Pompe disease (PD), also defined as acid maltase deficiency, is a rare autosomal recessive disease that causes glycogen accumulation due to a deficiency of the lysosomal enzyme acid α-glucosidase. An excessive amount of undisposed glycogen causes progressive muscle weakness throughout the body. It particularly affects skeletal muscles and the nervous system, especially in the late-onset phase. Here, we present a clinical case of late-onset PD (LOPD) with normal CK (creatinine kinase) values treated after a misdiagnosis of demyelinating motor polyneuropathy and chronic inflammatory neuropathy. The suspicion of possible fibromyalgia induced the patient to seek a rheumatology consultation, and the investigations performed led to the diagnosis of PD. The patient was investigated for genetic and enzymatic studies. PD was diagnosed using the α-glucosidase assay on DBS. In LOPD, clinical manifestations, such as muscle weakness, exercise intolerance, myalgia, or even high hyperCKemia, often appear as nonspecific and may mimic a wide variety of other muscle disorders, such as limb muscle dystrophies, congenital, metabolic, or inflammatory myopathies. In our case, the patient had CK values in the normal range but with continued complaints typical of PD. An analysis of enzyme activity revealed a pathologic value, and genetic analysis identified the c.-32-13T>G mutation in homozygosis. The association of the pathological enzyme value and mutation in homozygosity with LOPD led to a familial segregation study. Our results contribute to the characterization of PD in Italy and support the importance of rheumatologic attention. This suggests further studies are needed to define the broad clinical and pathological spectrum observed in this disease.

Studying a patient with Pompe disease (PD) is like opening Pandora’s box. The specialist is faced with numerous clinical features similar to those of several diseases, and very often the symptoms are well hidden and none is associated with this rare disease. In recent years, scientific interest in this disease has been growing more and more, but still no symptom is recognized as key to a correct diagnosis of it, nor is there any specific disease marker to date. New diagnostic/therapeutic proposals on disease allow for the diffusion of knowledge of this pathology for timely diagnosis of the patient. Due to unawareness and difficulty in diagnosis, many adults with PD are diagnosed with great delay. In this article, we report and discuss current knowledge of PD and provide new data from work conducted on a cohort of 2934 Italian subjects recruited in recent years. A genetic analysis of the GAA gene was performed on patients with significant clinical signs and pathological enzyme activity to define the genetic profile of subjects. This identified 39 symptomatic PD subjects with low acid alpha-glucosidase enzyme activity and the presence of two causative mutations in GAA gene regions. Furthermore, 22 subjects with genetic variants of uncertain significance (GVUS) were identified.

Pompe disease is a neuromuscular disorder caused by a deficiency of the enzyme acid alpha-glucosidase (GAA), which leads to lysosomal glycogen accumulation and progressive development of muscle weakness. Two distinct isoforms have been identified. In the infantile form, the weakness is often severe and leads to motor difficulties from the first few months of life. In adult patients, the progression is slower but can still lead to significant loss of mobility. The current inherent difficulties of the disease lie in both early diagnosis and the use of biomarkers. Given that this is a multifactorial disease, a number of components may exert an influence on the disease process; from the degree of pre-ERT (enzyme replacement therapy) muscle damage to the damaged autophagic system and the different pathways involved. What methodology should be employed to study the complex characteristics of Pompe disease? Our approach relies on the application of genetic and epigenetic knowledge, with a progression from proteomics to transcriptomics. It is also becoming increasingly evident that artificial intelligence is a significant area of interest. The objective of this study is to conduct a comprehensive review of the existing literature on the known data and complications associated with the disease in patients with disorders attributed to Pompe disease.

VEXAS syndrome (Vacuoles, E1-enzyme, X-linked, Autoinflammation, and Somatic) is a recently identified late-onset autoinflammatory disorder characterized by a unique interplay between hematological and inflammatory manifestations. It results from somatic mutations in the UBA1 gene, located on the short arm of the X chromosome. Initially, females were considered mere carriers, with the syndrome primarily affecting males over 50. However, recent evidence indicates that heterozygous females can exhibit symptoms as severe as those seen in hemizygous males. The disease manifests as systemic inflammation, macrocytic anemia, thrombocytopenia, chondritis, neutrophilic dermatoses, and steroid-dependent inflammatory symptoms. Due to its overlap with autoimmune and hematologic disorders such as relapsing polychondritis, Still’s disease, and myelodysplastic syndromes, misdiagnosis is common. At the molecular level, VEXAS syndrome is driven by impaired ubiquitination pathways, resulting in dysregulated immune responses and clonal hematopoiesis. A key diagnostic marker is the presence of cytoplasmic vacuoles in myeloid and erythroid precursors, though definitive diagnosis requires genetic testing for UBA1 mutations. Traditional immunosuppressants and TNF inhibitors are generally ineffective, while JAK inhibitors and IL-6 blockade provide partial symptom control. Azacitidine and decitabine have shown promise in reducing disease burden, but hematopoietic stem cell transplantation (HSCT) remains the only curative treatment, albeit with significant risks. This review provides a comprehensive analysis of VEXAS syndrome, examining its clinical features, differential diagnoses, diagnostic challenges, and treatment approaches, including both pharmacological and non-pharmacological strategies. By enhancing clinical awareness and optimizing therapeutic interventions, this article aims to bridge emerging genetic insights with practical patient management, ultimately improving outcomes for those affected by this complex and often life-threatening disease.

Background: Multiplex Ligation Probe Amplification (MLPA) is a widely used technique for the diagnosis of lysosomal storage diseases (LSDs). It analyses over 40 DNA sequences in a single reaction, identifying copy number variations and large deletions/insertions in genes. The diagnostic process in LSDs starts with analysis of the missing or reduced enzyme, followed by genetic investigation and, if possible, a search for accumulated substrates. However, while genetic analysis using Sanger sequencing is excellent at detecting small genetic variations such as single-nucleotide variants (SNVs) and small insertions or deletions, it cannot detect large deletions or insertions. Methods: In the present study, a total of 800 patients with clinical suspicion of Fabry, Gaucher, or Pompe diseases were investigated. An enzyme assay was carried out on each patient, followed by genetic analysis using PCR, Sanger sequencing, and MLPA. Results: Nine patients with deficient or absent enzyme activity had Sanger sequencing results that could not confirm the molecular genetic diagnosis because either no mutation (Fabry) or only one mutation (Gaucher and Pompe) was identified. Subsequent analysis by MLPA identified two males with a hemizygous deletion and two females with a heterozygous deletion for FD. For PD, one female and two males had a heterozygous deletion. For GD, one male had a homozygous deletion and one female had a heterozygous deletion. The remaining patients were analyzed by MLPA with negative results. Conclusions: The results obtained suggest that MLPA should be used in combination with classical sequencing methods to ensure a correct and timely diagnosis of LSDs.

Mucopolysaccharidosis type I (MPS-I) is an autosomal recessive, progressive, multisystem hereditary lysosomal storage disease (LSD), which is characterized by the gradual accumulation of dermatan sulphate (DS), heparan sulphate (HS), and glycosaminoglycans (GAGs) in all organs and tissues due to the deficiency of the enzyme α-L-hyduronidase. The multisystem clinical manifestations of varying severities of MPS-I are present in two forms—the “severe form of MPS I” (Hurler type) and the “attenuated form of MPS-I” (Hurler–Scheie or Scheie type). These forms represent the entire case history of the disease. The three phenotypes share common symptoms, including musculoskeletal abnormalities, facial dysmorphisms, hernias, short stature, finger stiffness, carpal tunnel syndrome, and corneal opacities. Abnormalities affecting the internal organs include hepatomegaly, splenomegaly, and valvulopathy. There is some evidence to suggest a similarity and overlap with the clinical symptoms of MPS-I, particularly in cases of another rare LSD that is autosomal and recessively inherited—l’α-mannosidosis. This disorder has been observed to result from a dysfunction of the corresponding α-mannosidase enzyme, which has been shown to lead to the accumulation of mannose-rich N-linked oligosaccharides. This review compares the phenotypic similarities and molecular differences between mucopolysaccharidosis type I (MPS-I) and α-mannosidosis. We review genotype–phenotype correlations, diagnostic difficulties, and the applicability of artificial intelligence for the assistance of differential diagnosis, with the goal of facilitating the earlier and more accurate diagnosis of these rare lysosomal storage diseases.