The management and clinical outcomes of pregnancies in women with urea cycle disorders: A review of the literature and results of an international survey.

An increasing number of women with urea cycle disorders (UCDs) are reaching child-bearing age and becoming pregnant. Improved diagnostics and increased awareness of inherited metabolic diseases has also led to more previously undetected women being diagnosed with a UCD during or shortly after pregnancy. Pregnancy increases the risk of acute metabolic decompensation with hyperammonemia-which can occur in any trimester, and/or the postpartum period, and may lead to encephalopathy, psychosis, coma, and even death, if not diagnosed promptly and treated appropriately. There are also (theoretical) concerns that a maternal UCD, or its treatment, may cause potential risks for the unborn child. Currently evidence on management and outcome of pregnancies in UCDs is limited to case reports and there are no clear guidelines. In order to inform management and investigate outcomes of pregnancies in women with a UCD, we performed a retrospective review of published cases and analyzed data collected from an international online survey. We conclude that, although risk during the intra- and postpartum period exists, multidisciplinary management by an experienced team and a prospective plan usually result in successful pregnancy, labor, delivery, and postpartum period. No deaths were reported in mothers managed accordingly. With the exception of male neonates with Ornithine Transcarbamylase deficiency, the clinical outcome of children born to mothers with UCDs appears positive, although follow-up is limited. The outcome for women presenting with a first acute metabolic decompensation during pregnancy or postpartum is less favorable. Deaths were associated with diagnostic delay/late management of hyperammonemia in previously undiagnosed women.

Knowledge, perceptions and behaviours regarding dietary management of adults living with phenylketonuria.

BACKGROUND: Lifelong dietary treatment remains the mainstay for many with phenylketonuria (PKU); however, adherence is known to reduce with age. It remains unclear whether knowledge and perceptions of the PKU diet amongst adults with PKU influence dietary behaviours. METHODS: A nationwide questionnaire survey was performed to investigate the knowledge and perceptions, and associated diet behaviours of adults with PKU in the UK. The survey was sent to adults with PKU under the care of the host hospital and members of the National Society of PKU. RESULTS: One hundred and thirty-seven respondents (n = 78 females, 56.9%) completed the survey with a mean age of 34 years and 4 months (16-65 years). Sixty (43.8%) respondents had always followed a PKU diet, 39 (28.5%) returned to diet and 35 (25.5%) were off diet. Overall mean ± SD knowledge score was 75.2% ± 13.4%, with significantly higher scores for knowledge of PKU (80.7% ± 16.2%) compared to knowledge specifically of the PKU diet (72.6% ± 14.5%, p < 0.001). Knowledge was associated with dietary adherence. Respondents who always followed a PKU diet had similar knowledge to those who returned to diet, whereas respondents off diet had significantly lower scores. Perception of the diet was not a predictor of dietary adherence, with the exception of whether patients had concerns for their long-term health when on diet or felt well when not following a diet. CONCLUSIONS: The present study highlights the importance of ongoing dietetic input in building knowledge and skills for dietary management. Further research is needed to understand the motivators and beliefs that influence dietary adherence.

Low cholesterol syndrome and drug development.

PURPOSE OF REVIEW: Low cholesterol syndromes were considered curiosities. The present article reviews some hypolipidaemic disorders and the drugs developed from the insights they provided. RECENT FINDINGS: Abetalipopoproteinaemia and hypobetalipoproteinaemia are associated with low cholesterol concentrations and caused by mutations in apolipoprotein (apo) B or microsomal transfer protein. This led to the development of mipomersen and lomitapide which are used to treat homozygous familial hypercholesterolaemia. Mutations in proprotein convertase subtilisin kexin-9 (PCSK9) can cause either high or low cholesterol. Loss of function PCSK9 mutations prompted the development of antibody therapies to PCSK9 which are now widely used to treat hypercholesterolaemia. Mutations in apolipoprotein C-3 and angiopoietin-like protein 3 (ANGPTL3) cause hypolipoproteinaemia and reduced triglycerides. Antisense therapies to apolipoprotein C-3 and antibodies to ANGPTL3 are in development to treat familial chylomicronaemia syndrome. Activating mutations in apoA-1 result in hyper-functioning high-density lipoprotein (HDL) and suggest that modifying HDL turnover may reduce cardiovascular disease (CVD) risk. SUMMARY: Orphan lipid disorders have provided insights into mechanisms involved in lowering cholesterol levels and the potential safety and efficacy of interventional processes. They have been not only enabled development of drugs to treat rare lipid disorders but also those finding wider use in general lowering of CVD risk.

Pro-protein subtilisin kexin-9 (PCSK9) inhibition in practice: lipid clinic experience in 2 contrasting UK centres.

BACKGROUND: Prescribing criteria have been suggested for proprotein convertase subtilisin kexin-9 (PCSK-9) inhibitors but few studies exist of their real-world effectiveness. METHODS: This study audited PCSK-9 inhibitor therapy in 105 consecutive patients from two hospital centres-a university hospital (UH; n = 70) and a district general hospital (DGH; n = 35). Baseline characteristics including cardiovascular disease risk factors, NICE qualification criteria, efficacy and side effects were assessed. RESULTS: Baseline LDL-C levels were similar in both centres. NICE criteria were met for 2.05 items in the whole study (UH patients 1.7 and DGH patients 2.7). District general hospital patients were more likely to have familial hypercholesterolaemia (89 vs 69%; P = .02); intolerance to statins (94 vs 52%; P < .001) and polyvascular disease (42% vs 17%; P = .005). Prescriptions (evolocumab 73%; alirocumab 23%) were collected by 76% of patients (UH 64% vs DGH 100%). Therapy was discontinued by time of review in 15% of patients (UH 7% vs DGH 25%; P = .02). In adherent patients PCSK-9 inhibitor treatment reduced TC by 28% (2.24 ± 2.39 mmol/L; P < .001) and LDL-C by 49% (2.10 ± 1.33 mmol/L; P < .001). A LDL-C < 2.5 mmol/L was achieved in 30% of patients and <2.0 mmol/L in 20%. PCSK-9 therapy was effective and safe in patients with increased lipoprotein (a), diagnosed muscle diseases (including myopathies and muscular dystrophy) or poststatin rhabdomyolysis, nephrotic syndrome or HIV disease. Mixed results were obtained in patients with significant mixed hyperlipidaemia. CONCLUSIONS: This study suggests that PCSK-9 inhibitors are effective but that prescriptions should not be changed to long-term delivery until patients have been reviewed and shown to be adherent.

An island of stability in a sea of fingers: emergent global features of the viscous-flow instability.

The displacement of a more viscous fluid by a less viscous one in a quasi-two dimensional geometry leads to the formation of complex fingering patterns. This fingering has been characterized by a most unstable wavelength, λc, which depends on the viscosity difference between two immiscible fluids and sets the characteristic width of the fingers. How the finger length grows after the instability occurs is an equally important, but previously overlooked, aspect that characterizes the global features of the patterns. Long after the instability onset, once the fingers are growing in a nearly steady-state regime, there is a stable inner region where the outer fluid is completely displaced. We show that the ratio of the finger length to the radius of this stable region depends only on the viscosity ratio of the fluids and is decoupled from λc.

Long-term effects of volanesorsen on triglycerides and pancreatitis in patients with familial chylomicronaemia syndrome (FCS) in the UK Early Access to Medicines Scheme (EAMS).

BACKGROUND AND AIMS: The VOL4002 study assessed the efficacy and safety of volanesorsen in 22 adults with genetically confirmed familial chylomicronaemia syndrome (FCS) treated in the UK Early Access to Medicines Scheme (EAMS), with ("prior exposure") or without ("treatment naive") previous treatment in the APPROACH and/or APPROACH-OLE volanesorsen phase 3 studies. METHODS: Data collection focused on triglyceride (TG) levels, platelet counts and pancreatitis events. Pancreatitis incidence during volanesorsen treatment was compared against the 5-year period preceding volanesorsen exposure. Volanesorsen 285 mg was self-administered subcutaneously once every 2 weeks. RESULTS: Individual patient volanesorsen exposure ranged from 6 to 51 months (total cumulative exposure, 589 months). Among treatment-naive patients (n = 12), volanesorsen treatment resulted in an averaged median 52% reduction (-10.6 mmol/L) from baseline (26.4 mmol/L) in TG levels at 3 months, which were maintained through time points over 15 months of treatment (47%-55% reductions). Similarly, prior-exposure patients (n = 10) experienced a 51% reduction (-17.8 mmol/L) from pre-treatment baseline (28.0 mmol/L), with reductions of 10%-38% over 21 months of treatment. A comparison of pancreatitis event rates found a 74% reduction from the 5-year period before (one event/2.8 years) and during (one event/11.0 years) volanesorsen treatment. Platelet declines were consistent with observations in phase 3 clinical trials. No patient recorded a platelet count <50 × 109/L. CONCLUSIONS: This longitudinal study supports the efficacy of volanesorsen in patients with FCS for lowering TG levels over treatment periods up to 51 months with no apparent safety signals related to increased duration of exposure.

Improved diagnostic accuracy for neuroendocrine neoplasms using two chromogranin A assays.

CONTEXT: Chromogranin A (Cg A) is the best available diagnostic marker for neuroendocrine neoplasms (NENs). However, clinical interpretation of Cg A results may be limited by considerable heterogeneity between commonly available Cg A assays. Variation in diagnostic accuracy of these assays largely reflects differences in antibody specificities. We compared the diagnostic utility of four Cg A assays [Imperial Supra-regional Assay Service radioimmunoassay (SAS) and three commercial assays, Cisbio, DAKO and Eurodiagnostica]. METHOD: Plasma Cg A was measured using these four assays in 125 patients with NENs, 41 patients with cancers other than NENs and 108 healthy controls. RESULT: There was no significant difference in diagnostic accuracy between any of the four assays alone and no single assay positively identified all patients with NEN. However, concordance between assays was variable. Cisbio and SAS assays were least concordant. We, therefore, hypothesized that using a combination of the least concordant Cg A assays will improve NEN diagnosis by detecting a larger number of Cg A epitopes and hence patients with NEN. Consistent with our hypothesis, multiple logistic regression analysis showed that the combination of Cisbio and SAS assays was more useful than any other combinations or any assay alone in predicting a NEN diagnosis. CONCLUSION: Although individually, all four Cg A assays are similarly useful for the measurement of Cg A in the diagnosis of a NEN, in patients with a suspected NEN, negative results by one assay should prompt analysis by a second assay. The combination of Cisbio and SAS assays may have greatest diagnostic utility.

Pregnancy and its management in women with GSD type III - a single centre experience.

We present a review of our experience and pregnancy outcome in patients with GSD III managed by our centre. Between 1997 and 2010 there were 15 pregnancies in seven women with GSD III. Four women had GSD IIIb (nine pregnancies) and three GSD IIIa (six pregnancies). There was a successful outcome in all 15 pregnancies with delivery of 15 liveborn infants. Four infants were of low birthweight (<2nd centile) but all have developed normally apart from one with behavioural/psychiatric problems. Three women had pre-existing cardiomyopathy prior to pregnancy. One of these women had deterioration of her cardiomyopathy during pregnancy and again in the post-partum period. Women with GSD III do not seem to have any issues with fertility. Overall the outcome of pregnancy for both mother and child is good. Care needs to be taken to avoid maternal hypoglycemia which may be associated with intrauterine growth restriction and low birth weight. Cardiac function should be monitored carefully particularly in those with pre-existing cardiomyopathy.

Lipidomics in diabetes.

PURPOSE OF REVIEW: Multiple studies have shown a strong association between lipids and diabetes. These are usually described through the effects of cholesterol content of lipid particles and in particular low-density lipoprotein. However, lipoprotein particles contain other components, such as phospholipids and more complex lipid species, such as ceramides and sphingolipids. Ceramides, such as sphingolipids are also produced intracellularly and have signalling actions in regulating cell metabolism including effects on inflammation, and potentially have a mechanistic role in the development of insulin resistance. RECENT FINDINGS: Recently, techniques have been developed to analyse detailed molecular profiles of lipid particles - lipidomics. Proteomics has confirmed the different proteins associated with different particles but far less is known about the relationship of individual lipid species with diabetes and cardiovascular risk. A number of studies have now shown that the plasma lipidome, and in particular, ceramides and sphingolipids may predict the development of diabetes. SUMMARY: Lipidomics had identified ceramides and sphingolipids as potential mediators of cellular dysfunction in diabetes. Further work is required to ascertain whether they have clinical utility.

Survey of Health Care Provider Understanding of Gene Therapy Research for Inherited Metabolic Disorders.

PURPOSE: The treatment of inherited metabolic disorders (IMDs) has traditionally relied on dietary interventions that are difficult to maintain, expensive, and socially isolating. The development of gene therapy for IMDs aims to provide sufficient gene activity to address the underlying causes of these conditions. This study surveyed health care providers (HCPs) to characterize their familiarity with gene therapy technologies and to identify educational needs across roles in a multidisciplinary care team. METHODS: The link to a Web-based, 26-question survey was distributed to HCPs in North America and Europe who were involved in IMD patient care. Results were analyzed using descriptive statistics. FINDINGS: Of the 590 survey link recipients, 64 completed the survey. Of these, 35 (55%) respondents were physicians, 23 (36%) were dietitians, 3 (5%) were nurse practitioners, 2 (3%) were genetic counselors, and 1 (2%) was a nurse. Most survey respondents (88% [n = 56 of 64]) reported the belief that gene therapy for IMDs would be available within 5 years of study conduct. Although nearly all physicians (97% [n = 34 of 35]) expressed awareness of gene therapy, rates of reported familiarity were lower among dietitians (57% [n = 13 of 23]); confidence in conversations with colleagues and patients/caregivers was also discordant. Nearly all HCPs wanted education on gene therapy advancements, and the most preferred informational sources were published literature and congress presentations. IMPLICATIONS: There is an urgent need for education on topics related to gene therapy modalities. Professional education on gene therapies is desired across all specialties and will be important for unified treatment practices in IMD care.

A novel variant of fructose-1,6-bisphosphatase gene identified in an adult with newly diagnosed hepatitis C.

Hepatic fructose-1,6-bisphosphatase (FBPase) deficiency commonly presents with acute crises during infancy when glycogen stores are depleted. In these patients, dependence on glycogenolysis means that the duration of normoglycaemia is related to liver glycogen stores. Clinical hallmarks of FBPase deficiency include hypoglycaemia and lactic acidosis with or without ketosis. Patients commonly present with hyperventilation, vomiting, tachycardia, reduced consciousness and glucagon-resistant hypoglycaemia. Between crises, patients are usually well with normal growth and development; however significant ingestion of fructose, sucrose or glycerol during acute crises may be fatal, hence the importance of a prompt diagnosis. We present the case of a 30-year-old male who presented to our tertiary centre acutely unwell, shortly following a diagnosis of hepatitis C, which we speculate may have precipitated this severe presentation. He had similar, milder episodes throughout childhood. Furthermore, a pathological homozygous sequence variant in fructose-1,6-bisphosphatase (FBP1) gene, previously unreported, was identified. Diagnosis in adulthood is underreported in the literature, however, represents an important, albeit rare, cause of hypoglycaemia and lactic acidosis.

Hypertriglyceridaemia: an update.

Triglycerides (TGs) form part of the standard lipid profile. Elevations in TGs are associated with increased cardiovascular disease risk through triglyceride-rich lipoprotein particles found as part of non-HDL cholesterol. Many elevations of TGs are secondary to other causes, but primary hypertriglyceridaemia syndromes need to be identified. The genetic causes of hypertriglyceridaemia range from familial combined hyperlipidaemia through the autosomal recessive remnant hyperlipidaemia (related to apolipoprotein E variants) and familial chylomicronaemia syndromes. Patients with primary hypertriglyceridaemia >10 mmol/L require characterisation and specific intervention. Simple lipid profiles do not provide adequate information for detailed diagnosis and additional assays such as apolipoprotein (apo)B100, apoE genotype and next-generation sequencing may be useful. Management of raised TGs includes optimising diet, reducing exacerbating factors as well as lipid-lowering medications such as statins, fibrates, niacin and omega-3 fatty acids. Novel medications for orphan disease indications such as familial chylomicronaemia syndrome include volanesorsen, evinacumab and other antisense therapeutics. Extreme hypertriglyceridaemia syndromes, especially chylomicronaemia syndromes, which can be exposed by pregnancy or other factors are a medical emergency and require admission and specialist management sometimes including plasma exchange.

Protein status in phenylketonuria: A scoping review.

BACKGROUND & AIMS: The physical and functional outcomes of lifelong treatment with a phenylalanine restricted diet for the management of Phenylketonuria (PKU) remain unknown. Given that the mainstay of dietary management consists of modifying the sources of ingested protein, various aspects of body protein status could be compromised. OBJECTIVES: To examine the existing evidence regarding the protein status of people with PKU and identify nutritional and lifestyle variables that influence protein status. ELIGIBILITY CRITERIA: Studies reporting anthropometric, biochemical and/or functional measurements of body protein status in people with PKU were eligible. SOURCE OF EVIDENCE: MEDLINE (Ovid), Embase (Ovid), CENTRAL, Web of Science and Scopus, and conference abstracts. RESULTS: Seventy studies were included in the review. The majority of studies assessing protein status based on anthropometric measurements observed no differences between people with PKU and controls, although deficits in muscle mass were reported within PKU cohorts. Findings for biochemical assessment of protein status were mixed and limited studies assessed protein status using functional measures. Factors such as participant age, sex, metabolic control, protein source, type of protein substitute, and pharmacological treatments were found to modulate protein status of people with PKU. CONCLUSIONS: Findings were inconclusive regarding body protein status in people with PKU. The relationship between diet and protein status outcomes remains unclear and further research is warranted to determine the impact of dietary regimens on physical and functional outcomes, and to understand the best clinical assessments to reliably monitor the protein status in people with PKU.

Aerobic capacity and skeletal muscle characteristics in glycogen storage disease IIIa: an observational study.

BACKGROUND: Individuals with glycogen storage disease IIIa (GSD IIIa) (OMIM #232400) experience muscle weakness and exercise limitation that worsen through adulthood. However, normative data for markers of physical capacity, such as strength and cardiovascular fitness, are limited. Furthermore, the impact of the disease on muscle size and quality is unstudied in weight bearing skeletal muscle, a key predictor of physical function. We aim to produce normative reference values of aerobic capacity and strength in individuals with GSD IIIa, and to investigate the role of muscle size and quality on exercise impairment. RESULTS: Peak oxygen uptake (V̇O2peak) was lower in the individuals with GSD IIIa than predicted based on demographic data (17.0 (9.0) ml/kg/min, 53 (24)% of predicted, p = 0.001). Knee extension maximum voluntary contraction (MVC) was also substantially lower than age matched predicted values (MVC: 146 (116) Nm, 57% predicted, p = 0.045), though no difference was found in MVC relative to body mass (1.88 (2.74) Nm/kg, 61% of predicted, p = 0.263). There was a strong association between aerobic capacity and maximal leg strength (r = 0.920; p = 0.003). Substantial inter-individual variation was present, with a high physical capacity group that had normal leg strength (MVC), and relatively high V̇O2peak, and a low physical capacity that display impaired strength and substantially lower V̇O2peak. The higher physical capacity sub-group were younger, had larger Vastus Lateralis (VL) muscles, greater muscle quality, undertook more physical activity (PA), and reported higher health-related quality of life. CONCLUSIONS: V̇O2peak and knee extension strength are lower in individuals with GSD IIIa than predicted based on their demographic data. Patients with higher physical capacity have superior muscle size and structure characteristics and higher health-related quality of life, than those with lower physical capacity. This study provides normative values of these important markers of physical capacity.

Three-Country Snapshot of Ornithine Transcarbamylase Deficiency.

X-linked ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle defect. The disease severity ranges from asymptomatic carrier state to severe neonatal presentation with hyperammonaemic encephalopathy. We audited the diagnosis and management of OTCD, using an online 12-question-survey that was sent to 75 metabolic centres in Turkey, France and the UK. Thirty-nine centres responded and 495 patients were reported in total. A total of 208 French patients were reported, including 71 (34%) males, 86 (41%) symptomatic and 51 (25%) asymptomatic females. Eighty-five Turkish patients included 32 (38%) males, 39 (46%) symptomatic and 14 (16%) asymptomatic females. Out of the 202 UK patients, 66 (33%) were male, 83 (41%) asymptomatic and 53 (26%) symptomatic females. A total of 19%, 12% and 7% of the patients presented with a neonatal-onset phenotype in France, Turkey and the UK, respectively. Vomiting, altered mental status and encephalopathy were the most common initial symptoms in all three countries. While 69% in France and 79% in Turkey were receiving protein restriction, 42% were on a protein-restricted diet in the UK. A total of 76%, 47% and 33% of patients were treated with ammonia scavengers in Turkey, France and the UK, respectively. The findings of our audit emphasize the differences and similarities in manifestations and management practices in three countries.

Dietary protein and protein substitute requirements in adults with phenylketonuria: A review of the clinical guidelines.

Lifelong dietary treatment is recommended in the management of phenylketonuria (PKU). Accordingly, an increasing adult population require age-specific PKU guidelines on protein requirements to support changing metabolic demands across the lifespan. Given that protein intake for dietary management of PKU is primarily (52-80%) derived from protein substitutes, the prescribing practice of protein substitutes must be underpinned by robust evidence. Whilst dietary guidelines for PKU management is evolving to incorporate adult specific protein recommendations, the scientific evidence underpinning these guidelines is currently limited. Instead, the determination of protein requirements for people with PKU have previously been extrapolated from estimates derived from the general healthy population, based on arguably outdated nitrogen balance methodology. Furthermore, a compensatory factor of 20-40% has been incorporated to account for the reduced uptake and utilisation of the elemental amino acids contained in protein substitutes. However, research informing this compensatory factor has been conducted in younger adults, with the majority of studies in non-PKU individuals. Given extensive evidence that the muscle anabolic response to ingested protein is impaired in older vs. young adults, the validity of current dietary protein recommendations for adults and older adults with PKU has been challenged. This narrative review aims to critically evaluate the existing scientific evidence underpinning current guidelines on protein requirements for adults with PKU, highlighting existing gaps in knowledge and directions for future research. We argue that current guidelines on protein requirements need updating to optimise long-term physical and functional outcomes in older adults with PKU.

Protein status of people with phenylketonuria: a scoping review protocol.

INTRODUCTION: Phenylketonuria (PKU) is a disorder of protein metabolism resulting in an accumulation of phenylalanine in the body. Dietary management consists of altering the sources of ingested protein to limit phenylalanine intake. Current dietary protein guidelines for PKU are based on limited scientific evidence, thus it remains unclear whether current practice leads to optimal protein status in people with PKU. To date, no attempt has been made to systematically evaluate the protein status of people with PKU, using a combination of validated anthropometric, biochemical and functional measurement tools. Furthermore, factors known to influence protein status in the general population warrant consideration when determining protein status in individuals with PKU, alongside factors unique to PKU such as the type of protein substitute consumed. Understanding the impact of these variables on protein status is crucial to developing a personalised approach to protein recommendations for optimising health and functional outcomes in people with PKU. Therefore, the aim of this scoping review is to examine existing evidence regarding the protein status of people with PKU, and to investigate the nutritional and lifestyle variables that influence protein status. METHODS AND ANALYSIS: This review will be guided by Arksey and O'Malley's framework, along with guidance from Levac et al, Pawliuk et al and the Joanna Briggs Institute. The following databases will be searched: MEDLINE (Ovid), Embase, CENTRAL, Web of Science and Scopus, alongside grey literature. Identified literature will be assessed by two independent reviewers for inclusion. Descriptive numerical analysis will be performed and a narrative summary will accompany the tabulated results describing how study findings relate to the review questions. ETHICS AND DISSEMINATION: This review protocol does not require ethical approval. Findings will be disseminated through peer-reviewed publication, presented at relevant conferences, and shared with a patient research advisory group to inform discussions on future research.

The effects of kisspeptin-54 on blood pressure in humans and plasma kisspeptin concentrations in hypertensive diseases of pregnancy.

AIMS: To investigate (i) if kisspeptin administration alters heart rate (HR) or blood pressure (BP) in healthy male and female volunteers, (ii) whether circulating plasma kisspeptin concentrations in healthy pregnant women and women with hypertensive diseases of pregnancy correlate with BP and (iii) whether women with hypertensive diseases of pregnancy have altered plasma kisspeptin concentrations. METHODS: We have previously reported the effects of administration of kisspeptin-54 on gonadotrophin secretion in healthy male and female volunteers. In these studies, cardiovascular parameters were not a primary endpoint. However, data were also collected on BP and HR for 4h post administration of kisspeptin-54. Blood samples were taken from 105 women in the third trimester of pregnancy (27 women with hypertensive diseases of pregnancy and 78 controls). Samples were assayed for plasma kisspeptin immunoreactivity (IR). RESULTS: Administration of kisspeptin was not associated with significant changes in HR or BP in healthy men or women. There was no significant correlation between plasma kisspeptin concentration and BP in healthy pregnant women or in those with hypertensive diseases of pregnancy. No significant differences in plasma kisspeptin-IR concentrations were observed between women with hypertensive diseases of pregnancy and normotensive pregnant controls, plasma kisspeptin concentrations ±SE: controls 2878 ± 157pmol l(-1) ; pregnancy-induced hypertension 2696 ± 299pmoll(-1) (95% CI vs. controls -514, 878pmoll(-1) ); pre-eclampsia 3519 ± 357 (95% CI vs. controls -1644, 362pmoll(-1) ). CONCLUSIONS: Elevation of plasma kisspeptin-IR is not associated with an alteration in BP in humans.

Severe neurological crisis in adult patients with Tyrosinemia type 1.

We report six adult patients with Tyrosinaemia type 1 (HT-1) who presented with recurrent porphyria-like neurological crises after discontinuation/interruption of 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3 cyclohexanedione (NTBC) treatment. The crises were life-threatening for some of the patients, with respiratory muscle paralysis requiring ventilatory support, hemodynamic disturbance due to autonomic changes requiring resuscitation, acute progressive ascending motor neuropathy causing profound impairment, recurrent seizures, and neuropathic pain. Our patients' porphyria-like presentations were variably misdiagnosed, with delay to diagnosis resulting in more severe recurrent attacks. We report the first series of neurological crises in adult patients with HT-1. These crises, which may be fatal, can be prevented and treated effectively with neurologist/physician awareness and patient education.

Suboptimal rise in awakening-induced cortisol is an accurate marker of cortisol insufficiency in patients with normal renal function (eGFR >60 mL/min).

Background The insulin tolerance test is the gold standard for diagnosis of cortisol insufficiency. However, it is cumbersome, invasive, requires supervised hospital facilities and has unpleasant side-effects. A non-invasive outpatient-based test will be useful. We hypothesized that free cortisol concentrations in multiple spot urine samples can be used to diagnose cortisol insufficiency in patients with normal renal function (eGFR > 60 mL/min). Method Patients and controls provided urine samples at bedtime (S1), and first (S2) and second (S3) void the next day. Cortisol and creatinine were measured in all three samples, and cortisol:creatinine ratio (S1, S2 and S3) was used for further analysis. The sum of S1 + S2 + S3 was used to calculate total cortisol secretion (T). Variation (V) in cortisol secretion in response to circadian rhythm was calculated as the modulus of the difference between S1 and S2 and S2 and S3. Results Samples were collected from 96 controls and 11 patients. S1 was significantly lower vs . S2 and S3 in controls ( P < 0.0001) but not in patients. S2, S3, T and V were significantly lower in patients vs . controls ( P < 0.0001). ROC curve analysis using insulin tolerance test as gold standard showed that S2, S3, T and V were all equally accurate diagnostic markers for cortisol insufficiency (AUC: 0.87, NPV: 100%). The best balance of sensitivity and specificity was achieved using T (sensitivity: 100%, specificity: 58%). Conclusion Multiple spot urine samples test is an accurate, relatively inexpensive, non-invasive, convenient outpatient-based screening test for exclusion of cortisol insufficiency.