Clinical and genetic characteristics of a patient with phosphoribosyl pyrophosphate synthetase 1 deficiency and a systematic literature review.

Phosphoribosylpyrophosphate synthetase 1 (PRS-I) is an enzyme involved in nucleotide metabolism. Pathogenic variants in the PRPS1 are rare and PRS-I deficiency can manifest as three clinical syndromes: X-linked non-syndromic sensorineural deafness (DFN2), X-linked Charcot-Marie-Tooth neuropathy type 5 (CMTX5) and Arts syndrome. We present a Slovenian patient with PRS-I enzyme deficiency due to a novel pathogenic variant - c.424G > A (p.Val142Ile) in the PRPS1 gene, who presented with gross motor impairment, severe sensorineural deafness, balance issues, ataxia, and frequent respiratory infections. In addition, we report the findings of a systemic literature review of all described male cases of Arts syndrome and CMTX5 as well as intermediate phenotypes. As already proposed by other authors, our results confirm PRS-I deficiency should be viewed as a phenotypic continuum rather than three separate syndromes because there are multiple reports of patients with an intermediary clinical presentation.

Mapping of familial hypercholesterolemia and dyslipidemias basic management infrastructure in Pakistan: a cross-sectional study.

Background: Familial hypercholesterolemia (FH) is an autosomal inherited disorder characterised by elevated low-density lipoprotein cholesterol and premature cardiovascular events. Despite being declared as a public health priority, FH remains highly underdiagnosed, generally due to the lack of awareness and shortcomings in the available infrastructure, particularly in lower income countries. Methods: To map the existing infrastructure for the management of FH, a survey was conducted among 128 physicians (cardiologists, paediatricians, endocrinologists, and internal medicine specialists) from different regions of Pakistan. Findings: The respondents encountered a limited number of adults or children with diagnosed FH. A very small proportion of the population had access to free cholesterol and genetic testing even when indicated by a physician. In general, cascade screening of the relatives was not performed. Uniform diagnostic criteria for FH had not been established even within the same institution or province. The use of statins and ezetimibe in addition to lifestyle changes were the most common recommended treatment option for FH patients. The respondents considered lack of financial resources as a major barrier for the management of FH and stressed on taking relevant measures for a uniform FH screening programs around the country. Interpretation: National FH screening programmes are not in place worldwide hence FH is commonly undiagnosed, and many individuals are at a high risk for cardiovascular diseases. Timely screening of population for FH requires knowledge about FH among the clinicians and the availability of fundamental infrastructure coupled with sufficient financial resources. Funding: The authors confirm independence from the sponsor. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. FS received funding from Higher Education Commission, Pakistan (Grant 20-15760) and UG received grants from Slovenian Research Agency (J3-2536, P3-0343).

A simplified nasopharyngeal swab collection procedure for minimizing patient discomfort while retaining sample quality.

A nasopharyngeal swab (NPS) is the most frequently collected sample type when molecular diagnosis of respiratory viruses, including SARS CoV-2, is required. An optimal collection technique would provide sufficient sample quality for the diagnostic process and would minimize the discomfort felt by the patient. This study compares a simplified NPS collection procedure with only one rotation of the swab to a more standard procedure with five rotations. Swabs were collected from 76 healthy volunteers by the same healthcare professional on 2 consecutive days at a similar hour to minimize variability. The number of Ubiquitin C copy number per sample was measured by real-time quantitative PCR and patient discomfort was assessed by questionnaire. No statistically significant difference (p = 0.15) was observed in the Ubiquitin C copy number per sample between a NPS collected with one rotation (5.2 ± 0.6 log UBC number copies/sample) or five rotations (5.3 ± 0.5 log UBC number copies/sample). However, a statistically significant difference was observed in discomfort between these two procedures, the second being much more uncomfortable. Additional analysis of the results showed a weak correlation between discomfort and the number of human cells recovered (Spearman's rho = 0.202) and greater discomfort in younger people. The results of this study show that a NPS collected with one slow rotation has the same quality as a NPS collected with five rotations. However, the collection time is shorter and, most importantly, less unpleasant for patients.

Insulin Metabolism in Polycystic Ovary Syndrome: Secretion, Signaling, and Clearance.

Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder in women of reproductive age. Its heterogeneous clinical presentation is characterized by hyperandrogenemia, reproductive changes, polycystic ovary morphology, and insulin resistance (IR). The primary pathophysiological process in its multifactorial etiology has not yet been identified. However, the two most proposed core etiologies are the disruption of insulin metabolism and hyperandrogenemia, both of which begin to intertwine and propagate each other in the later stages of the disease. Insulin metabolism can be viewed as the interconnectedness of beta cell function, IR or insulin sensitivity, and insulin clearance. Previous studies of insulin metabolism in PCOS patients have yielded conflicting results, and literature reviews have focused mainly on the molecular mechanisms and clinical implications of IR. In this narrative review, we comprehensively explored the role of insulin secretion, clearance, and decreased sensitivity in target cells as a potential primary insult in PCOS pathogenesis, along with the molecular mechanism behind IR in PCOS.

Osilodrostat for Cushing Disease and Its Role in Pediatrics.

BACKGROUND: Cushing disease (CD) is a very rare form of hypercortisolism caused by an adrenocorticotropic hormone-secreting pituitary adenoma. Clinical manifestations of CD can include central fat accumulation, arterial hypertension, glucose intolerance, skin atrophy with striae, and hypogonadism. Children are frequently diagnosed due to a growth stunt and excessive weight gain while classic cushingoid signs might be initially absent. Other children-specific presentations of CD are early or delayed puberty and hyperandrogenism in girls. SUMMARY: We present the main outcomes of clinical trials of osilodrostat (Isturisa®, Recordati) for CD, and its initial development as an aldosterone synthase inhibitor. Osilodrostat is indicated only when the surgical therapy of the pituitary adenoma is not an option or has not been curative; additionally, other steroidogenesis inhibitors were briefly summarized. Clinical trials of osilodrostat in children are lacking and we describe its potential role in the pediatric population. KEY MESSAGES: Osilodrostat is the first adrenal steroidogenesis inhibitor to be European Medicines Agency- and United States Food and Drug Administration-approved (both in 2020) for the treatment of adults with Cushing syndrome/disease. Phase II and III clinical trials have shown its efficacy in normalizing 24-h urinary-free cortisol and a good safety profile. Osilodrostat's pharmacological properties and safety are currently being evaluated in a small Phase II trial (NCT03708900) - the first trial in the pediatric population (<18 years) with an estimated completion date in the year 2023.

The time is now: Achieving FH paediatric screening across Europe - The Prague Declaration.

Familial hypercholesterolaemia (FH) is the most common inherited metabolic disorder characterized by high cholesterol and if left untreated leads to premature cardiovascular disease, such as heart attacks. Treatment that begins early in life, particularly in childhood, is highly efficacious in preventing cardiovascular disease and cost-effective, thus early detection of FH is crucial. However, in Europe, less than 10% of people living with FH are diagnosed and even less receive life-saving treatment. The Prague Declaration is a call to action for national and European Union policymakers and decision-makers and a result of the Czech EU Presidency meeting on FH Paediatric Screening (early detection of inherited high cholesterol) at the Czech Senate in Prague on 6th September 2022. It builds on a considerable body of evidence which was discussed at the Technical Meeting under the auspices of the Slovenian EU Presidency in October 2021. The Prague meeting addressed the outstanding barriers to the systematic implementation of FH paediatric screening across Europe. In this article, we present the key points from the Prague meeting and concrete actions needed to move forward.

Paediatric familial hypercholesterolaemia screening in Europe: public policy background and recommendations.

Familial hypercholesterolaemia (FH) is under-recognized and under-treated in Europe leading to significantly higher risk for premature heart disease in those affected. As treatment beginning early in life is highly effective in preventing heart disease and cost-effective in these patients, screening for FH is crucial. It has therefore now been recognized by the European Commission Public Health Best Practice Portal as an effective strategy. Model programmes exist in Europe to identify young individuals with FH, which are based on cascade screening of first-degree relatives of affected individuals, universal screening for high cholesterol, opportunistic screening of high-risk individuals, or a combination of the above approaches. Recommendations presented herein to improve identification of FH emphasize that every country should have an FH screening programme. These programmes should be adapted from existing strategies to best fit the individual country's healthcare system, governments should provide financial support for these programmes and related care, and further research to optimize care and implementations should be conducted.

Towards Achieving Equity and Innovation in Newborn Screening across Europe.

Although individual rare disorders are uncommon, it is estimated that, together, 6000+ known rare diseases affect more than 30 million people in Europe, and present a substantial public health burden. Together with the psychosocial burden on affected families, rare disorders frequently, if untreated, result in a low quality of life, disability and even premature death. Newborn screening (NBS) has the potential to detect a number of rare conditions in asymptomatic children, providing the possibility of early treatment and a significantly improved long-term outcome. Despite these clear benefits, the availability and conduct of NBS programmes varies considerably across Europe and, with the increasing potential of genomic testing, it is likely that these differences may become even more pronounced. To help improve the equity of provision of NBS and ensure that all children can be offered high-quality screening regardless of race, nationality and socio-economic status, a technical meeting, endorsed by the Slovenian Presidency of the Council of the European Union, was held in October 2021. In this article, we present experiences from individual EU countries, stakeholder initiatives and the meeting's final conclusions, which can help countries attempting to establish new NBS programmes or expand existing provision.

Performance of nasopharyngeal swab and saliva in detecting Delta and Omicron SARS-CoV-2 variants.

A prospective cohort study was conducted during the Delta and Omicron severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) epidemic waves from paired nasopharyngeal swab (NPS or NP swab) and saliva samples taken from 624 participants. The study aimed to assess if any differences among participants from both waves could be observed and if any difference in molecular diagnostic performance could be observed among the two sample types. Samples were transported immediately to the laboratory to ensure the highest possible sample quality without any freezing and thawing steps before processing. Nucleic acids from saliva and NPS were prospectively extracted and SARS-CoV-2 was detected using a real-time reverse-transcription polymerase chain reaction. All observed results were statistically analyzed. Although the results obtained with NP and saliva agreed overall, higher viral loads were observed in NP swabs regardless of the day of specimen collection in both SARS-CoV-2 epidemic waves. No significant difference could be observed between the two epidemic waves characterized by Delta or Omicron SARS-CoV-2. To note, Delta infection resulted in higher viral loads both in NP and saliva and more symptoms, including rhinorrhea, cough, and dyspnea, whereas Omicron wave patients more frequently reported sore throat. An increase in the mean log RNA of SARS-CoV-2 was observed with the number of expressed symptoms in both waves, however, the difference was not significant. Data confirmed that results from saliva were concordant with those from NP swabs, although saliva proved to be a challenging sample with frequent inhibitions that required substantial retesting.

Long-Term Follow-Up of Three Family Members with a Novel NNT Pathogenic Variant Causing Primary Adrenal Insufficiency.

Nicotinamide nucleotide transhydrogenase (NNT) deficiency causes primary adrenal insufficiency (PAI) and possibly some extra-adrenal manifestations. A limited number of these patients were previously described. We present the clinical and genetic characteristics of three family members with a biallelic novel pathogenic variant in the NNT gene. The patients were followed until the ages of 21.6, 20.2, and 4.2 years. PAI was diagnosed in the eldest two brothers after an Addisonian crisis and the third was diagnosed at the age of 4.5 months in the asymptomatic stage due to the genetic screening of family members. Whole exome sequencing with a targeted interpretation of variants in genes related to PAI was performed in all the patients. The urinary steroid metabolome was determined by gas chromatography-mass spectrometry in the asymptomatic patient. The three patients, who were homozygous for c.1575dup in the NNT gene, developed isolated glucocorticoid deficiency. The urinary steroid metabolome showed normal excretion of cortisol metabolites. The adolescent patients had slow pubertal progression with low-normal testicular volume, while testicular endocrine function was normal. Bone mineral density was in the range for osteopenia in both grown-up siblings. Echocardiography revealed no structural or functional heart abnormalities. This article is among the first with a comprehensive and chronologically-detailed description of patients with NNT deficiency.

Clinical and genetic characteristics of two patients with tyrosinemia type 1 in Slovenia - A novel fumarylacetoacetate hydrolase (FAH) intronic disease-causing variant.

Tyrosinemia type 1 (HT1) is an inborn error of tyrosine catabolism that leads to severe liver, kidney, and neurological dysfunction. Newborn screening (NBS) can enable a timely diagnosis and early initiation of treatment. We presented the follow up of the only two Slovenian patients diagnosed with HT1. Metabolic control was monitored by measuring tyrosine, phenylalanine and succinylacetone from dried blood spots (DBSs). Retrograde screening of HT1 was performed from DBSs taken at birth using tandem mass spectrometry. First patient was diagnosed at the age of 6 months in the asymptomatic phase due to an abnormal liver echogenicity, the other presented at 2.5 months with an acute liver failure and needed a liver transplantation. The first was a compound heterozygote for a novel FAH intronic variant c.607-21A>G and c.192G>T whereas the second was homozygous for c.192G>T. At the non-transplanted patient, 66% of tyrosine and 79% of phenylalanine measurements were in strict reference ranges of 200-400 µmol/L and >30 µmol/L, respectively, which resulted in a favorable cognitive outcome at 3.6 years. On retrograde screening, both patients had elevated SA levels; on the other hand, tyrosine was elevated only at one. We showed that non-coding regions should be analyzed when clinical and biochemical markers are characteristic of HT1. DBSs represent a convenient sample type for frequent amino acid monitoring. Retrograde diagnosis of HT1 was possible after more than three years of birth with SA as a primary marker, complemented by tyrosine.

Data on phenylalanine-to-tyrosine ratios in assessment of tetrahydrobiopterin (BH4)-responsiveness in patients with hyperphenylalaninemia.

Blood phenylalanine-to-tyrosine (Phe/Tyr) ratio is an important indicator of metabolic control in phenylketonuria patients. We present the data that highlights the role of Phe/Tyr-ratio in the evaluation of tetrahydrobiopterin (BH4)-responsiveness in patients with hyperphenylalaninemia. Our data complements the results from the original research article by Tansek et al., 2012 [1]. We performed a BH4-loading test in 32 patients after four days of increased protein intake (2000 mg/kg body weight). Blood sampling was performed 96, 72, 48, 24, 16 h, and moments before oral administration of BH4 in a dose of 20 mg/kg body weight. Additional blood samples were collected 8 and 24 h after its administration. Phenylalanine (Phe) and Tyrosine (Tyr) levels were determined from dried blood spots by tandem mass spectrometry. Phe/Tyr-ratio reached a plateau after three days of increased dietary protein intake. Fifteen patients (47%) responded to BH4, defined as a decrease of Phe-of at least 30% after 24 h of BH4 administration. Phe/Tyr-ratios were significantly higher in non-responders compared to responders. In the responder group, Phe/Tyr-ratios decreased in average of 67% (p = 0.001) and 45% (p = 0.001) after 8 and 24 h of BH4 administration, respectively. Phe/Tyr-ratio decreased after 8 h of drug administration also in the non-responder group, but not 24 h after administration.