Search Results (152)

Background: Congenital Adrenal Hyperplasia (CAH) is a group of autosomal recessive disorders caused by impaired adrenal steroidogenesis, most frequently due to pathogenic variants in the CYP21A2 gene leading to 21-hydroxylase deficiency (21-OHD). Epidemiology and management vary across the Mediterranean Basin as a result of genetic and healthcare differences. Objective: To provide an overview of the epidemiology, diagnostic approaches and treatment patterns of CAH in Mediterranean countries. Methods: A structured review of the literature was performed using PubMed, using combined disease-related, geographic and methodological terms. Eligible studies reporting on epidemiology, diagnosis, or management of CAH were included. Data on study design, population characteristics, incidence, diagnostics, genetics and treatment availability were extracted. Results: Data were collected from 23 Mediterranean and neighboring regions covering over 8.7 million screened newborns. In countries with established newborn screening (e.g., Spain, Italy, France, Greece), the incidence of classic CAH ranged from 1:10,000 to 1:25,000 live births. Higher rates were reported in parts of North Africa and the Eastern Mediterranean. Diagnostic set-up and access to biochemical and genetic confirmation varied widely. Hydrocortisone remains the primary therapy, while access to mineralocorticoids and modified-release glucocorticoids differed across settings. Conclusions: Overall, considerable heterogeneity in CAH epidemiology and care exists across the Mediterranean region. Genetic factors such as founder effects, consanguinity and healthcare organization contribute to these differences. Expanding newborn screening, improving diagnostics and availability to treatments are critical to reducing disparities in CAH care. Full article

Newborn screening for congenital adrenal hyperplasia (CAH) is effective in identifying patients with severe forms before a potentially lethal crisis, but has a relatively high false-positive rate. The aim of this study was to improve the national neonatal screening program in Sweden and the positive predictive value by implementing LC-MS/MS second-tier testing. A combination of two independent parameters, the steroid hormone ratio (androstenedione+17-hydroxyprogesterone)/cortisol and the concentration of 21-deoxycortisol and adjustment of cut-off levels resulted in an increase in the positive predictive value (PPV) from 14% to 84% for full-term infants. In total, the false-positive screening cases decreased by 88%. CYP21A2 genotyping was used to determine the severity of CAH in identified cases. We report on the stepwise approach that was used to optimize the cut-off levels for full-term and preterm infants in order not to miss any true cases in the process. Full article

Phenylketonuria (PKU) is an autosomal recessive disorder characterised by an inborn error of phenylalanine (Phe) metabolism. Such errors are attributed to pathogenic gene variants causing phenylalanine hydroxylase (PAH) deficiency, impairing the hydroxylation of phenylalanine to tyrosine in the Phe metabolic pathway. This defect leads to plasma Phe concentrations above the normal range. If untreated, hyperphenylalaninemia can adversely affect brain function, leading to severe intellectual disability and seizures. Since 1969, the newborn dried blood spot test has remained the main method of early screening and diagnosis for PKU. The primary therapeutic management is a lifelong phenylalanine-restricted diet with the aim of decreasing plasma Phe levels. The recommended diet consists of avoiding high-protein foods such as meat, fish, eggs and nuts, and can be supplemented with high-protein medical formulas which are low in phenylalanine. Pharmacological interventions such as sapropterin, sepiapterin and pegvaliase can also be used as treatment adjuncts in patients with PKU. Currently, small-molecule inhibitors reducing renal phenylalanine reabsorption are being explored as a potential therapeutic intervention. Furthermore, novel gene-editing techniques are under evaluation as potential curative strategies, with preclinical studies showing promising results in correcting pathogenic phenylalanine hydroxylase variants. This non-systematic review synthesises current literature on the management of PKU, with a focus on dietary interventions and recommendations. Full article

Background/Objectives: Non-classical congenital adrenal hyperplasia (NCCAH) due to 21-hydroxylase deficiency represents the mildest form of congenital adrenal hyperplasia and is frequently diagnosed only after the onset of clinical signs in childhood. Newborn screening programs for CAH are primarily designed to detect classical forms and show limited sensitivity for NCCAH. The clinical significance of neonatal 17-hydroxyprogesterone (17-OHP) values below recall thresholds remains incompletely defined. Methods: We retrospectively analyzed clinical, auxological, hormonal, and genetic data from pediatric patients diagnosed with NCCAH between 2018 and 2023 at a tertiary referral center. Neonatal screening 17-OHP concentrations, basal and ACTH-stimulated 17-OHP levels at diagnosis, bone age advancement, pubertal status, and hydrocortisone treatment were evaluated. Correlations between hormonal parameters, age at onset, and treatment dose were assessed. Results: Thirty-five patients (30 females) were included, with a mean age at clinical onset of 7.52 ± 0.36 years for females and 6.25 ± 0.29 years for males. Premature pubarche was the most frequent presenting sign (94.3%), and central precocious puberty was diagnosed in 31.4% of cases. The mean neonatal screening 17-OHP level was 4.53 ± 0.7 ng/mL; only two patients exceeded the screening recall cut-off. At diagnosis, mean basal and ACTH-stimulated 17-OHP levels were 15.1 ± 3.35 and 55.2 ± 11.3 ng/mL, respectively. Age at clinical onset was inversely correlated with both basal and stimulated 17-OHP levels, while hydrocortisone dose correlated positively with biochemical severity. Bone age advancement was observed in all patients. Conclusions: Most children with NCCAH display mildly elevated neonatal 17-OHP values that do not trigger screening recall. Higher biochemical severity is associated with earlier clinical presentation and higher glucocorticoid requirements. Neonatal 17-OHP concentrations, even when below cut-off values, may represent an early indicator of disease severity and warrant further investigation. Full article

Background and Clinical Significance: Scurvy, caused by chronic vitamin C deficiency, is re-emerging in Western countries, particularly among pediatric patients with highly selective diets. While its musculoskeletal and mucocutaneous manifestations are well-known, its association with pulmonary arterial hypertension (PAH) is rare and poorly understood. Ascorbic acid and iron are essential cofactors for prolyl hydroxylases (PHD), which regulate Hypoxia-Inducible Factors. Their combined deficiency may trigger a “pseudohypoxic” state, leading to pulmonary vascular remodeling and vasoconstriction. Case Presentation: A 30-month-old female presented with a one-month history of limping, lower limb pain, and gingival hypertrophy. Dietary history revealed an almost exclusive cow’s milk-based intake. Physical examination showed diffuse petechiae, pallor, and right knee edema. Laboratory findings confirmed scurvy (undetectable vitamin C), severe iron-deficiency anemia (Hb: 72 g/L; ferritin: 22 mcg/L; RDW: 30%), folate deficiency, and hyperhomocysteinemia. Notably, elevated copper and vitamin B12 levels suggested a state of metabolic dysregulation. Echocardiography revealed moderate PAH phenotype (estimated sPAP: 47–50 mmHg) and a hyperdynamic contractility. A “perfect storm” mechanism was hypothesized, involving iron–ascorbate-dependent PHD impairment, high-output state, and oxidative-stress-induced hepcidin dysregulation (suggested by elevated copper). Following intravenous vitamin C and multivitamin supplementation, pulmonary pressures normalized within one week. Conclusions: PAH phenotype in scurvy represents a reversible metabolic disruption of pulmonary vascular tone rather than a structural disease. This case underscores the synergistic role of vitamin C, iron, and folate in vascular homeostasis. Clinicians should maintain high suspicion for scurvy in children with selective diets and unexplained PAH, as nutritional restoration is curative. Full article

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by age-dependent degeneration of dopaminergic neurons in the substantia nigra, a process mediated by α-synuclein aggregation, mitochondrial dysfunction, and impaired proteostasis. While BAP31—an endoplasmic reticulum protein critical for protein trafficking and degradation—has been implicated in neuronal processes, its role in PD pathogenesis remains poorly understood. To investigate the impact of BAP31 deficiency on PD progression, we generated dopamine neuron-specific BAP31 conditional knockout with DAT-Cre (cKO) mice (Slc6a3cre-BAP31^fl/fl) and subjected them to MPTP-lesioned Parkinsonian models. Compared to BAP31^fl/fl controls, Slc6a3cre-BAP31^fl/fl mice exhibited exacerbated motor deficits following MPTP treatment, including impaired rotarod performance, reduced balance beam traversal time, and diminished climbing and voluntary motor capacity abilities. BAP31 conditional deletion showed no baseline phenotype, with deficits emerging only after MPTP. Our results indicate that these behavioral impairments correlated with neuropathological hallmarks: decreased NeuN neuronal counts, elevated GFAP astrogliosis, reduced tyrosine hydroxylase levels in the substantia nigra, and aggravated dopaminergic neurodegeneration. Mechanistically, BAP31 deficiency disrupted mitochondrial homeostasis by suppressing the PINK1–Parkin mitophagy pathway. Further analysis revealed that BAP31 regulates PINK1 transcription via the transcription factor Engrailed Homeobox 1. Collectively, our findings identify BAP31 as a neuroprotective modulator that mitigates PD-associated motor dysfunction by preserving mitochondrial stability, underscoring its therapeutic potential as a target for neurodegenerative disorders. Full article

Background and Clinical Significance: This report presents the case of a 33-year-old female with recurrent miscarriage, investigated for an adrenal cortical adenoma characterized by autonomous secretion of 17-hydroxyprogesterone (17-OHP). The findings challenge the established diagnostic paradigm, which predominantly attributes elevated serum 17-OHP to congenital adrenal hyperplasia (CAH) or non-classical CAH (NCCAH). Case Presentation: The patient was found to have elevated serum 17-OHP and a 2 cm left adrenal mass. Normal testosterone and precursor levels, along with whole-exome sequencing (WES), argued against a diagnosis of non-classical 21-hydroxylase deficiency (NC-21OHD). An ACTH stimulation test elicited a mild-to-moderate rise in 17-OHP, while adrenal venous sampling (AVS) confirmed marked lateralization of 17-OHP hypersecretion to the left side. Postoperative normalization of 17-OHP levels further supported the diagnosis of a 17-OHP-secreting tumor. Histopathological analysis identified tumor regions with non-uniformly high expression of CYP17A1 and CYP21A2. Preliminary transcriptomic profiling revealed that differentially expressed genes (DEGs) were enriched in microRNA-related and PI3K-Akt signaling pathways. Conclusions: This paradigm-shifting case indicates that, in addition to 21OHD, a 17-OHP-hypersecreting adrenal adenoma should be considered in the differential diagnosis of elevated 17-OHP. The integration of multimodal diagnostic techniques, particularly AVS, is valuable for localizing hormonally active tumors. Preliminary mechanistic insights suggest a potential role for epigenetic dysregulation in the pathogenesis of this tumor type. Full article

This study was designed to assess the effectiveness of neonatal congenital adrenal hyperplasia (CAH) screening in Guangzhou, China. A total of 818,417 newborns were screened for CAH by measuring 17-hydroxyprogesterone (17-OHP) concentrations. Cut-off values were stratified based on gestational age (GA) and the timing of sample collection. Neonates with initial positive results (17-OHP ≥ cut-off value) were recalled for a second dried blood spot sample to reassess 17-OHP levels. Confirmatory testing involved biochemical analyses, Sanger sequencing, and multiplex ligation-dependent probe amplification of the CYP21A2 gene. From 2018 to 2024, a total of 40 patients with classical 21-hydroxylase deficiency were identified, including 28 cases (70%) of the salt-wasting form and 12 cases (30%) of the simple virilizing form. The overall incidence of CAH was 1 in 20,653 (95% confidence interval: 1:34,928, 1:14,661). No statistically significant differences in prevalence were observed between sexes or between preterm and full-term infants (p > 0.05). 17-OHP concentrations are influenced by GA and the timing of sample collection. The screening efficiency for CAH could be improved by adopting a multitiered cut-off value system adjusted for GA and collection time. Full article

Phenylketonuria (PKU) is a rare inherited metabolic disorder caused by phenylalanine hydroxylase deficiency, leading to phenylalanine (Phe) accumulation and neurological dysfunction if untreated. While metabolomics holds promise for biomarker discovery in PKU, few studies have examined urinary metabolites using untargeted approaches. This study applied untargeted metabolomics using HPLC-QTOF-MS to analyze urine from 36 adult patients with PKU and 34 healthy controls. Biomarker Analysis was performed with MetaboAnalyst 6.0. A total of 73 significant metabolites (FDR < 0.05; VIP > 1) were identified, with 29 upregulated and 44 downregulated in PKU. A 23% of these metabolites were related to Phe metabolism, while 77% were associated with alterations across more than 10 metabolic pathways, including leucine and tryptophan metabolism, acylcarnitines, vitamins, and diet- or microbiota-derived compounds, among others. Specifically, upregulated metabolites with an AUC > 0.9 included several Phe-derived compounds, the nucleoside 8-hydroxy-7-methylguanine, and indole compounds (1H-indole-3-carboxaldehyde). Conversely, downregulated metabolites with an AUC > 0.9 included N-acetyl(iso)leucine and a heptenoylcarnitine isomer. The Random Forest-based model demonstrated enhanced predictive performance when integrating 10 metabolites, supporting their potential utility as biomarkers for PKU. These findings improve the biological understanding of metabolic disturbances beyond Phe, and may support the development of new therapeutic and dietary strategies. Full article

Vitamin D deficiency is highly prevalent in Pakistan, but there is limited data on its genetic aspects. This case–control pilot study aimed to determine the association of rs782153744, rs200183599, rs118204011, and rs28934604 with vitamin D deficiency along rs7041 which has been studied in our population. The DNA of a total of 600 subjects (300 cases and 300 controls) was extracted and genotyped by tetra ARMS PCR, followed by Sanger DNA sequencing of exon 4 of the CYP2R1 and CYP27B1 genes and exon 8 of the GC gene. SNP Stat was employed to analyze the data, while logistic regression was used to calculate the p-values and odds ratios (ORs). The R package version R studio (2025.05.1) Build 513 was used to statistically analyze rs782153744. In silico modeling of wild and mutant CYP2R1 and GC proteins was performed in Swiss-Model, Swiss-Dock, Discovery Studio, and PyMol using 3c6g and IJ78 as templates to perform binding pocket analysis of vitamin D3. The rs782153744 showed a protective association in the additive (OR: 0.15, 95% CI: 0.08–0.27, p-value < 0.001), recessive (OR: 0.19, 95% CI: 0.10–0.33, p-value < 0.001), and dominant (OR: 0.19, CI = 0.10–0.33, p-value < 0.001) models, while GC rs7041 (T > A, T > G) displayed a p-value < 0.0001 across all genetic models. Sanger sequencing yielded insignificant results, and the SNPs rs200183599, rs118204011, and rs28934604 had no significant association with vitamin D deficiency. The molecular pocket analysis of wild and mutant CYP2R1 proteins carrying rs782153744 polymorphisms revealed no changes. GC proteins carrying the rs7041 polymorphism revealed a shift in their 3D and 2D configuration, as well as a change in the amino acid residue of the binding pocket of VD3. The risk-associated rs7041 and protective rs782153744 variants back genetic screening for vitamin D deficiency risk stratification, allowing targeted supplementation in predisposed subjects and assisting in formulating a genotype-specific therapeutic approach. Full article

Fatty-acid-hydroxylase-associated neurodegeneration (FAHN) is a rare neurodegenerative disorder caused by loss-of-function mutations in the FA2H gene, leading to impaired enzymatic activity and resulting in myelin sheath instability, demyelination, and axonal degeneration. In this study, we established a human in vitro model using neurons and oligodendrocytes derived from induced pluripotent stem cells (hiPSCs) of a FAHN patient. This coculture system enabled the investigation of myelination processes and myelin integrity in a disease-relevant context. Analyses using immunofluorescence and Western blot revealed impaired expression and localisation of key myelin proteins in oligodendrocytes and cocultures. FA2H-deficient cells showed reduced myelination, shortened internodes, and disrupted formation of the nodes of Ranvier. Additionally, we identified autophagy defects—a hallmark of many neurodegenerative diseases—including reduced p62 expression, elevated LC3B levels, and impaired fusion of autophagosomes with lysosomes. This study presents a robust hiPSC-based model to study FAHN, offering new insights into the molecular pathology of the disease. Our findings suggest that FA2H mutations compromise both the structural integrity of myelin and the efficiency of the autophagic machinery, highlighting potential targets for future therapeutic interventions. Full article

Background: Parkinson’s disorder (PD) affects around 1:500 individuals and is associated with enlarged ventricles and symptoms of normal pressure hydrocephalus (NPH). These features suggest disrupted cerebrospinal fluid (CSF) dynamics and folate metabolism. With L-DOPA treatment showing diminishing benefits over time, there is an urgent need to investigate upstream metabolic disruptions, including folate and tetrahydrobiopterin (BH4) pathways, in post-mortem CSF and brain tissue to understand their roles in PD pathogenesis. Methods: CSF and brain tissue from 20 PD patients (mean age 84 years; 55% male; disease duration 10–30 years) and 20 controls (mean age 82 years; 50% male) were analysed. Western and Dot Blots measured proteins and metabolites, spectroscopic assays assessed enzyme activities, BH4 and Neopterin levels were measured using ELISA, and levels of hydrogen peroxide, used as a proxy for reactive oxygen species, and calcium were quantified using horseradish peroxidase and flame photometry assays, respectively. ClinVar genetic data were analysed for variants in genes encoding key enzymes. Statistical significance was assessed using unpaired t-tests (p < 0.05). Results: All enzymes were significantly reduced in PD compared to controls (p < 0.01) except for methyltetrahydrofolate reductase (MTHFR), which was elevated (p < 0.0001). Enzymes were functional in control but undetectable in PD CSF except tyrosine hydroxylase (TH). BH4 and Neopterin were elevated in PD CSF (p < 0.0001, p < 0.001) but significantly reduced (p < 0.001) or unchanged in tissue. Peroxide was increased in both PD CSF (p < 0.001) and tissue (p < 0.0001) selectively inhibiting TH. Calcium was 40% higher in PD than controls (p < 0.05). No pathogenic variants in enzyme genes were found in ClinVar data searches, suggesting the observed deficiencies are physiological. Conclusions: We identified significant disruptions in folate and BH4 pathways in PD, with enzyme deficiencies, oxidative stress and calcium dysregulation pointing to choroid plexus dysfunction. These findings highlight the choroid plexus and CSF as key players in cerebral metabolism and promote further exploration of these as therapeutic targets to address dopaminergic dysfunction and ventricular enlargement in PD. Full article

Background: Congenital adrenal hyperplasia (CAH) represents a group of autosomal recessive disorders characterized by impaired cortisol synthesis in the adrenal glands. Over 90% of CAH cases result from a deficiency of the enzyme 21-hydroxylase (21OHD). The clinical spectrum of 21OHD ranges from the severe, life-threatening salt-wasting classic form, often presenting with prenatal virilization in females, to the non-classic (milder) form, which lacks glucocorticoid deficiency. Females with the non-classic form may experience symptoms of hyperandrogenism or infertility later in life, while males with non-classic CAH are often undiagnosed due to the subtler presentation. The coexistence of genetic anomalies and CAH is rarely reported in the literature, particularly in cases involving Triple X syndrome—a condition typically associated with a mild and frequently underdiagnosed clinical course. Case presentation: Here, we present a unique case of a 38-year-old woman with a history of premature ovarian failure and subsequent clinical features of hyperandrogenism. Further investigation revealed a novel association between partial 21OHD and a Triple X karyotype—an association not previously documented in the literature. Conclusions: This case highlights the potential for coexisting rare genetic conditions and underscores the critical importance of thorough and meticulous clinical evaluation. Full article

Long-read sequencing (LRS) provides comprehensive genetic information, but research of LRS applied to congenital adrenal hyperplasia (CAH) newborn screening is limited. This study aimed to evaluate the clinical utility of LRS in genetic diagnosis and second-tier newborn screening. Neonates born between January 2017 and December 2022 in Fujian, China, were recruited for biochemical and LRS-based genetic screening assay. The LRS covers the entire gene regions and exon–intron boundary regions for CYP21A2, CYP11B1, CYP17A1, HSD3B2, and StAR. In this retrospective study, 1,774,555 newborns received 17α-OHP screening, yielding a screening positive rate of 0.20%. Of these high-risk neonates, 3411 were successfully recalled for re-evaluation. Finally, 66 neonates were diagnosed with CAH, with a positive predictive value of 28.82%. Based on this data, the overall prevalence of CAH in Fujian was estimated to be 1:26,883. LRS was performed on 57 neonates with 21-hydroxylase deficiency (21-OHD) and 109 variant alleles were identified. The c.293-13C>G variant (31.19%) was the most prevalent in Fujian. Additionally, 647 neonates with suspected positive results were genotyped, and 41 were identified as carriers, with carrier frequencies of 1:18 for CYP21A2, 1:162 for HSD3B2, and 1:324 for CYP17A1 in Xiamen. Therefore, LRS can provide comprehensive genotypes in approximately 1.5 days at a cost of less than $20 USD per sample, and effectively improve screening efficiency, reduce anxiety of parents during newborn screening (NBS), and shorten the time to referral of CAH patients (approximately 10 days). Such a combined screening strategy is worthy to be recommended for NBS programs in the future. Full article