A rare co-occurrence of phosphorylase kinase deficiency (GSD type IXd) and alpha-glycosidase deficiency (GSD Type II) in a 53-year-old man presenting with an atypical glycogen storage disease phenotype.

Glycogen Storage Disease (GSD) IXd, caused by PHKA1 gene mutations, is an X-linked rare disorder that can be asymptomatic or associated with exercise intolerance. GSD type II is an autosomal recessive disorder caused by mutations in the GAA gene that lead to severe cardiac and skeletal muscle myopathy. We report the first case of co-occurrence of type IXd and type II GSDs in a 53-year-old man with an atypical glycogen storage disease presentation consisting in myalgia in the lower limbs at both rest and after exercise and increased levels of transaminases from the age of 16. At the age of 43, the patient presented a steppage gait, inability to run and walk on his heels, hypotrophy of the pectoral and proximal muscles, reflexes not elicitable, and CK levels 3.6 times the upper reference limit. Next Generation Sequencing (NGS) identified one variant in the PHKA1 gene, c.1360A > G p.Ile454Val (exon 14) inherited by his mother, and two heterozygous variants in the GAA gene, c.784G > A (exon 4) and c.956-6T > C (exon 6). A review of GSD IXd cases reported to date in the literature is also provided.

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

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.

Glycogen Storage Disease: Expert Opinion on Clinical Diagnosis Revisited after Molecular Testing.

This study sought to analyze whether an accurate diagnosis of the type and subtype of hepatic Glycogen Storage Diseases (GSDs) could be performed based on general clinical and biochemical aspects via comparing the proposed diagnostic hypotheses with the molecular results. Twelve physicians with experience in hepatic GSDs reviewed 45 real cases comprising a standardized summary of clinical and laboratory data. There was no relation between the hit rate and the time since graduation, the time of experience in GSD, and the number of patients treated during their careers. The average assertiveness was 47%, with GSD Ia and Ib being the best-identified types, while no expert correctly identified GSD IXc. Underage investigation for later manifestations, incomplete clinical description, and complementary analysis, the overvaluation of a specific clinical finding ("false positive") or the discarding of the diagnosis in the absence of it ("false negative"), as well as the lack of knowledge of the rarest GSD types, may have impacted the accuracy of the assessment. This study emphasized that characteristics considered as determinants in identifying the specific types or subtypes of GSD are not exclusive, thus becoming factors that may have induced the evaluators to misdiagnose.

Glycogen storage diseases.

Glycogen storage diseases (GSDs) are a group of rare, monogenic disorders that share a defect in the synthesis or breakdown of glycogen. This Primer describes the multi-organ clinical features of hepatic GSDs and muscle GSDs, in addition to their epidemiology, biochemistry and mechanisms of disease, diagnosis, management, quality of life and future research directions. Some GSDs have available guidelines for diagnosis and management. Diagnostic considerations include phenotypic characterization, biomarkers, imaging, genetic testing, enzyme activity analysis and histology. Management includes surveillance for development of characteristic disease sequelae, avoidance of fasting in several hepatic GSDs, medically prescribed diets, appropriate exercise regimens and emergency letters. Specific therapeutic interventions are available for some diseases, such as enzyme replacement therapy to correct enzyme deficiency in Pompe disease and SGLT2 inhibitors for neutropenia and neutrophil dysfunction in GSD Ib. Progress in diagnosis, management and definitive therapies affects the natural course and hence morbidity and mortality. The natural history of GSDs is still being described. The quality of life of patients with these conditions varies, and standard sets of patient-centred outcomes have not yet been developed. The landscape of novel therapeutics and GSD clinical trials is vast, and emerging research is discussed herein.

Glycogen storage diseases: An update.

Glycogen storage diseases (GSDs), also referred to as glycogenoses, are inherited metabolic disorders of glycogen metabolism caused by deficiency of enzymes or transporters involved in the synthesis or degradation of glycogen leading to aberrant storage and/or utilization. The overall estimated GSD incidence is 1 case per 20000-43000 live births. There are over 20 types of GSD including the subtypes. This heterogeneous group of rare diseases represents inborn errors of carbohydrate metabolism and are classified based on the deficient enzyme and affected tissues. GSDs primarily affect liver or muscle or both as glycogen is particularly abundant in these tissues. However, besides liver and skeletal muscle, depending on the affected enzyme and its expression in various tissues, multiorgan involvement including heart, kidney and/or brain may be seen. Although GSDs share similar clinical features to some extent, there is a wide spectrum of clinical phenotypes. Currently, the goal of treatment is to maintain glucose homeostasis by dietary management and the use of uncooked cornstarch. In addition to nutritional interventions, pharmacological treatment, physical and supportive therapies, enzyme replacement therapy (ERT) and organ transplantation are other treatment approaches for both disease manifestations and long-term complications. The lack of a specific therapy for GSDs has prompted efforts to develop new treatment strategies like gene therapy. Since early diagnosis and aggressive treatment are related to better prognosis, physicians should be aware of these conditions and include GSDs in the differential diagnosis of patients with relevant manifestations including fasting hypoglycemia, hepatomegaly, hypertransaminasemia, hyperlipidemia, exercise intolerance, muscle cramps/pain, rhabdomyolysis, and muscle weakness. Here, we aim to provide a comprehensive review of GSDs. This review provides general characteristics of all types of GSDs with a focus on those with liver involvement.

Clinical and genetic spectrum of GSD type 6 in Korea.

BACKGROUND: Glycogen storage disease type VI (GSD VI) is a rare disease in which liver glycogen metabolism is impaired by mutations in the glycogen phosphorylase L (PYGL). This study aimed to examine the clinical features, genetic analyses, and long-term outcomes of patients with GSD VI in Korea. METHODS: From January 2002 to November 2022, we retrospectively reviewed patients diagnosed with GSD VI using a gene panel at Seoul National University Hospital. We investigated the clinical profile, liver histology, molecular diagnosis, and long-term outcomes of patients with GSD VI. RESULTS: Five patients were included in the study. The age at onset was 18-30 months (median, 21 months), and current age was 3.7-17 years (median, 11 years). All patients showed hepatomegaly, elevated liver transaminase activity, and hypertriglyceridaemia. Hypercholesterolaemia and fasting hypoglycaemia occurred in 60% and 40% of patients, respectively. Ten variants of PYGL were identified, of which six were novel: five missense (p.[Gly607Val], p.[Leu445Pro], p.[Gly695Glu], p.[Val828Gly], p.[Tyr158His]), and one frameshift (p.[Arg67AlafsTer34]). All patients were treated with a high-protein diet, and four also received corn starch. All patients showed improved liver function tests, hypertriglyceridaemia, hepatomegaly, and height z score. CONCLUSIONS: The GSD gene panel is a useful diagnostic tool for confirming the presence of GSD VI. Genetic heterogeneity was observed in all patients with GSD VI. Increased liver enzyme levels, hypertriglyceridaemia, and height z score in patients with GSD VI improved during long-term follow-up.

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.

Distinct features in adult polyglucosan body disease: a case series.

Adult polyglucosan body disease (APBD) is caused by bi-allelic pathogenic variants in GBE1 and typically shows middle age onset urinary symptoms followed by progressive gait disturbances and possibly cognitive decline. Here we present a Belgian cohort of four patients from three families showing both classical and atypical signs of APBD. By clinical phenotyping, detailed neuroimaging of both central nervous system and skeletal muscle, genetic and biochemical testing, we confront our findings with the classical presentation of adult polyglucosan body disease and emphasize the importance of a multidisciplinary approach when diagnosing these patients.

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

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.

Rare interstitial lung disease in a preterm neonate with congenital lobar emphysema.

Congenital lobar emphysema (CLE)/congenital alveolar overdistension/congenital lobar overinflation or infantile lobar emphysema is a rare developmental anomaly of the lower respiratory tract which is characterised by hyperinflation of one or more of the pulmonary lobes. Histopathology may be variable, which may show abnormality in the cartilage, granulation tissue, mucosal folds, etc. We report a rare underlying histopathology in a preterm neonate with CLE. This entity referred to as pulmonary interstitial glycogenosis (PIG) is a group of heterogeneous lung disease affecting the lung parenchyma and is characterised by the presence of glycogen laden cells in the lung interstitium. This impairs the gas exchange and typically manifest as tachypnoea, retractions, hypoxia and increased respiratory support. Our case report highlights the association of CLE and PIG and a review of literature. One should always have a detailed histopathology in children presenting with CLE to rule out PIG.

[Genetic analysis of a child with glycogen storage disease type IXa due to a novel variant in PHKA2 gene].

OBJECTIVE: To explore the genetic etiology of a patient with glycogen storage diseases. METHODS: Clinical data of child and his parents were collected. The genes associated with glycogen storage diseases were subjected to high-throughput sequencing to screen the variants. Candidate variant was validated by Sanger sequencing. Pathogenicity of the variant was predicted by bioinformatic analysis. RESULTS: High-throughput sequencing results showed that the boy has carried a hemizygous c.749C>T (p.S250L) variant of the PHKA2 gene. Sanger sequencing verified the results and confirmed that it was inherited from his mother. This variant was unreported previously and predicted to be pathogenic by bioinformatic analysis. CONCLUSION: The patient was diagnosed with glycogen storage disease type IXa due to a novel c.749C>T (p.S250L) hemizygous variant of the PHKA2 gene. High-throughput sequencing can facilitate timely and accurate differential diagnosis of glycogen storage disease type IXa.

Update on glycogen storage disease: primary hepatic involvement.

PURPOSE OF REVIEW: Glycogen storage disease is a group of disorders primarily characterized by hepatomegaly and fasting hypoglycemia. This group of disorders may also affect the muscle, kidneys, and neurodevelopment. With an overall prevalence of 1 : 20 000, GSDs are disorders that clinicians should diagnose in a timely manner because adequate management can prevent complications, such as neurodevelopmental delay and liver disease [1] . As there are numerous types of GSDs, being able to distinguish one type from another can be overwhelming. In this review, we focus on hepatic GSDs to provide a concise review of clinical presentation, diagnosis, and current management. RECENT FINDINGS: GSDs are considered rare disorders, and one of the main challenges is the delay in diagnosis, misdiagnosis, or under diagnosis. However, with molecular genetic testing now readily available, confirming the diagnosis is no longer as difficult or invasive as it was in the past. SUMMARY: Current therapy for this group of disorders requires maintaining stable glucose levels. Avoiding hypoglycemia, as well as hyperglycemia, is critical in managing these patients. Being able to distinguish the types of GSDs and understanding the specific treatments for each enzymatic defect will optimize patient care.

Hepatic glycogen storage diseases type 0, VI and IX: description of an italian cohort.

BACKGROUND: Glycogen storage disease (GSD) type 0, VI and IX are inborn errors of metabolism involving hepatic glycogen synthesis and degradation. We performed a characterization of a large Italian cohort of 30 patients with GSD type 0a, VI, IXa, IXb and IXc. A retrospective evaluation of genetical, auxological and endocrinological data, biochemical tests, and nutritional intakes was assessed. Eventual findings of overweight/obesity and insulin-resistance were correlated with diet composition. RESULTS: Six GSD-0a, 1 GSD-VI, and 23 GSD-IX patients were enrolled, with an age of presentation from 0 to 72 months (median 14 months). Diagnosis was made at a median age of 30 months, with a median diagnostic delay of 11 months and a median follow-up of 66 months. From first to last visit, patients gained a median height of 0.6 SDS (from - 1.1 to 2.1 SDS) and a median weight of 0.5 SDS (from - 2.5 to 3.3 SDS); mean and minimal glucose values significant improved (p < 0.05). With respect to dietary intakes, protein intake (g/kg) and protein intake (g/kg)/RDA ratio directly correlated with the glucose/insulin ratio (p < 0.05) and inversely correlated with HOMA-IR (Homeostasis model assessment of insulin resistance, p < 0.05), BMI SDS (p < 0.05) and %ibw (ideal body weight percentage, p < 0.01). CONCLUSION: A prompt establishment of specific nutritional therapy allowed to preserve growth, improve glycemic control and prevent liver complication, during childhood. Remarkably, the administration of a high protein diet appeared to have a protective effect against overweight/obesity and insulin-resistance.

Glycogen storage diseases with liver involvement: a literature review of GSD type 0, IV, VI, IX and XI.

BACKGROUND: Glycogen storage diseases (GSDs) with liver involvement are classified into types 0, I, III, IV, VI, IX and XI, depending on the affected enzyme. Hypoglycemia and hepatomegaly are hallmarks of disease, but muscular and renal tubular involvement, dyslipidemia and osteopenia can develop. Considering the paucity of literature available, herein we provide a narrative review of these latter forms of GSDs. MAIN BODY: Diagnosis is based on clinical manifestations and laboratory test results, but molecular analysis is often necessary to distinguish the various forms, whose presentation can be similar. Compared to GSD type I and III, which are characterized by a more severe impact on metabolic and glycemic homeostasis, GSD type 0, VI, IX and XI are usually known to be responsive to the nutritional treatment for achieving a balanced metabolic homeostasis in the pediatric age. However, some patients can exhibit a more severe phenotype and an important progression of the liver and muscular disease. The effects of dietary adjustments in GSD type IV are encouraging, but data are limited. CONCLUSIONS: Early diagnosis allows a good metabolic control, with improvement of quality of life and prognosis, therefore we underline the importance of building a proper knowledge among physicians about these rare conditions. Regular monitoring is necessary to restrain disease progression and complications.

A very rare case report of glycogen storage disease type IXc with novel PHKG2 variants.

BACKGROUND: Pathogenic mutations in the PHKG2 are associated with a very rare disease-glycogen storage disease IXc (GSD-IXc)-and are characterized by severe liver disease. CASE PRESENTATION: Here, we report a patient with jaundice, hypoglycaemia, growth retardation, progressive increase in liver transaminase and prominent hepatomegaly from the neonatal period. Genetic testing revealed two novel, previously unreported PHKG2 mutations (F233S and R320DfsX5). Functional experiments indicated that both F223S and R320DfsX5 lead to a decrease in key phosphorylase b kinase enzyme activity. With raw cornstarch therapy, hypoglycaemia and lactic acidosis were ameliorated and serum aminotransferases decreased. CONCLUSION: These findings expand the gene spectrum and contribute to the interpretation of clinical presentations of these two novel PHKG2 mutations.

A new phenotype of muscle glycogen synthase deficiency (GSD0B) characterized by an adult onset myopathy without cardiomyopathy.

Muscle Glycogenosis type 0 (GSD0B) is an extremely rare disorder first recognized in 2007 in three siblings with childhood onset and severe cardiomyopathy. Since then, a few cases with severe cardiac involvement and premature death have been reported. We describe two unrelated cases presenting with an adult-onset myopathy with no heart involvement. Clinical features were quite similar in both patients, mainly characterized by early fatigability, myalgia and muscle weakness. Muscle biopsy revealed marked glycogen depletion in nearly all myofibers. Biochemical assay demonstrated a marked reduction of Glycogen Synthase (GS) activity. Sequence analysis of GYS1 revealed two new variants: a homozygous G to C substitution in the splice donor consensus site (c.678+1G>C) in patient1 and a homozygous missense variant c.630G>C in exon 3 (p. Asp145His) in patient 2. This study describes a new phenotype of muscle GSD0B presenting with adult onset, proximal myopathy, no cardiac abnormalities and a quite benign disease course. This report highlights the importance of a systematic diagnostic approach that includes muscle morphology and enzymatic assay to facilitate the identification of adult patients with GSD0B.

Neonatal interstitial lung disease in a girl with Jacobsen syndrome: a case report.

BACKGROUND: We report a case of the neonatal interstitial lung disease pulmonary interstitial glycogenosis in a girl with Jacobsen syndrome. While Jacobsen syndrome is caused by a deletion on the long arm of chromosome 11 and is genetically confirmed, pulmonary interstitial glycogenosis is of unknown etiology and is diagnosed by lung biopsy. Pulmonary interstitial glycogenosis has not previously been described in association with Jacobsen syndrome. CASE PRESENTATION: A term newborn small for gestational age Caucasian girl presented with respiratory distress, pulmonary hypertension, congenital heart defects, immunodeficiency, and thrombocytopenia. She was diagnosed with Jacobsen syndrome, but also had pulmonary interstitial glycogenosis, which contributed to significant morbidity. There was striking clinical improvement after steroid treatment of the pulmonary interstitial glycogenosis. CONCLUSIONS: Interstitial lung disease should be considered as a differential diagnosis when respiratory distress and hypoxemia in the perinatal period worsens or persists despite standard treatment. Importantly, pulmonary interstitial glycogenosis may be treatable with corticosteroids. Whether there is a genetic link between pulmonary interstitial glycogenosis and Jacobsen syndrome is still unknown.