The cardiovascular phenotype of adult patients with phenylketonuria

BACKGROUND: Patients with Phenylketonuria (PKU) are exposed to multiple cardiovascular risk factors, but the clinical significance of these abnormalities is yet unknown. The purpose of this study was to characterize the cardiovascular phenotype in adult patients with PKU by clinical and dietary data, measurements of biochemical markers, and non-invasive examination of vascular functions. RESULTS: Twenty-three adult patients with PKU (age: 18-47 y; 30.8 ± 8.4 y) and 28 healthy controls (age: 18-47 y; 30.1 ± 9.1 y) were included in this study. PKU patients had significantly higher systolic and diastolic blood pressure, increased resting heart rate and a higher body mass index. Total cholesterol and non-HDL cholesterol levels were significantly increased in PKU patients, whereas plasma levels of HDL cholesterol and its subfraction HDL2 (but not HDL3) were significantly decreased. The inflammatory markers C-reactive protein and serum amyloid A protein and the serum oxidative stress marker malondialdehyde were significantly higher in patients with PKU. Venous occlusion plethysmography showed marked reduction in post-ischemic blood flow and the carotid to femoral pulse wave velocity was significantly increased demonstrating endothelial dysfunction and increased vascular stiffness. CONCLUSIONS: This study shows that the cardiovascular phenotype of adult PKU patients is characterized by an accumulation of traditional cardiovascular risk factors, high levels of inflammatory and oxidative stress markers, endothelial dysfunction and vascular stiffness. These data indicate the need for early cardiovascular risk reduction in patients with PKU

Enzyme replacement therapy with velmanase alfa (human recombinant alpha-mannosidase) : novel global treatment response model and outcomes in patients with alpha-mannosidosis

Alpha-mannosidosis is an ultra-rare monogenic disorder resulting from a deficiency in the lysosomal enzyme alpha-mannosidase, with a prevalence estimated to be as low as 1:1,000,000 live births. The resulting accumulation of mannose-rich oligosaccharides in all tissues leads to a very heterogeneous disorder with a continuum of clinical manifestations with no distinctive phenotypes. Long-term enzyme replacement therapy (ERT) with velmanase alfa is approved in Europe for the treatment of non-neurological manifestations in patients with mild to moderate alpha-mannosidosis. The clinical heterogeneity and rarity of the disease limit the sensitivity of single parameters to detect clinically relevant treatment effects. Thus, we propose a novel multiple variable responder analysis to evaluate the efficacy of ERT for alpha-mannosidosis and present efficacy analyses for velmanase alfa using this method. Global treatment response to velmanase alfa (defined by response to ≥2 domains comprising pharmacodynamic, functional, and quality of life outcomes) was applied post hoc to data from the pivotal placebo-controlled rhLAMAN-05 study and to the longer-term integrated data from all patients in the clinical development program (rhLAMAN-10). After 12 months of treatment, a global treatment response was achieved by 87% of patients receiving velmanase alfa (n=15) compared with 30% of patients receiving placebo (n=10). Longer-term data from all patients in the clinical program (n=33) showed 88% of patients were global responders, including all (100%) pediatric patients (n=19) and the majority (71%) of adult patients (n=14). The responder analysis model demonstrates a clinically meaningful treatment effect with velmanase alfa and supports the early initiation and continued benefit of longer-term treatment of all patients with alpha-mannosidosis with this ERT.Phase I/II studies rhLAMAN-02, -03, and -04 and phase III study rhLAMAN-05 were conducted under and co-funded by the EU FP7 project ALPHA-MAN [FP7-HEALTH-2010-261331]. Long-term continuation studies rhLAMAN-07 and -09 were initially sponsored by Zymenex A/S and are currently sponsored by Chiesi Farmaceutici S.p.A. Zymenex sponsored rhLAMAN-10. Chiesi Farmaceutici S.p.A. funded third-party writing assistance for the current manuscript, provided by PAREXEL.https://www.elsevier.com/locate/ymgmeam2019Paediatrics and Child Healt

Cross-sectional observational study of 208 patients with non-classical urea cycle disorders

Urea cycle disorders (UCDs) are inherited disorders of ammonia detoxification often regarded as mainly of relevance to pediatricians. Based on an increasing number of case studies it has become obvious that a significant number of UCD patients are affected by their disease in a non-classical way: presenting outside the newborn period, following a mild course, presenting with unusual clinical features, or asymptomatic patients with only biochemical signs of a UCD. These patients are surviving into adolescence and adulthood, rendering this group of diseases clinically relevant to adult physicians as well as pediatricians. In preparation for an international workshop we collected data on all patients with non-classical UCDs treated by the participants in 20 European metabolic centres. Information was collected on a cohort of 208 patients 50% of which were ≥ 16 years old. The largest subgroup (121 patients) had X-linked ornithine transcarbamylase deficiency (OTCD) of whom 83 were female and 29% of these were asymptomatic. In index patients, there was a mean delay from first symptoms to diagnosis of 1.6 years. Cognitive impairment was present in 36% of all patients including female OTCD patients (in 31%) and those 41 patients identified presymptomatically following positive newborn screening (in 12%). In conclusion, UCD patients with non-classical clinical presentations require the interest and care of adult physicians and have a high risk of neurological complications. To improve the outcome of UCDs, a greater awareness by health professionals of the importance of hyperammonemia and UCDs, and ultimately avoidance of the still long delay to correctly diagnose the patients, is crucial

Incentivizing the Dynamic Workforce: Learning Contracts in the Gig-Economy

In principal-agent models, a principal offers a contract to an agent to perform a certain task. The agent exerts a level of effort that maximizes her utility. The principal is oblivious to the agent's chosen level of effort, and conditions her wage only on possible outcomes. In this work, we consider a model in which the principal is unaware of the agent's utility and action space. She sequentially offers contracts to identical agents, and observes the resulting outcomes. We present an algorithm for learning the optimal contract under mild assumptions. We bound the number of samples needed for the principal obtain a contract that is within $\epsilon$ of her optimal net profit for every $\epsilon>0$

Cross-sectional observational study of 208 patients with non-classical urea cycle disorders

Urea cycle disorders (UCDs) are inherited disorders of ammonia detoxification often regarded as mainly of relevance to pediatricians. Based on an increasing number of case studies it has become obvious that a significant number of UCD patients are affected by their disease in a non-classical way: presenting outside the newborn period, following a mild course, presenting with unusual clinical features, or asymptomatic patients with only biochemical signs of a UCD. These patients are surviving into adolescence and adulthood, rendering this group of diseases clinically relevant to adult physicians as well as pediatricians. In preparation for an international workshop we collected data on all patients with non-classical UCDs treated by the participants in 20 European metabolic centres. Information was collected on a cohort of 208 patients 50% of which were ≥ 16 years old. The largest subgroup (121 patients) had X-linked ornithine transcarbamylase deficiency (OTCD) of whom 83 were female and 29% of these were asymptomatic. In index patients, there was a mean delay from first symptoms to diagnosis of 1.6 years. Cognitive impairment was present in 36% of all patients including female OTCD patients (in 31%) and those 41 patients identified presymptomatically following positive newborn screening (in 12%). In conclusion, UCD patients with non-classical clinical presentations require the interest and care of adult physicians and have a high risk of neurological complications. To improve the outcome of UCDs, a greater awareness by health professionals of the importance of hyperammonemia and UCDs, and ultimately avoidance of the still long delay to correctly diagnose the patients, is crucial

New insights in the treatment of phenylketonuria

Trotz Etablierung neuer Therapieoptionen ist die Phenylalanin-bilanzierte Diät weiterhin die Therapie der Wahl bei Patienten mit einer Phenylketonurie (PKU). Bekannte Langzeitprobleme bei Patienten mit PKU sind neurologische Defizite, Mikronährstoff-Defizite, Osteopenie und Adipositas. Wir konnten zudem nachweisen, dass PKU-Patienten unter der Phenylalanin-bilanzierten Diät ein erhöhtes Risiko haben, eine arterielle Hypertonie sowie eine chronische Nierenerkrankung mit eingeschränkter Nierenfunktion, Proteinurie, Mikroalbuminurie und Hyperkalziurie zu entwickeln. Mögliche Ursachen der chronischen Nierenerkrankung bei PKU-Patienten sind die hohe Gesamteiweißzufuhr, die hohe Zufuhr von Mono-Aminosäuren über das Aminosäurengemisch, lokale Schädigungen durch die hohe Phenylalanin- Ausscheidung sowie erhöhter oxidativer Stress. Die Therapie mit Tetrahydrobiopterin (BH4), dem Kofaktor der Phenylalaninhydroxylase, stellt eine neue Option in der Behandlung der PKU dar. Das Ansprechen auf BH4 wird vorwiegend durch den Genotyp und den daraus resultierenden Phänotyp bestimmt. Populationen mit einer hohen Rate an Nullmutationen weisen eine geringere Rate an BH4-responsiven PKU-Patienten auf. Anhand unserer Daten konnten wir nachweisen, dass durch bestimmte laborchemische, molekulargenetische und klinische Parameter bereits in der Neonatalperiode eine Einschätzung über eine potentielle Langzeit-BH4-Responsivität möglich ist. Bei BH4-responsiven PKU- Patienten führt die Therapie mit BH4 zu einer Reduzierung der Phenylalanin- Blutwerte und zu einer Steigerung der individuellen Phenylalanin-Toleranz. Vorwiegend Patienten mit einer milden PKU profitieren von der BH4-Therapie, während Patienten mit einem schweren PKU-Phänotyp zwar BH4-responsiv sein können, aber unter der Langzeittherapie mit BH4 meist nur eine geringe Steigerung ihrer Phenylalanin-Toleranz erreichen. Die Indikation zu einer BH4-Langzeittherapie muss daher kritisch gestellt werden: Für die Langzeittherapie mit BH4 sollte eine mindestens 2,5-fache Steigerung der individuellen Phenylalanin-Toleranz erreicht werden. Mögliche Nebenwirkungen der BH4-Langzeittherapie können gastrointestinale Probleme, Kopfschmerzen und Mikronährstoff-Defizite sein. Zudem betragen die Kosten einer BH4-Therapie 1,5- bis 4-fach mehr als die der Phenylalanin-bilanzierten Diät. Dennoch ist die Bedeutung von BH4 in der Behandlung der PKU nicht zu unterschätzen. BH4 nimmt als Kofaktor der Nitritoxid-Synthase eine Schlüsselfunktion in der Regulation der vaskulären Homöostase ein. Ein relativer BH4-Mangel könnte somit bei PKU-Patienten einen Einfluss auf den erhöhten oxidativen Stress, die arterielle Hypertonie und die chronische Nierenerkrankung haben. In diesem Zusammenhang könnte BH4 eine zusätzliche Bedeutung in der Behandlung von PKU- Patienten einnehmen. Weitere neue Therapieoptionen werden derzeit in klinischen Studien und in Tiermodellen untersucht und könnten in Zukunft die Phenylalanin-bilanzierte Diät ersetzen.In patients with phenylketonuria (PKU) life-long treatment with phenylalanine- restricted diet and substitution of a phenylalanine-free amino acid formula is recommended. On long-term follow-up of patients with PKU neurological disease, deficiency in micronutrients, osteopenia and obesity have been described. Furthermore, our studies revealed that patients with PKU may develop arterial hypertension and chronic kidney disease with impaired renal function, proteinuria, microalbuminuria and hypercalciuria. High acid load due to the intake of mono amino acids, increased oxidative stress and local damage through high phenylalanine excretion may contribute to the pathomechanisms of renal impairment. Treatment with tetrahydrobiopterin (BH4) has been established within the last decade. BH4 treatment results in a decrease of blood phenylalanine concentrations and in an increase of the individual phenylalanine tolerance. Mainly patients with a mild PKU phenotype benefit from BH4 treatment, whereas patients with a more severe PKU phenotype only show incomplete long-term BH4 response. Therefore, we recommend a strict indication for long-term BH4 treatment: BH4 should only be applied if the individual phenylalanine tolerance can be increased at least 2.5fold or even more. Possible side effects of long-term treatment with BH4 are gastrointestinal problems, headache and deficiency in micronutrients. Furthermore, costs for treatment with BH4 are 1.5- to 4fold higher than for the dietary treatment. We could identify clinical, biochemical and genetic parameters which may predict long-term BH4 responsiveness already during neonatal period. However, treatment with BH4 may be of further interest in patients with PKU. As BH4 is a cofactor of nitritoxide synthase, it plays an important role in the regulation of vascular homoeostasis. A shortage of BH4 may contribute to the increased oxidative stress, the arterial hypertension and the chronic kidney disease in patients with PKU. This may underline the importance of BH4 in the treatment of PKU. New treatment options are examined in clinical and experimental studies and may replace dietary treatment in future

Retinal thinning in phenylketonuria and Gaucher disease type 3

Purpose!#!Retinal alterations in inherited metabolic diseases associated with neurodegeneration are poorly studied. The objective was to study retinal thickness, specifically the components of the ganglion cell complex (GCC)-nerve fiber layer (NFL), ganglion cell layer (GCL), and inner plexiform layer (IPL)-using spectral-domain optical coherence tomography (SD-OCT) in two different diseases with potential dopaminergic depletion, phenylketonuria (PKU) and Gaucher disease type 3 (GD3).!##!Methods!#!Retinal layers in 19 patients with PKU, 15 patients with GD3, and 93 healthy individuals were measured using peripapillary ring scan and macular SD-OCT. Linear mixed models were computed including an adjustment for age, sex, and spherical equivalent. We calculated Spearman's rank correlations between retinal layer measurements and clinical and/or laboratory parameters.!##!Results!#!Thinning of total retinal thickness was found in the macular inner ring (p = 0.002), and outer ring (p = 0.012), sparing the fovea (p = 0.12) in PKU, while in GD3, all subfields were thinned (fovea p < 0.001, inner ring p = 0.047, outer ring 0.07). In both conditions, thinning was most evident in the NFL, GCL, and IPL, while OPL (outer plexiform layer) was thickened. Peripapillary retinal nerve fiber layer measurements remained normal. GCL and IPL in PKU correlated with tyrosine serum concentration.!##!Conclusion!#!Thinning of the NFL, GCL, and IPL, with thickened OPL, are both found in PKU and in GD3. Low dopamine concentrations in the retina might promote these effects. However, these data do not give evidence that retinal measurements can be used as a biomarker for disease severity in patients with GD3

Eight-Year Follow-Up of Neuropsychiatric Symptoms and Brain Structural Changes in Fabry Disease.

Brain structural alterations and neuropsychiatric symptoms have been described repeatedly in Fabry disease, yet cognitive deficits have been shown to be only mild. Here, we aimed to investigate neuropsychiatric symptoms and brain structure longitudinally. We expected no clinically relevant increase of neuropsychiatric symptoms in parallel to increased brain structural alterations. We assessed 14 Fabry patients (46.1 ± 10.8 years) who had participated in our investigation eight years ago. Patients engaged in neuropsychiatric testing, as well as structural magnetic resonance imaging and angiography to determine white matter lesions, hippocampal volume, and the diameter of the larger intracranial arteries. While Fabry patients did not differ on cognitive performance, they showed progressive and significant hippocampal volume loss over the 8-year observation period. White matter lesions were associated with older age and higher white matter lesion load at baseline, but did not reach statistical significance when comparing baseline to follow-up. Likewise, intracranial artery diameters did not increase significantly. None of the imaging parameters were associated with the neuropsychiatric parameters. Depression frequency reduced from 50% at baseline to 21% at follow-up, but it did not reach significance. This investigation demonstrates clinical stability in cognitive function, while pronounced hippocampal atrophy is apparent throughout the 8 years. Our middle-aged Fabry patients appeared to compensate successfully for progressive hippocampal volume loss. The hippocampal volume decline indicates brain regional neuronal involvement in Fabry disease