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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., (© 2023. Springer Nature Limited.)

Late-onset Pompe disease (LOPD) is a multisystem disorder with significant myopathy. The standard treatment is enzyme replacement therapy (ERT), a therapy that is lifesaving, yet with limitations. Clinical trials have emerged for other potential treatment options, including adeno-associated virus (AAV) gene therapy. We present clinical parameters and AAV antibody titers for 19 individuals with LOPD undergoing screening for a Phase I clinical trial with an AAV serotype 8 vector targeting hepatic transduction (AAV2/8-LSPhGAA). Reported clinical parameters included GAA genotype, assessments of muscle function, upright and supine spirometry, anti-recombinant human GAA antibody titers, and biomarkers. Variability in measured parameters and phenotypes of screened individuals was evident. Eligibility criteria required that all participants have six-minute walk test (6MWT) and upright forced vital capacity (FVC) below the expected range for normal individuals, and were stably treated with ERT for >2 years. All participants had Pompe disease diagnosed by enzyme deficiency, and all had the common c.-32-13T>G LOPD pathogenic variant. Screening identified 14 patients (74%) with no or minimal detectable neutralizing antibodies against AAV8 (titer ≤1:5). 6MWT distance varied significantly (percent of expected distance ranging from 24% to 91% with an average of 60 and standard deviation of 21). Upright FVC percent predicted ranged from 35% predicted to 91% predicted with an average of 66 and standard deviation of 18. None of the participants had significantly elevated alanine transaminase, which has been associated with LOPD and could complicate screening for hepatitis related to AAV gene therapy. We review the parameters considered in screening for eligibility for a clinical trial of AAV8 vector-mediated gene therapy., Competing Interests: Dr. Dwight D. Koeberl and Dr. Priya S. Kishnani have developed the technology that is being used in the study. If the technology is commercially successful in the future, the developers and Duke University may benefit financially. Dr. Dwight D. Koeberl has served as a consultant for Sangamo Therapeutics and for Genzyme Sanofi, Amicus, and Vertex; has received grant support from Viking Therapeutics, Genzyme Sanofi, Roivant Rare Diseases, and Amicus; and has equity in Askbio, which is developing gene therapy for Pompe disease. Dr. William B. Hannah has received consulting fees from PTC Therapeutics and ReCode Therapeutics. Dr. Edward C. Smith received salary support for his role as PI on this study. Dr. Laura E. Case has received honoraria from Genzyme Sanofi and Amicus, has participated in research supported by Genzyme Sanofi, Amicus, AskBio, Valerion, Biomarin, and by Roivant Sciences; and is a member of the Pompe Registry North American Board of Advisors Genzyme Sanofi. Dr. Deeksha Bali has received research grant support and travel funds from Genzyme Sanofi, Baebies Inc., Biomarin, Alexion Inc., SOBI biopharma, and JCR biopharma. Dr. Priya S. Kishnani has received research/grant support from Sanofi Genzyme and Amicus Therapeutics. She received consulting fees and honoraria from Sanofi Genzyme, Amicus Therapeutics, Maze Therapeutics, JCR Pharmaceutical, and Asklepios Biopharmaceutical, Inc. (AskBio). She is a member of the Pompe and Gaucher Disease Registry Advisory Board for Sanofi Gezyme, Amicus Therapeutics, and Baebies. Dr. Priya S. Kishnani has equity in Asklepios Biopharmaceutical, Inc. (AskBio) which is developing gene therapy for Pompe disease and has equity in Maze Therapeutics which is developing a small molecule therapy for Pompe disease., (© 2023 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)

There is a broad differential diagnosis of infantile hepatosplenomegaly, with some etiologies being debilitating and treatable. A structured approach to history, examination, and laboratory and radiographic findings is important in diagnosis. Herein, we present a case of Wolman disease presenting as hepatosplenomegaly in an infant. This case details important learning points to help distinguish the diagnosis of Wolman disease from other conditions with overlapping clinical features, such as hemophagocytic lymphohistiocytosis (HLH). The advent of enzyme replacement therapy has dramatically changed the natural history of Wolman disease, and this child showed remarkable improvement with treatment. This child was later found to have extensive adenopathy with retroperitoneal lymph node biopsy demonstrating diffuse infiltration by lipid-laden macrophages, fatty deposits, cholesterol crystals, and calcifications. Similar to the collection of characteristic cells in other lysosomal storage disorders, we postulate that this is characteristic of underlying Wolman disease. We conclude with a summary of learning points from this presentation on infantile hepatosplenomegaly, pertinent to the geneticist, pediatrician, and pediatric subspecialists., (© 2022 Wiley Periodicals LLC.)

Background: Primary ciliary dyskinesia (PCD) is a motile ciliopathy characterised by otosinopulmonary infections. Inheritance is commonly autosomal recessive, with extensive locus and allelic heterogeneity. The prevalence is uncertain. Most genetic studies have been done in North America or Europe. The aim of the study was to estimate the worldwide prevalence and ethnic heterogeneity of PCD., Methods: We calculated the allele frequency of disease-causing variants in 29 PCD genes associated with autosomal recessive inheritance in 182 681 unique individuals to estimate the global prevalence of PCD in seven ethnicities (African or African American, Latino, Ashkenazi Jewish, Finnish, non-Finnish European, east Asian, and south Asian). We began by aggregating variants that had been interpreted by Invitae, San Francisco, CA, USA, a genetics laboratory with PCD expertise. We then determined the allele frequency of each variant (pathogenic, likely pathogenic, or variant of uncertain significance [VUS]) in the Genome Aggregation Database (gnomAD), a publicly available next-generation sequencing database that aggregates exome and genome sequencing information from a wide variety of large-scale projects and stratifies allele counts by ethnicity. Using the Hardy-Weinberg equilibrium equation, we were able to calculate a lower-end prevalence of PCD for each ethnicity by including only pathogenic and likely pathogenic variants; and upper-end prevalence by also including VUS. This approach was similar to previous work on Li-Fraumeni (TP53 variants) prevalence. We were not diagnosing PCD, but rather estimating prevalence based on known variants., Findings: The overall minimum global prevalence of PCD is calculated to be at least one in 7554 individuals, although this is likely to be an underestimate because some variants currently classified as VUS might be disease-causing and some pathogenic variants might not be detected by our methods. In the overall cohort, Invitae data could be included for variants without gnomAD data for a primary ethnicity. When using only gnomAD allele frequencies to calculate prevalence in individual ethnicities, the estimated prevalence of PCD was lower in each ethnicity compared with the overall cohort. This is because the overall cohort includes additional data from the Invitae database such as copy number variants and other variants not present in gnomAD. With gnomAD we found the expected PCD frequency to be higher in individuals of African ancestry than in most other populations (excluding VUS: 1 in 9906 in African or African American vs 1 in 10 388 in non-Finnish European vs 1 in 14 606 in east Asian vs 1 in 16 309 in Latino; including VUS: 1 in 106 in African or African American vs 1 in 178 in non-Finnish European vs 1 in 196 in Latino vs 1 in 188 in east Asian). In addition, we found that the top 5 genes most commonly implicated in PCD differed across ethnic ancestries and contrasted commonly published findings., Interpretation: PCD appears to be more common than has been recognised, particularly in individuals of African ancestry. We identified gene distributions that differ from those in previous European and North American studies. These results could have an international impact on case identification. Our analytic approach can be expanded as more PCD loci are identified, and could be adapted to study the prevalence of other inherited diseases., Funding: None., Competing Interests: Declaration of interests WBH receives support from the National Institutes of Health (NIH) Loan Repayment Program, outside of the submitted work. BAS reports other from Duke University School of Medicine (salary from ABMGG Laboratory Genetics and Genomics Fellowship), other from Medical Science and Computing (salary as Clinical Molecular Geneticist contractor at the National Institute of Allergy and Infectious Diseases [NIAID] and NIH), and other from American College of Medical Genetics and Genomics (ACMG; US$100 000, registration, travel, and transportation fees to attend ACMG Annual Meeting as the 2019 Richard King Trainee Awardee), outside of the submitted work. RT and KN are employees and stockholders at Invitae—a genetic testing provider offering testing for Primary Ciliary Dyskinesia. MAZ has salary support from research grants from NIH, outside of the submitted work. BG received salary support from research grants from NIH, outside of the submitted work. KA and YZ declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Competing Interests: Harrison N. Jones has received research/grant support and honoraria from Sanofi Genzyme Priya S. Kishnani has received research/grant support from Sanofi Genzyme, Valerion Therapeutics, and Amicus Therapeutics; consulting fees and honoraria from Sanofi Genzyme, Amicus Therapeutics, Vertex Pharmaceuticals and Asklepios Biopharmaceutical, Inc. (AskBio); is a member of the Pompe and Gaucher Disease Registry Advisory Board for Sanofi Genzyme, Amicus Therapeutics, and Baebies; and has equity in Actus Therapeutics, which is developing gene therapy for Pompe disease.

Objective: To evaluate whether cystic fibrosis transmembrane conductance regulator (CFTR) variants are more common among individuals tested for primary ciliary dyskinesia (PCD) compared with controls., Study Design: Data were studied from 1021 individuals with commercial genetic testing for suspected PCD and 91 777 controls with genetic testing at the same company (Invitae) for symptoms/diseases unrelated to PCD or CFTR testing. The prevalence of CFTR variants was compared between controls and each of 3 groups of individuals tested for PCD (PCD-positive, -uncertain, and -negative molecular diagnosis)., Results: The prevalence of 1 pathogenic CFTR variant was similar among the individual groups. When combining the PCD-uncertain and PCR-negative molecular diagnosis groups, there was a higher prevalence of single pathogenic CFTR variants compared with controls (P = .03). Importantly, >1% of individuals who had negative genetic testing results for PCD had 2 pathogenic CFTR variants (8 of 723), and the incidence of cystic fibrosis (CF) (2 pathogenic variants) is roughly 1 in 3000 individuals of Caucasian ethnicity (∼0.03%). This incidence was also greater than that of 2 pathogenic CFTR variants in the control population (0.09% [84 of 91 777]; P = 9.60 × 10 -16 ). These variants correlate with mild CFTR-related disease., Conclusions: Our results suggest that a single pathogenic CFTR variant is not likely to be a PCD-mimetic, but ongoing studies are needed in individuals in whom PCD is suspected and genetic testing results are uncertain or negative. Furthermore, CF may be misdiagnosed as PCD, reflecting phenotypic overlap. Among individuals evaluated for PCD, CF should be considered in the differential even in the CF newborn screening era., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Although individuals of Amish descent with propionic acidemia (PA) are generally thought to have a milder disease phenotype, we now have a better understanding of the natural history of PA in this population. Here we describe two Amish patients with emergent presentations of PA, one with metabolic decompensation and another with cardiogenic shock. PA can present with life-threatening metabolic decompensation or an adult-onset severe cardiomyopathy. We discuss critical clinical implications of this observation., (© 2019 The Authors.)

While joint damage is the primary co-morbidity of hemophilia, osteoporosis and osteopenia are also observed. Coagulation factor VIII deficient (FVIII -/- ) mice develop an osteoporotic phenotype in the absence of induced hemarthrosis that is exacerbated two weeks after an induced joint injury. Here we have compared comprehensively the bone health of clotting factor VIII, factor IX, and Von Willebrand Factor knockout (FVIII -/- , FIX -/- , and VWF -/- respectively) mice both in the absence of joint hemorrhage and following induced joint injury. We found FVIII -/- and FIX -/- mice, but not VWF -/- mice, developmentally have an osteoporotic phenotype. Unilateral induced hemarthrosis causes further bone damage in both FVIII -/- and FIX -/- mice, but has little effect on VWF -/- bone health, indicating that the FVIII.VWF complex is not required for normal bone remodeling in vivo. To further investigate the bone healing following hemarthrosis in hemophilia we examined a two week time course using microCT, serum chemistry, and histological analysis. Elevated ratio of osteoprotegerin (OPG)/receptor activator of nuclear factor-kappa B ligand (RANKL), increased osterix + osteoblastic cells, and decreased smoothness of the cortical bone surface were evident within several days of injury, indicative of acute heterotopic mineralization along the cortical surface. This was closely followed by increased interleukin-6 (IL-6) levels, increased osteoclast numbers, and significant trabecular bone loss. Uncoupled and disorganized bone formation and resorption continued for the duration of the study resulting in significant deterioration of the joint. Further elucidation of the shared mechanisms underlying abnormal bone homeostasis in the absence of FVIII or FIX is needed to guide evidence-based approaches to the screening and treatment of the prevalent bone defects in hemophilia A and B.

Background: OFD1 has long been recognized as the gene implicated in the classic dysmorphology syndrome, oral-facial-digital syndrome type I (OFDSI). Over time, pathogenic variants in OFD1 were found to be associated with X-linked intellectual disability, Joubert syndrome type 10 (JBTS10), Simpson-Golabi-Behmel syndrome type 2 (SGBS2), and retinitis pigmentosa. Recently, OFD1 pathogenic variants have been implicated in primary ciliary dyskinesia (PCD), a disorder of the motile cilia with a phenotype that includes recurrent oto-sino-pulmonary infections, situs abnormalities, and decreased fertility., Methods: We describe three male patients with PCD who were found to have hemizygous pathogenic variants in OFD1, further supporting that PCD is part of a clinical spectrum of OFD1-related disorders. In addition, we provide a review of the available clinical literature describing patients with OFD1 variants and highlight the phenotypic variability of OFD1-related disease., Results: Some individuals with hemizygous OFD1 variants have PCD, either apparently isolated or in combination with other features of OFD1-related disorders., Conclusion: As clinicians consider the presence or absence of conditions allelic at OFD1, PCD should be considered part of the spectrum of OFD1-related disorders. Understanding the OFD1-related disease spectrum may allow for more focused genetic testing and more timely management of treatable sequelae., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Previous reports of lung function in cystic fibrosis (CF) patients with liver disease have shown worse, similar, or even better forced expiratory volume in 1 second (FEV1), compared to CF patients without liver disease. Varying definitions of CF liver disease likely contribute to these inconsistent relationships reported between CF lung function and liver disease. We retrospectively evaluated spirometric data in 179 subjects (62% male; 58% Phe508del homozygous) with severe CF liver disease (CFLD; defined by presence of portal hypertension due to cirrhosis). FEV1 values were referenced to both a normal population (FEV1% predicted) and CF population (CF-specific FEV1 percentile). We utilized a linear mixed model with repeated measures to assess changes in lung function (before and after diagnosis of CFLD), relative to both the normal and CF populations. At diagnosis of CFLD, the mean FEV1 was 81% predicted, or at the 53rd percentile referenced to CF patients without CFLD. There was a significant difference in post-CFLD slope compared to pre-CFLD slope (post-pre) using FEV1% predicted (-1.94, p-value < 0.0001). However, there was insignificant evidence of this difference using the CF-specific FEV1 percentile measure (-0.99, p-value = 0.1268). Although FEV1% predicted values declined in patients following CFLD diagnosis, there was not significant evidence of lung function decline in CF-specific FEV1 percentiles. Thus, the observed study cohort indicates diagnosis of severe CFLD was not associated with worsened CF lung disease when compared to a large CF reference population., Competing Interests: The authors have declared that no competing interests exist.

Vector capsid dose-dependent inflammation of transduced liver has limited the ability of adeno-associated virus (AAV) factor IX (FIX) gene therapy vectors to reliably convert severe to mild hemophilia B in human clinical trials. These trials also identified the need to understand AAV neutralizing antibodies and empty AAV capsids regarding their impact on clinical success. To address these safety concerns, we have used a scalable manufacturing process to produce GMP-grade AAV8 expressing the FIXR338L gain-of-function variant with minimal (<10%) empty capsid and have performed comprehensive dose-response, biodistribution, and safety evaluations in clinically relevant hemophilia models. The scAAV8.FIXR338L vector produced greater than 6-fold increased FIX specific activity compared with wild-type FIX and demonstrated linear dose responses from doses that produced 2-500% FIX activity, associated with dose-dependent hemostasis in a tail transection bleeding challenge. More importantly, using a bleeding model that closely mimics the clinical morbidity of hemophilic arthropathy, mice that received the scAAV8.FIXR338L vector developed minimal histopathological findings of synovitis after hemarthrosis, when compared with mice that received identical doses of wild-type FIX vector. Hemostatically normal mice (n=20) and hemophilic mice (n=88) developed no FIX antibodies after peripheral intravenous vector delivery. No CD8(+) T cell liver infiltrates were observed, despite the marked tropism of scAAV8.FIXR338L for the liver in a comprehensive biodistribution evaluation (n=60 animals). With respect to the role of empty capsids, we demonstrated that in vivo FIXR338L expression was not influenced by the presence of empty AAV particles, either in the presence or absence of various titers of AAV8-neutralizing antibodies. Necropsy of FIX(-/-) mice 8-10 months after vector delivery revealed no microvascular or macrovascular thrombosis in mice expressing FIXR338L (plasma FIX activity, 100-500%). These preclinical studies demonstrate a safety:efficacy profile supporting an ongoing phase 1/2 human clinical trial of the scAAV8.FIXR338L vector (designated BAX335).

While chronic degenerative arthropathy is the main morbidity of haemophilia, a very high prevalence of low bone density is also seen in men and boys with haemophilia. This study investigates bone degradation in the knee joint of haemophilic mice resulting from haemarthrosis and the efficacy of aggressive treatment with factor VIII in the period surrounding injury to prevent bone pathology. Skeletally mature factor VIII knock-out mice were subjected to knee joint haemorrhage induced by puncture of the left knee joint capsule. Mice received either intravenous factor VIII treatment or placebo immediately prior to injury and at hours 4, 24, 48, 72 and 96 after haemorrhage. Mice were killed 2-weeks after injury and the joint morphology and loss of bone in the proximal tibia was assessed using microCT imaging. Quantitative microCT imaging of the knee joint found acute bone loss at the proximal tibia following injury including loss of trabecular bone volumetric density and bone mineral density, as well as trabecular connectivity density, number and thickness. Unexpectedly, joint injury also resulted in calcification of the joint soft tissues including the tendons, ligaments, menisci and cartilage. Treatment with factor VIII prevented this bone and soft tissue degeneration. Knee joint haemorrhage resulted in acute changes in adjacent bone including loss of bone density and mineralization of joint soft tissues. The rapid calcification and loss of bone has implications for the initiation and progression of osteoarthritic degradation following joint bleeding., (© 2014 John Wiley & Sons Ltd.)

Context: A subset (approximately 3%-5%) of patients with cystic fibrosis (CF) develops severe liver disease with portal hypertension., Objective: To assess whether any of 9 polymorphisms in 5 candidate genes (alpha(1)-antitrypsin or alpha(1)-antiprotease [SERPINA1], angiotensin-converting enzyme [ACE], glutathione S-transferase [GSTP1], mannose-binding lectin 2 [MBL2], and transforming growth factor beta1 [TGFB1]) are associated with severe liver disease in patients with CF., Design, Setting, and Participants: Two-stage case-control study enrolling patients with CF and severe liver disease with portal hypertension (CFLD) from 63 CF centers in the United States as well as 32 in Canada and 18 outside of North America, with the University of North Carolina at Chapel Hill as the coordinating site. In the initial study, 124 patients with CFLD (enrolled January 1999-December 2004) and 843 control patients without CFLD were studied by genotyping 9 polymorphisms in 5 genes previously studied as modifiers of liver disease in CF. In the second stage, the SERPINA1 Z allele and TGFB1 codon 10 genotype were tested in an additional 136 patients with CFLD (enrolled January 2005-February 2007) and 1088 with no CFLD., Main Outcome Measures: Differences in distribution of genotypes in patients with CFLD vs patients without CFLD., Results: The initial study showed CFLD to be associated with the SERPINA1 Z allele (odds ratio [OR], 4.72; 95% confidence interval [CI], 2.31-9.61; P = 3.3 x 10(-6)) and with TGFB1 codon 10 CC genotype (OR, 1.53; 95% CI, 1.16-2.03; P = 2.8 x 10(-3)). In the replication study, CFLD was associated with the SERPINA1 Z allele (OR, 3.42; 95% CI, 1.54-7.59; P = 1.4 x 10(-3)) but not with TGFB1 codon 10. A combined analysis of the initial and replication studies by logistic regression showed CFLD to be associated with SERPINA1 Z allele (OR, 5.04; 95% CI, 2.88-8.83; P = 1.5 x 10(-8))., Conclusions: The SERPINA1 Z allele is a risk factor for liver disease in CF. Patients who carry the Z allele are at greater risk (OR, approximately 5) of developing severe liver disease with portal hypertension.

Thirteen auxenic compounds were discovered in a screen of 10 000 compounds for auxin-like activity in Arabidopsis roots. One of the most potent substances was 2-(4-chloro-2-methylphenoxy)-N-(4-H-1,2,4-triazol-3-yl)acetamide (WH7) which shares similar structure to the known auxenic herbicide 2,4-dichlorophenoxyacetic acid (2,4-D). A selected set of 20 analogues of WH7 was used to provide detailed information about the structure-activity relationship based on their efficacy at inhibiting and stimulating root and shoot growth, respectively, and at induction of gene expression. It was shown that WH7 acts in a genetically defined auxin pathway. These small molecules will extend the arsenal of substances that can be used to define auxin perception site(s) and to dissect subsequent signalling events.