ahead of print] 108119

Severe CNS involvement in a subset of long-term treated children with infantile-onset Pompe disease.

Daniel Kenney-Jung, Aditi Korlimarla, Gail A Spiridigliozzi, Walter Wiggins, Michael Malinzak, Gretchen Nichting, Seung-Hye Jung, Angela Sun, Raymond Y Wang, Aisha Al Shamsi, Chanika Phornphutkul, James Owens, James M Provenzale, Priya S Kishnani.

  INTRODUCTION: The standard of care for patients with infantile-onset Pompe disease (IOPD) is enzyme replacement therapy (ERT), which does not cross the blood brain barrier. While neuromuscular manifestations of IOPD are well-described, central nervous system (CNS) manifestations of this disorder are far less characterized. Here we describe severe CNS-related neurological manifestations including seizures and encephalopathy in six individuals with IOPD.METHOD: We identified six children with IOPD who developed CNS manifestations such as seizures and/or encephalopathy. We studied their brain magnetic resonance imaging scans (MRIs) and graded the severity of white matter hyperintensities (WMHI) using the Fazekas scale scoring system as previously published. Longitudinal cognitive measures were available from 4/6 children.
RESULTS: All six IOPD patients (4 males/2 females) had been treated with ERT for 12-15 years. Seizures and/or encephalopathy were noted at a median age at onset of 11.9 years (range 9-15 years). All were noted to have extensive WMHI in the brain MRIs and very high Fazekas scores which preceded the onset of neurological symptoms. Longitudinal IQ scores from four of these children suggested developmental plateauing.
DISCUSSION: Among a subset of IOPD patients on long-term ERT, CNS manifestations including hyperreflexia, encephalopathy and seizures may become prominent, and there is likely an association between these symptoms and significant WMHI on MRI. Further study is needed to identify risk factors for CNS deterioration among children with IOPD and develop interventions to prevent neurological decline.

Keywords:  Case series; Epilepsy; Pompe disease; White matter disease

DOI:  https://doi.org/10.1016/j.ymgme.2023.108119
Asia Pac J Oncol Nurs. 2023 Nov;10(Suppl 1): 100335

Exercise-based interventions for cancer cachexia: A systematic review of randomised and non-randomised controlled trials.

Canaan Cheung, Emily Boocock, Antonio J Grande, Matthew Maddocks.

  Objective: Cachexia is a multifactorial syndrome characterised by involuntary weight loss and functional limitation. There is a strong theoretical rationale for the use of exercise in the management of cachexia, and evidence of benefit from exercise in general cancer patients. However, clinical studies of exercise interventions in cancer cachexia are limited. We aimed to synthesise current evidence on the delivery, acceptability, safety and outcomes of exercise interventions for adults with cancer cachexia.Methods: We conducted a systematic review. Four databases were searched up to February 2023 for randomised (RCTs) and non-randomised (NRCTs) controlled studies. Eligibility and quality were independently assessed by two authors. Data on intervention components and structure, participant flow and adherence were tabulated. Clinical outcome data on body stature and composition, muscle strength, functional performance, and health-related quality of life were synthesised using effect direction plots.
Results: Twelve studies (9 RCTs, 3 NRCTs) involving a total of 898 patients (study range 20-374) as part of a multicomponent approach. Median programme completion was 75% (range 43%-100%) and adherence was generally high. Five adverse events were considered possibly related to an intervention, including muscle or joint pain, breathlessness on exertion. Overall, 12/16 (75%) outcomes demonstrated a positive direction of effect on body stature and composition, 8/10 (80%) on muscle strength, 14/22 (64%) on functional performance, and 3/8 (38%) on health-related quality of life. Multicomponent interventions showed more consistent effects on body stature, and resistance training interventions on muscle strength.
Conclusions: Exercise interventions appear to be safe and acceptable to people with cancer cachexia. Positive effects from exercise are more consistently observed for body stature or composition and muscle strength outcomes, than in functional capacity and health-related quality of life. The synergistic effects of exercise with other cachexia interventions, including drugs, should be examined in future robust studies.

Keywords:  Cachexia; Cancer; Exercise; Function; Physical activity

DOI:  https://doi.org/10.1016/j.apjon.2023.100335