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BACKGROUND AND OBJECTIVES: Fibrosis contributes to 45% of deaths in industrialized nations and is characterized by an abnormal accumulation of extracellular matrix (ECM). There are no specific anti-fibrotic treatments for liver fibrosis, and previous unsuccessful attempts at drug development have focused on preventing ECM deposition. Because liver fibrosis is largely acknowledged to be reversible, regulating fibrosis resolution could offer novel therapeutical options. However, little is known about the mechanisms controlling ECM remodeling during resolution. Changes in proteolytic activity are essential for ECM homeostasis and macrophages are an important source of proteases. Herein, in this study we evaluate the role of macrophage-derived cathepsin D (CtsD) during liver fibrosis. METHODS: CtsD expression and associated pathways were characterized in single-cell RNA sequencing and transcriptomic datasets in human cirrhosis. Liver fibrosis progression, reversion and functional characterization were assessed in novel myeloid-CtsD and hepatocyte-CtsD knock-out mice. RESULTS: Analysis of single-cell RNA sequencing datasets demonstrated CtsD was expressed in macrophages and hepatocytes in human cirrhosis. Liver fibrosis progression, reversion and functional characterization were assessed in novel myeloid-CtsD (CtsDΔMyel) and hepatocyte-CtsD knock-out mice. CtsD deletion in macrophages, but not in hepatocytes, resulted in enhanced liver fibrosis. Both inflammatory and matrisome proteomic signatures were enriched in fibrotic CtsDΔMyel livers. Besides, CtsDΔMyel liver macrophages displayed functional, phenotypical and secretomic changes, which resulted in a degradomic phenotypical shift, responsible for the defective proteolytic processing of collagen I in vitro and impaired collagen remodeling during fibrosis resolution in vivo. Finally, CtsD-expressing mononuclear phagocytes of cirrhotic human livers were enriched in lysosomal and ECM degradative signaling pathways. CONCLUSIONS: Our work describes for the first-time CtsD-driven lysosomal activity as a central hub for restorative macrophage function during fibrosis resolution and opens new avenues to explore their degradome landscape to inform drug development.
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Catepsina D , Cirrosis Hepática , Macrófagos , Ratones Noqueados , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Cirrosis Hepática/genética , Animales , Catepsina D/metabolismo , Catepsina D/genética , Macrófagos/metabolismo , Ratones , Humanos , Masculino , Ratones Endogámicos C57BL , Matriz Extracelular/metabolismo , Hepatocitos/metabolismoRESUMEN
3-methylcrotonyl-CoA carboxylase deficiency (3MCCD) is a hereditary disorder of leucine catabolism caused by pathogenetic variants in the MCCC1 or MCCC2 genes. Typically diagnosed through newborn screening (NBS), 3MCCD is characterized by elevation of 3-hydroxyisovalerylcarnitine (C5OH) in blood as well as increased excretion of 3-methylcrotonylglycine (3-MCG) in urine. While most diagnosed children remain asymptomatic, data on adults are scarce. To date, only 39 molecularly confirmed adult individuals have been reported, all being mothers diagnosed subsequent to their child NBS results. Herein, we present a 36-year-old asymptomatic man who was incidentally diagnosed with 3MCCD following his son NBS recall. Molecular analysis revealed compound heterozygosity for two pathogenic variants in the MCCC1 gene. This is the first molecularly confirmed adult man with 3MCCD reported. This case highlights the need for additional longitudinal follow-up data on individuals with 3MCCD to clarify the clinical significance of this condition and guide clinical practice, including NBS strategy.
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BACKGROUND: Methylmalonic acidemia (MMA) is a rare inborn error of propionate metabolism caused by deficiency of the mitochondrial methylmalonyl-CoA mutase (MUT) enzyme. As matter of fact, MMA patients manifest impairment of the primary metabolic network with profound damages that involve several cell components, many of which have not been discovered yet. We employed cellular models and patients-derived fibroblasts to refine and uncover new pathologic mechanisms connected with MUT deficiency through the combination of multi-proteomics and bioinformatics approaches. RESULTS: Our data show that MUT deficiency is connected with profound proteome dysregulations, revealing molecular actors involved in lysosome and autophagy functioning. To elucidate the effects of defective MUT on lysosomal and autophagy regulation, we analyzed the morphology and functionality of MMA-lysosomes that showed deep alterations, thus corroborating omics data. Lysosomes of MMA cells present as enlarged vacuoles with low degradative capabilities. Notwithstanding, treatment with an anti-propionigenic drug is capable of totally rescuing lysosomal morphology and functional activity in MUT-deficient cells. These results indicate a strict connection between MUT deficiency and lysosomal-autophagy dysfunction, providing promising therapeutic perspectives for MMA. CONCLUSIONS: Defective homeostatic mechanisms in the regulation of autophagy and lysosome functions have been demonstrated in MUT-deficient cells. Our data prove that MMA triggers such dysfunctions impacting on autophagosome-lysosome fusion and lysosomal activity.
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Mucopolysaccharidoses (MPSs) are lysosomal disorders with neurological involvement for which no cure exists. Here, we show that recombinant NK1 fragment of hepatocyte growth factor rescues substrate accumulation and lysosomal defects in MPS I, IIIA and IIIB patient fibroblasts. We investigated PI3K/Akt pathway, which is of crucial importance for neuronal function and survival, and demonstrate that PI3K inhibition abolishes NK1 therapeutic effects. We identified that autophagy inhibition, by Beclin1 silencing, reduces MPS IIIB phenotype and that NK1 downregulates autophagic-lysosome (ALP) gene expression, suggesting a possible contribution of autophagosome biogenesis in MPS. Indeed, metabolomic analyses revealed defects of mitochondrial activity accompanied by anaerobic metabolism and inhibition of AMP-activated protein kinase (AMPK), which acts on metabolism and autophagy, rescues lysosomal defects. These results provide insights into the molecular mechanisms of MPS IIIB physiopathology, supporting the development of new promising approaches based on autophagy inhibition and metabolic rewiring to correct lysosomal pathology in MPSs.
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ß2-microglobulin (ß2-m) is a plasma protein derived from physiological shedding of the class I major histocompatibility complex (MHCI), causing human systemic amyloidosis either due to persistently high concentrations of the wild-type (WT) protein in hemodialyzed patients, or in presence of mutations, such as D76N ß2-m, which favor protein deposition in the adulthood, despite normal plasma levels. Here we describe a new transgenic Caenorhabditis elegans (C. elegans) strain expressing human WT ß2-m at high concentrations, mimicking the condition that underlies dialysis-related amyloidosis (DRA) and we compare it to a previously established strain expressing the highly amyloidogenic D76N ß2-m at lower concentrations. Both strains exhibit behavioral defects, the severity of which correlates with ß2-m levels rather than with the presence of mutations, being more pronounced in WT ß2-m worms. ß2-m expression also has a deep impact on the nematodes' proteomic and metabolic profiles. Most significantly affected processes include protein degradation and stress response, amino acids metabolism, and bioenergetics. Molecular alterations are more pronounced in worms expressing WT ß2-m at high concentration compared to D76N ß2-m worms. Altogether, these data show that ß2-m is a proteotoxic protein in vivo also in its wild-type form, and that concentration plays a key role in modulating pathogenicity. Our transgenic nematodes recapitulate the distinctive features subtending DRA compared to hereditary ß2-m amyloidosis (high levels of non-mutated ß2-m vs. normal levels of variant ß2-m) and provide important clues on the molecular bases of these human diseases.
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Amniotic fluid is essential for fetus wellbeing and is used to monitor pregnancy and predict fetal outcomes. Sex affects health and medicine from the beginning of life, but knowledge of its influence on cell-depleted amniotic fluid (AF) and amniotic fluid cells (AFCs) is still neglected. We evaluated sex-related differences in AF and in AFCs to extend personalized medicine to prenatal life. AFCs and AF were obtained from healthy Caucasian pregnant women who underwent amniocentesis at the 16th-18th week of gestation for advanced maternal age. In the AF, inflammation biomarkers (TNFα, IL6, IL8, and IL4), malondialdehyde, nitrites, amino acids, and acylcarnitines were measured. Estrogen receptors and cell fate (autophagy, apoptosis, senescence) were measured in AFCs. TNFα, IL8, and IL4 were higher in female AF, whereas IL6, nitrites, and MDA were similar. Valine was higher in male AF, whereas several acylcarnitines were sexually different, suggesting a mitochondrial involvement in establishing sex differences. Female AFCs displayed higher expression of ERα protein and a higher ERα/ERß ratio. The ratio of LC3II/I, an index of autophagy, was higher in female AFCs, while LC3 gene was similar in both sexes. No significant sex differences were found in the expression of the lysosomal protein LAMP1, while p62 was higher in male AFCs. LAMP1 gene was upregulated in male AFCs, while p62 gene was upregulated in female ones. Finally, caspase 9 activity and senescence linked to telomeres were higher in female AFCs, while caspase 3 and ß-galactosidase activities were similar. This study supports the idea that sex differences start very early in prenatal life and influence specific parameters, suggesting that it may be relevant to appreciate sex differences to cover knowledge gaps. This might lead to improving the diagnosis of risk prediction for pregnancy complications and achieving a more satisfactory monitoring of fetus health, even preventing future diseases in adulthood.
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Introduction: Crohn's disease (CD) is an immune-mediated inflammatory disorder of the gastrointestinal tract with a relapsing-remitting course. Amino acids (AAs) may play critical roles in the intestinal manifestations of disease, due to their involvement in many metabolic and immune functions. The present study aimed to explore serum AA concentrations in adult patients with CD, looking into their variations due to disease activity, surgery and protein content of diet. Eventually, the link between AAs and inflammatory markers was also assessed. Methods: Consecutive adult patients aged 18-65 years with diagnosis of CD were recruited. All participants underwent anthropometry and were instructed to fill in a 3-day food record to assess protein intake. Disease activity was clinically defined using the Crohn's Disease Activity Index (CDAI), while blood samples were taken to analyze serum AA profile and inflammatory markers. Results: A total of 103 patients with CD (61 men and 42 women; age:39.9 ± 13.9 years, BMI: 23.4 ± 3.51 kg/m2) were included. Tryptophan levels were found to be remarkably decreased in most subjects, unrelated to disease activity. On the contrary, concentration of lysine, leucine, valine and glutamine decreased in active versus quiescent CD patients, while aspartic acid, glutamate and glycine increased. The latter AAs were also directly correlated with CDAI and serum interleukin (IL)- 1ß concentration. Considering the total protein intake, expressed as g/kg/body weight, we observed a reduction in some essential AAs in patients with unmet protein requirements compared to patients who met the recommendation. Discussion: In conclusion, specific AAs varied according to disease activity and protein intake, adjusted to body weight and disease status. Glu and Asp concentrations raised with increasing IL-1ß. However, extensive research is needed to understand the mechanisms underpinning the link between variation in serum AAs, disease activity and protein intake in patients with CD.
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Sexual dimorphism creates different biological and cellular activities and selective regulation mechanisms in males and females, thus generating differential responses in health and disease. In this scenario, the sex itself is a source of physiologic metabolic disparities that depend on constitutive genetic and epigenetic features that characterize in a specific manner one sex or the other. This has as a direct consequence a huge impact on the metabolic routes that drive the phenotype of an individual. The impact of sex is being clearly recognized also in disease, whereas male and females are more prone to the development of some disorders, or have selective responses to drugs and therapeutic treatments. Actually, very less is known regarding the probable differences guided by sex in the context of inherited metabolic disorders, owing to the scarce consideration of sex in such restricted field, accompanied by an intrinsic bias connected with the rarity of such diseases. Metabolomics technologies have been ultimately developed and adopted for being excellent tools for the investigation of metabolic mechanisms, for marker discovery or monitoring, and for supporting diagnostic procedures of metabolic disorders. Hence, metabolomic approaches can excellently embrace the discovery of sex differences, especially when associated to the outcome or the management of certain inborn errors of the metabolism.
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BACKGROUND: Glycogen storage disease type Ia (GSDIa) is an inborn metabolic disorder caused by the deficiency of glucose-6-phospatase-α (G6Pase-α) leading to mitochondrial dysfunction. It remains unclear whether mitochondrial dysfunction is present in patients' peripheral blood mononuclear cells (PBMC) and whether dietary treatment can play a role. The aim of this study was to investigate mitochondrial function in PBMC of GSDIa patients. METHODS: Ten GSDIa patients and 10 age-, sex- and fasting-time matched controls were enrolled. Expression of genes involved in mitochondrial function and activity of key fatty acid oxidation (FAO) and Krebs cycle proteins were assessed in PBMC. Targeted metabolomics and assessment of metabolic control markers were also performed. RESULTS: Adult GSDIa patients showed increased CPT1A, SDHB, TFAM, mTOR expression (p < 0.05) and increased VLCAD, CPT2 and citrate synthase activity in PBMC (p < 0.05). VLCAD activity directly correlated with WC (p < 0.01), BMI (p < 0.05), serum malonycarnitine levels (p < 0.05). CPT2 activity directly correlated with BMI (p < 0.05). CONCLUSION: Mitochondrial reprogramming is detectable in PBMC of GSDIa patients. This feature may develop as an adaptation to the liver enzyme defect and may be triggered by dietary (over)treatment in the frame of G6Pase-α deficiency. PBMC can represent an adequate mean to assess (diet-induced) metabolic disturbances in GSDIa.
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BACKGROUND: the deficiency of 5,10-Methylenetetrahydrofolate reductase (MTHFR) constitutes a rare and severe metabolic disease and is included in most expanded newborn screening (NBS) programs worldwide. Patients with severe MTHFR deficiency develop neurological disorders and premature vascular disease. Timely diagnosis through NBS allows early treatment, resulting in improved outcomes. METHODS: we report the diagnostic yield of genetic testing for MTHFR deficiency diagnosis, in a reference Centre of Southern Italy between 2017 and 2022. MTHFR deficiency was suspected in four newborns showing hypomethioninemia and hyperhomocysteinemia; otherwise, one patient born in pre-screening era showed clinical symptoms and laboratory signs that prompted to perform genetic testing for MTHFR deficiency. RESULTS: molecular analysis of the MTHFR gene revealed a genotype compatible with MTHFR deficiency in two NBS-positive newborns and in the symptomatic patient. This allowed for promptly beginning the adequate metabolic therapy. CONCLUSIONS: our results strongly support the need for genetic testing to quickly support the definitive diagnosis of MTHFR deficiency and start therapy. Furthermore, our study extends knowledge of the molecular epidemiology of MTHFR deficiency by identifying a novel mutation in the MTHFR gene.
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Homocistinuria , Metilenotetrahidrofolato Reductasa (NADPH2) , Humanos , Recién Nacido , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Homocistinuria/diagnóstico , Homocistinuria/genética , Pruebas Genéticas , Diagnóstico PrecozRESUMEN
Gyrate atrophy of choroid and retina (GACR) is a chorioretinal degeneration caused by pathogenic variants in the gene encoding ornithine aminotransferase (OAT), an enzyme mainly expressed in liver. Affected patients have increased ornithine concentrations in blood and other body fluids and develop progressive constriction of vision fields leading to blindness. Current therapies are unsatisfactory and better treatments are highly needed. In two mouse models of OAT deficiency that recapitulates biochemical and retinal changes of GACR, we investigated the efficacy of an intravenously injected serotype 8 adeno-associated (AAV8) vector expressing OAT under the control of a hepatocyte-specific promoter. Following injections, OAT-deficient mice showed reductions of ornithine concentrations in blood and eye cups compared with control mice injected with a vector expressing green fluorescent protein. AAV-injected mice showed improved electroretinogram response and partial restoration of retinal structure up to one-year post-injection. In summary, hepatic OAT expression by AAV8 vector was effective at correction of hyperornithinemia and improved function and structure of the retina. In conclusion, this study provides proof-of-concept of efficacy of liver-directed AAV-mediated gene therapy of GACR.
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Atrofia Girata , Degeneración Retiniana , Animales , Ratones , Atrofia Girata/genética , Atrofia Girata/patología , Ornitina-Oxo-Ácido Transaminasa/genética , Ornitina-Oxo-Ácido Transaminasa/metabolismo , Degeneración Retiniana/genética , Degeneración Retiniana/patología , Ornitina/genética , Ornitina/metabolismo , Terapia Genética , Hígado/patologíaRESUMEN
Cystic fibrosis is a hereditary metabolic disorder characterized by impaired traffic of chloride ions and water through membranes of the respiratory and gastrointestinal, that causes inadequate hydration of airway surfaces, dehydrated mucous secretions and a high-sodium chloride sweat. Although the classical presentation of the condition is well known, a better characterization of metabolic alterations related is need. In particular, the metabolic composition alterations of biological fluids may be influence by the disease state and could be captured as putative signature to set targeted therapeutic strategies. A targeted comprehensive mass spectrometry-based platform was employed to dissect the lipid content of saliva samples form CF patients, in order to investigate alterations in the lipid metabolic homeostasis related to the pathology, chronic obstructive pulmonary disease, Pseudomonas Aeruginosa infection, pancreatic insufficiency, liver disfunction and diabetes-related complications.
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Fibrosis Quística , Humanos , Fibrosis Quística/metabolismo , Saliva/metabolismo , Lipidómica , Regulador de Conductancia de Transmembrana de Fibrosis Quística/uso terapéutico , Lípidos , Pseudomonas aeruginosaRESUMEN
Urea cycle disorders (UCDs) are a group of rare inborn errors of metabolism caused by a deficiency in one of the six enzymes or one of the two transporters involved in the urea cycle. Current guidelines suggest that early diagnosis and treatment of mild UCDs may improve survival and prevent decompensation and neurocognitive impairment. Nevertheless, clinical studies are very difficult to carry out in this setting due to the rarity of the diseases, and high-level evidence is scant and insufficient to draw conclusions and provide clinical guidelines. With the early introduction of newborn screening, the Italian healthcare organization fostered an advancement in expertise in metabolic disease management and screening programs, by allocating resources, and favoring the expansion of newborn screening. A group of experts operating in Italian centers decided to share their experience and provide advice for the management of mild UCDs in clinical practice. A consensus was reached by the Estimate-Talk-Estimate (ETE) method. Five items were identified, and statements for each item were agreed. Briefly, the panel advised completing the diagnosis by expanded newborn screening (ENS) with biochemical and genetic confirmation and by following up with the patient during the first year of life, with a routine laboratory and metabolic profile as well as with clinical observation. Early initiation of therapy is advised and should be followed by therapy adjustment once the diagnostic profile is completed. The therapy should be based on a low-protein diet and nitrogen scavengers. The long-term follow-up is based on growth and nutritional assessment, clinical and neurocognitive evaluation, and laboratory and instrumental parameter monitoring.
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Testimonio de Experto , Trastornos Innatos del Ciclo de la Urea , Recién Nacido , Humanos , Tamizaje Neonatal , Trastornos Innatos del Ciclo de la Urea/diagnóstico , Trastornos Innatos del Ciclo de la Urea/terapia , Cognición , ConsensoRESUMEN
BACKGROUND: Aging and sedentary behavior are independent risk factors for non-communicable diseases. An active lifestyle and structured physical activity are positively associated with a healthier quality of life in the elderly. Here, we explored the proteomic/metabolomic muscular signature induced by lifelong football training associated with successful aging. METHODS: The study was performed on nine lifelong football players (67.3 ± 2.8 yrs) and nine aged-matched untrained subjects. We performed a proteomic/metabolomic approach on V. lateralis muscle biopsies; the obtained data were analyzed by means of different bioinformatic tools. RESULTS: Our results indicated that lifelong football training is able to enhance the muscles' oxidative capacity in the elderly by promoting fatty acids as preferential energetic substrates and hence determining a healthier body composition and metabolic profile; furthermore, we showed that the total polyamine content is higher in lifelong football players' muscle, enforcing the involvement of polyamines in muscle growth and hypertrophy. CONCLUSIONS: Lifelong football training, as a structured physical activity, significantly influences the expression of the proteins and metabolites involved in oxidative metabolism and muscle hypertrophy associated with successful aging.
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Fútbol Americano , Fútbol , Anciano , Humanos , Calidad de Vida , Proteómica , Músculo Esquelético/fisiologíaRESUMEN
Chronic kidney disease (CKD) is a major clinical sign of patients with Bardet-Biedl syndrome (BBS), especially in those carrying BBS10 mutations. Twenty-nine patients with BBS and 30 controls underwent a serum-targeted metabolomic analysis. In vitro studies were conducted in two kidney-derived epithelial cell lines, where Bbs10 was stably deleted (IMCD3-Bbs10-/-cells) and over-expressed. The CKD status affected plasmatic metabolite fingerprinting in both patients with BBS and controls. Specific phosphatidylcholine and acylcarnitines discriminated eGFR decline only in patients with BBS. IMCD3-Bbs10-/ cells displayed intracellular lipidaccumulation, reduced mitochondrial potential membrane and citrate synthase staining. Mass-Spectrometry-based analysis revealed that human BBS10 interacted with six mitochondrial proteins, in vitro. In conclusion, renal dysfunction correlated with abnormal phosphatidylcholine and acylcarnitines plasma levels in patients with BBS; in vitro, Bbs10 depletion caused mitochondrial defects while human BBS10 interacted with several mitochondria-related proteins, suggesting an unexplored role of this protein.
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Introduction: Short/branched-chain acyl-CoA dehydrogenase deficiency (SBCADD) is an inherited disorder of L-isoleucine metabolism due to mutations in the ACADSB gene. The role of current diagnostic biomarkers [i.e., blood 2-methylbutyrylcarnitine (C5) and urine 2-methylbutyrylglycine (2MBG)] in patient monitoring and the effects of proposed treatments remain uncertain as follow-data are lacking. This study presents first systematic longitudinal biochemical assessment in SBCADD patients. Methods: A retrospective, observational single-center study was conducted on newborns born between 2017 and 2020 and suspected with SBCADD. Biochemical, molecular, clinical and dietary data collected upon NBS recall and during the subsequent follow-up were recorded. Results: All enrolled subjects (n = 10) received adequate protein intake and L-carnitine supplementation. Nine subjects were diagnosed with SBCADD. During the follow-up [median: 20.5 (4-40) months] no patient developed symptoms related to SBCADD. No patient normalized serum C5 and urine 2MBG values. In 7/9 SBCADD patients mean serum C5 values decreased or stabilized compared to their first serum C5 value. A major increase in serum C5 values was observed in two patients after L-carnitine discontinuation and during intercurrent illness, respectively. Urine 2MBG values showed moderate intra-patient variability. Discussion: The relatively stable serum C5 values observed during L-carnitine supplementation together with C5 increase occurring upon L-carnitine discontinuation/intercurrent illness may support the value of serum C5 as a monitoring biomarker and the benefit of this treatment in SBCADD patients. The role of urine 2MBG in patient monitoring remains uncertain. As all patients were asymptomatic, no association between biochemical parameters and clinical phenotype could be investigated in this study.
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Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy resulting in multiple organ dysfunctions, including chronic kidney disease (CKD). Despite the recent progress in the 'ciliopathy' field, there is still little information on the mechanisms underlying renal disease. To elucidate these pathomechanisms, we conducted a translational study, including (i) the characterization of the urine metabolomic pattern of BBS patients and controls in a pilot and confirmation study and (ii) the proteomic analysis of the BBS10 interactome, one of the major mutated BBS genes in patients, in a renal-epithelial-derived cell culture model. The urine metabolomic fingerprinting of BBS patients differed from controls in both pilot and confirmation studies, demonstrating an increased urinary excretion of several monocarboxylates, including lactic acid (LA), at both early and late CKD stages. Increased urine LA was detected in the absence of both increased plasmatic LA levels and generalized proximal tubular dysfunction, suggesting a possible renal-specific defective handling. The inner medulla renal epithelial (IMCD3) cell line, where Bbs10 was stably invalidated, displayed an increased proliferative rate, increased ATP production, and an up-regulation of aerobic glycolysis. A mass spectrometry-based analysis detected several putative BBS10 interactors in vitro, indicating a potential role of BBS10 in several biological processes, including renal metabolism, RNA processing, and cell proliferation. The present study suggests that the urine metabolomic pattern of BBS patients may reflect intra-renal metabolic aberrations. The analysis of BBS10 interactors unveils possible novel functions, including cell metabolism.
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Síndrome de Bardet-Biedl , Chaperoninas , Insuficiencia Renal Crónica , Síndrome de Bardet-Biedl/genética , Chaperoninas/genética , Humanos , Mutación , ProteómicaRESUMEN
Newborn screening (NBS) for inborn errors of metabolism is one of the most advanced tools for secondary prevention in medicine, as it allows early diagnosis and prompt treatment initiation. The expanded newborn screening was introduced in Italy between 2016 and 2017 (Law 167/2016; DM 13 October 2016; DPCM 12-1-2017). A total of 1,586,578 infants born in Italy were screened between January 2017 and December 2020. For this survey, we collected data from 15 Italian screening laboratories, focusing on the metabolic disorders identified by tandem mass spectrometry (MS/MS) based analysis between January 2019 and December 2020. Aminoacidemias were the most common inborn errors in Italy, and an equal percentage was observed in detecting organic acidemias and mitochondrial fatty acids beta-oxidation defects. Second-tier tests are widely used in most laboratories to reduce false positives. For example, second-tier tests for methylmalonic acid and homocysteine considerably improved the screening of CblC without increasing unnecessary recalls. Finally, the newborn screening allowed us to identify conditions that are mainly secondary to a maternal deficiency. We describe the goals reached since the introduction of the screening in Italy by exchanging knowledge and experiences among the laboratories.
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Galactosemia is an inborn disorder of carbohydrate metabolism characterized by the inability to metabolize galactose, a sugar contained in milk (the main source of nourishment for infants), and convert it into glucose, the sugar used by the body as the primary source of energy. Galactosemia is an autosomal recessive genetic disease that can be diagnosed at birth, even in the absence of symptoms, with newborn screening by assessing the level of galactose and the GALT enzyme activity, as GALT defect constitutes the most frequent cause of galactosemia. Currently, galactosemia cannot be cured, but only treated by means of a diet with a reduced content of galactose and lactose. Although the diet is able to reverse the neonatal clinical picture, it does not prevent the development of long-term complications. This review provides an overview of galactose metabolism, molecular genetics, newborn screening and therapy of galactosemia. Novel treatments for galactosemia currently being investigated in (pre)clinical studies and potentially able to prevent long-term complications are also presented.
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Galactosemias , Galactosa/metabolismo , Galactosemias/diagnóstico , Galactosemias/genética , Galactosemias/terapia , Humanos , Recién Nacido , Biología Molecular , Tamizaje Neonatal , UTP-Hexosa-1-Fosfato Uridililtransferasa/genéticaRESUMEN
Since its discovery in 2000 [...].