Background: GD and ASMD are lysosomal storage disorders that enter into differential diagnosis due to the possible overlap in their clinical manifestations. The availability of safe and effective enzymatic therapies has recently led many investigators to develop and validate new screening tools, such as algorithms, for the diagnosis of LSDs where the lack of disease awareness or failure to implement newborn screening results in a delayed diagnosis.
Results: the proposed algorithm allows for the clinical and biochemical differentiation between GD and ASMD.
Heterozygous mutations in the gene encoding RagD GTPase were shown to cause a novel autosomal dominant condition characterized by kidney tubulopathy and cardiomyopathy. We previously demonstrated that RagD, and its paralogue RagC, mediate a non-canonical mTORC1 signaling pathway that inhibits the activity of TFEB and TFE3, transcription factors of the MiT/TFE family and master regulators of lysosomal biogenesis and autophagy. Here we show that RagD mutations causing kidney tubulopathy and cardiomyopathy are "auto- activating", even in the absence of Folliculin, the GAP responsible for RagC/D activation, and cause constitutive phosphorylation of TFEB and TFE3 by mTORC1, without affecting the phosphorylation of "canonical" mTORC1 substrates, such as S6K.
View Article and Find Full Text PDFIntroduction: Short/branched-chain acyl-CoA dehydrogenase deficiency (SBCADD) is an inherited disorder of L-isoleucine metabolism due to mutations in the gene. The role of current diagnostic biomarkers [i.e.
View Article and Find Full Text PDFBACKGROUND: Mucopolysaccharidosis type VI (MPS VI) is an inherited multisystem lysosomal disorder due to arylsulfatase B (ARSB) deficiency that leads to widespread accumulation of glycosaminoglycans (GAG), which are excreted in increased amounts in urine. MPS VI is characterized by progressive dysostosis multiplex, connective tissue and cardiac involvement, and hepatosplenomegaly. Enzyme replacement therapy (ERT) is available but requires life-long and costly intravenous infusions; moreover, it has limited efficacy on diseased skeleton and cardiac valves, compromised pulmonary function, and corneal opacities.
View Article and Find Full Text PDFBackground: Severe skeletal muscle damage has been recently reported in patients with SARS-CoV-2 infection and as a rare vaccination complication.
Case Summary: On Apr 28, 2021 a 68-year-old man who was previously healthy presented with an extremely severe rhabdomyolysis that occurred nine days following the first dose of SARS-CoV-2 ChAdOx1 nCov-19 vaccination. He had no risk factors, and denied any further assumption of drugs except for fermented red rice, and berberine supplement.
Background: Classic infantile onset of Pompe disease (c-IOPD) leads to hypotonia and hypertrophic cardiomyopathy within the first days to weeks of life and, without treatment, patients die of cardiorespiratory failure in their first 1-2 years of life. Enzymatic replacement therapy (ERT) with alglucosidase alfa is the only available treatment, but adverse immune reactions can reduce ERT's effectiveness and safety. It is therefore very important to identify strategies to prevent and manage these complications.
View Article and Find Full Text PDFPompe disease is a metabolic myopathy due to acid alpha-glucosidase deficiency. In addition to glycogen storage, secondary dysregulation of cellular functions, such as autophagy and oxidative stress, contributes to the disease pathophysiology. We have tested whether oxidative stress impacts on enzyme replacement therapy with recombinant human alpha-glucosidase (rhGAA), currently the standard of care for Pompe disease patients, and whether correction of oxidative stress may be beneficial for rhGAA therapy.
View Article and Find Full Text PDFHypoglycemia is the result of defects/impairment in glucose homeostasis. The main etiological causes are metabolic and/or endocrine and/or other congenital disorders. Despite hypoglycemia is one of the most common emergencies in neonatal age and childhood, no consensus on the definition and diagnostic work-up exists yet.
View Article and Find Full Text PDFBackground: Besides major clinical/biochemical features, neutropenia and inflammatory bowel disease (IBD) constitute common complications of Glycogen storage disease type Ib (GSD Ib). However, their management is still challenging. Although previous reports have shown benefit of empagliflozin administration on neutropenia, no follow-up data on bowel (macro/microscopic) morphology are available.
View Article and Find Full Text PDFBackground: If symptomatic in infants, the autosomal recessive disease lysosomal acid lipase deficiency (LAL-D; sometimes called Wolman disease or LAL-D/Wolman phenotype) is characterized by complete loss of LAL enzyme activity. This very rare, rapidly progressive form of LAL-D results in severe manifestations leading to failure to thrive and death, usually by 6 months of age. We report results from 2 open-label studies of enzyme replacement therapy with sebelipase alfa, a recombinant human LAL, in infants with LAL-D: the phase 2/3 Survival of LAL-D Infants Treated With Sebelipase Alfa (VITAL) study (NCT01371825) and a phase 2 dose-escalation study (LAL-CL08 [CL08]; NCT02193867).
View Article and Find Full Text PDFIntroduction: Lysosomal storage diseases (LSDs) are rare inherited metabolic diseases characterized by an abnormal accumulation of various toxic materials in the cells as a result of enzyme deficiencies leading to tissue and organ damage. Among clinical manifestations, cardiac diseases are particularly important in Pompe glycogen storage diseases (PD), in glycosphingolipidosis Fabry disease (FD), and mucopolysaccharidoses (MPS). Here, we evaluated the occurrence of aortopathy in knock out (KO) mouse models of three different LSDs, including PD, FD, and MPS IIIB.
View Article and Find Full Text PDFThe recent advancements in the knowledge of lysosomal biology and function have translated into an improved understanding of the pathophysiology of mucopolysaccharidoses (MPSs). The concept that MPS manifestations are direct consequences of lysosomal engorgement with undegraded glycosaminoglycans (GAGs) has been challenged by new information on the multiple biological roles of GAGs and by a new vision of the lysosome as a signaling hub involved in many critical cellular functions. MPS pathophysiology is now seen as the result of a complex cascade of secondary events that lead to dysfunction of several cellular processes and pathways, such as abnormal composition of membranes and its impact on vesicle fusion and trafficking; secondary storage of substrates; impairment of autophagy; impaired mitochondrial function and oxidative stress; dysregulation of signaling pathways.
View Article and Find Full Text PDFBiallelic variants in nuclear gene have been reported so far in only three children with variable presentations including Leigh syndrome or leukoencephalopathy. Herein, we report a further female child affected by -related disorder presenting with cavitating and tigroid-like pattern of leukodystrophy and without systemic biochemical abnormalities of mitochondrial disorders.
View Article and Find Full Text PDFNiemann-Pick type C (NPC) disease is an autosomal recessive lysosomal storage disorder caused by mutations in or genes. In 2009, the molecular characterization of 44 NPC Italian patients has been published. Here, we present an update of the genetic findings in 105 Italian NPC patients belonging to 83 unrelated families (77 NPC1 and 6 NPC2).
View Article and Find Full Text PDFIn the last years tandem mass spectrometry (MS/MS) has become a leading technology used for neonatal screening purposes. Newborn screening by MS/MS on dried blood spot samples (DBS) has one of its items in methionine levels: the knowledge of this parameter allows the identification of infant affected by homocystinuria (cystathionine β-synthase, CBS, deficiency) but can also lead, as side effect, to identify cases of methionine adenosyltransferase (MAT) type I/III deficiency. We started an expanded newborn screening for inborn errors of metabolism in Campania region in 2007.
View Article and Find Full Text PDFBackground: Hereditary fructose intolerance (HFI) is a rare genetic disorder of fructose metabolism due to aldolase B enzyme deficiency. Treatment consists of fructose, sorbitol, and sucrose (FSS)-free diet. We explore possible correlations between daily fructose traces intake and liver injury biomarkers on a long-term period, in a cohort of young patients affected by HFI.
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