ABSTRACT Glycogen Storage Disease Type XV (GSD XV) is a rare autosomal recessive disorder caused by biallelic pathogenic variants in GYG1 , encoding glycogenin‐1. Although primarily a myopathic disease, cardiac involvement is increasingly recognized and overlapping features with other neuromuscular disorders contribute to underdiagnosis. We performed a systematic search of databases without restrictions on publication dates. Twenty‐one articles describing individuals with GSD XV were included, providing clinical, histological, and genetic data. In addition to the systematic review, we present an illustrative case of GSD XV diagnosed at our institution. We identified 49 individuals, of whom 98% were symptomatic with onset ranging from childhood to late adulthood; manifestations were isolated neuromuscular (81.6%), cardiac (8.2%), or mixed (8.2%). One case (2.0%) was asymptomatic. Among neuromuscular cases, 12% required a walking aid, while four cardiac patients required implantable cardioverter‐defibrillators and two underwent heart transplantation. Muscle biopsy frequently revealed PAS‐positive, diastase‐resistant polyglucosan bodies, although polyglucosan bodies were not consistently identified by electron microscopy. Molecular diagnosis was confirmed in all cases, with c.143+3G>C in GYG1 being the most prevalent variant, homozygous in 36.7% of patients and associated with both juvenile and adult‐onset phenotypes. GSD XV should be considered in cases with unexplained myopathy or cardiomyopathy, regardless of age at onset. Genetic testing remains the gold standard for diagnosis, although muscle biopsy can guide investigations, particularly in atypical cases or when genetic analysis is inconclusive. Further studies are needed to clarify the full clinical spectrum, refine genotype–phenotype correlations, and guide long‐term management strategies.
ABSTRACT Mucopolysaccharidosis type VII (MPS VII; Sly syndrome) is a rare autosomal recessive lysosomal storage disorder caused by deficiency of β‐glucuronidase due to pathogenic variants in the GUSB gene. Impaired degradation of glycosaminoglycans (GAGs) results in multiorgan dysfunction with highly variable clinical presentation, ranging from severe neonatal disease to attenuated adult phenotypes. We report an incidental diagnosis of MPS VII in a 31‐year‐old woman identified through routine laboratory testing. Review of a peripheral blood smear was prompted by automated hematology analyzer flags and revealed Alder–Reilly anomaly with characteristic aberrant leukocyte granulation. Subsequent biochemical analysis showed elevated urinary dermatan sulfate and heparan sulfate, alongside reduced β‐glucuronidase activity (~2%–3% of normal). Genetic testing of GUSB identified compound heterozygosity for a likely pathogenic frameshift variant (c.133_134del) and a missense variant (c.454G>A) previously associated with pseudodeficiency. Despite biochemical and genetic findings consistent with MPS VII, the patient exhibited no typical clinical manifestations, and detailed phenotyping showed no organ involvement. This case illustrates an atypical, asymptomatic presentation of MPS VII diagnosed in adulthood, in which Alder–Reilly anomaly served as a critical diagnostic clue. The combination of a null allele with a pseudodeficiency‐associated variant resulted in reduced enzyme activity without overt disease. These findings highlight the importance of peripheral blood smear evaluation in identifying lysosomal storage disorders and underscore the complexity of genotype–phenotype correlations in MPS VII.
ABSTRACT Newborn screening (NBS) has significantly improved early detection and survival in fatty acid oxidation disorders (FAODs). However, the expanding phenotypic spectrum challenges prognostic stratification, and long‐term morbidity remains incompletely characterized. We conducted an observational, retrospective, single‐center study of patients with FAODs identified through NBS and followed between 2011 and 2024. Clinical, biochemical, genetic, and nutritional data were extracted from medical records. Correlations between biochemical markers, enzymatic activity, and clinical outcomes were analyzed. The study was approved by the Research Committee of the Instituto de Investigación, Hospital 12 de Octubre (Madrid). Sixty‐five patients were included: 42 MCADD, 11 VLCADD, 5 LCHADD, 2 CPT1D, 3 CPT2D, 1 CACTD, and 1 MADD. Median age at last follow‐up was 7.2 years (range 0.4–13.6). Two patients died during follow‐up (overall mortality 3.1%). In MCADD, confirmatory C8 concentrations correlated with residual enzyme activity and metabolic decompensations. In VLCADD, NBS and confirmatory C14:1 levels correlated with enzyme activity but not with clinical severity. VLCADD showed marked clinical heterogeneity, whereas LCHADD patients had the highest disease burden and required the most intensive nutritional management. Overall, 40% of patients experienced at least one metabolic decompensation, occurring significantly more frequently in LC‐FAOD than in MCADD. Neuropsychological manifestations were observed in 16.9% of patients. In summary, NBS markedly improves survival in FAODs, but morbidity remains substantial, particularly in LC‐FAOD. Current biochemical markers are useful for early risk stratification but remain insufficient to predict long‐term clinical severity. These findings support individualized multidisciplinary follow‐up, including specialized nutritional care and systematic neuropsychological assessment.
ABSTRACT Inherited metabolic diseases (IMDs) are individually (ultra)rare but collectively relatively common. The Extension for Community Healthcare Outcomes (ECHO) model has been used worldwide since 2003 to disseminate knowledge and best practices in chronic diseases. In 2024, the Dutch Society for Inborn Errors of Metabolism (ESN) launched a pilot Metabolic Diseases ECHO Program. We aimed to evaluate whether ECHO is a feasible model for IMD knowledge dissemination. We conducted a retrospective review of the design, implementation, and impact of the program. Since February 2025, two ECHO hubs have been established in two Dutch medical education and training regions (ETRs). Data have been prospectively collected through the iECHO platform. Program impact was assessed using Moore's Expanded Outcomes Framework, covering seven levels ranging from participation and satisfaction to competence development and population outcomes. The Metabolic Diseases ECHO Program has achieved broad geographic reach and strong engagement among healthcare professionals. To date, 15 sessions have been completed and 10 additional sessions are scheduled. A total of 208 professionals from diverse disciplines, including pediatrics, clinical genetics, clinical chemistry, and nursing, have participated, representing 10 of the 12 Dutch provinces. The program has stimulated the development of two regional treatment protocols and integrates all core academic tasks: patient care, education, and research. The ECHO model is a feasible and sustainable approach for disseminating expertise on IMDs. Our program demonstrates meaningful impact across the first four levels of Moore's framework. Long‐term continuation and expansion to other Dutch‐speaking regions are under consideration. Future work will focus on assessing the direct benefits for IMD patients.
ABSTRACT Mitochondrial disease is a common inherited multisystem neurometabolic disorder. Pancreatic dysfunction is a recognised manifestation, most frequently presenting as mitochondrial diabetes. Although pancreatitis cases have been reported in association with mitochondrial disease, acute and chronic pancreatitis in this context remain poorly characterised. Following the PRISMA framework, we performed a systematic literature review to identify all published cases in which acute or chronic pancreatitis occurred in individuals with a genetically confirmed mitochondrial disease. Literature search yielded 604 publications, of which 19 fit the inclusion criteria. During revision two additional publications were identified, one of which fit the inclusion criteria. These 20 reports described 24 individuals with mitochondrial disease and documented history of acute or chronic pancreatitis. Mean age at first recorded pancreatitis was 13 years, with median age 10 years (range 3 months to 53 years). Pancreatitis was recurrent or chronic in 63% of cases. The most reported presenting symptoms were abdominal pain (38%) and vomiting (33%). None had established pancreatitis risk factors such as gallstones or alcohol misuse. In those who underwent imaging, no structural abnormalities of the pancreas or biliary tree were identified. Most frequent genetic aetiologies were large‐scale mitochondrial DNA (mtDNA) deletions and the m.3243A>G mtDNA variant (29% each). Six patients (25%) died shortly after hospital admission with pancreatitis. Pancreatitis associated with mitochondrial disease often presents in childhood and is frequently recurrent or chronic. Although uncommon, it represents a clinically significant and potentially life‐threatening complication that warrants increased awareness.
