[Dental rehabilitation in a young patient with glycogen storage disease type 1B]. / Dentale rehabilitatie bij jonge patiënt met glycogeenstapelingsziekte type 1B.

A young woman, known to have glycogen storage disease type 1B (GSD1B) presents with severe periodontitis. GDS1B causes decreased hepatic and renal glucose production and in many cases neutropenia and neutrophil dysfunction leading to recurrent infections. It was decided to treat the patient by extraction of the most affected teeth and retention of the remaining teeth through periodontal treatment, both with antibiotic prophylaxis. After a follow-up period of 1.5 years, during which there was no visible improvement, it was decided to do a full dental extraction and fabricate complete dentures. Due to subsequent bone resorption in both jaws, the dentures were not functional. After consulting the internist and the oral and maxillofacial surgeon, the decision was then made to place dental implants in both the upper and lower jaw for implant-supported prosthetics. After successful treatment and an osseointegration period, the prosthetics were placed. 1 year after placement, there is a stable implantological situation, without pockets or apparent bone loss. The start of SGLT2 medication may have played a significant role in this.

Food or medicine? A European regulatory perspective on nutritional therapy products to treat inborn errors of metabolism.

Dietary or nutritional management strategies are the cornerstone of treatment for many inborn errors of metabolism (IEMs). Though a vital part of standard of care, the products prescribed for this are often not formally registered as medication. Instead, they are regulated as food or as food supplements, impacting the level of oversight as well as reimbursed policies. This scoping literature review explores the European regulatory framework relevant to these products and its implications for current clinical practice. Searches of electronic databases (PubMed, InfoCuria) were carried out, supplemented by articles identified by experts, from reference lists, relevant guidelines and case-law by the European Court of Justice. In the European Union (EU), nutritional therapy products are regulated as food supplements, food for special medical purposes (FSMPs) or medication. The requirements and level of oversight increase for each of these categories. Relying on lesser-regulated food products to treat IEMs raises concerns regarding product quality, safety, reimbursement and patient access. In order to ascertain whether a nutritional therapy product functions as medication and thus could be classified as such, we developed a flowchart to assess treatment characteristics (benefit, pharmacological attributes, and safety) with a case-based approach. Evaluating nutritional therapy products might reveal a justifiable need for a pharmaceutical product. A flowchart can facilitate systematically distinguishing products that function medication-like in the management of IEMs. Subsequently, finding and implementing appropriate solutions for these products might help improve the quality, safety and accessibility including reimbursement of treatment for IEMs.

Early start of enzyme replacement therapy in pediatric male patients with classical Fabry disease is associated with attenuated disease progression.

BACKGROUND: Enzyme replacement therapy (ERT) slows disease progression of Fabry disease (FD), especially when initiated before the onset of irreversible organ damage. However, with the clinically asymptomatic progression of renal, cardiac and cerebral disease manifestations spanning decades, optimal timing of ERT initiation remains unclear. METHODS: In this cross-sectional retrospective study, seven male FD patients with a classical disease phenotype (cFD) who started treatment with agalsidase-beta in childhood were evaluated after 10 years of treatment (median age at evaluation 24 years, range 14-26). Cardiac imaging (echocardiography and MRI), electrophysiological and biochemical data of these patients were compared to those of untreated male cFD patients (n = 23, median age 22 years, range 13-27). RESULTS: Albuminuria was less common and less severe in treated patients (albumin to creatinine ratio, ACR 0-8.8 mg/mmol, median 0.4) compared to untreated patients (ACR 0-248 mg/mmol, median 3.7, p = 0.02). The treated group had a lower left ventricular mass, measured using echocardiography (median 80 g/m2 versus 94 g/m2, p = 0.02) and MRI (median 53 g/m2 versus 68 g/m2, p = 0.02). Myocardial fibrosis was absent in all included patients. eGFR was normal in all treated patients whereas 7/23 (30%) of untreated patients had abnormal eGFR. Cerebral manifestations did not differ. CONCLUSIONS: Start of treatment with ERT before age 16, in male cFD patients is associated with reduced occurrence of renal and cardiac manifestations of FD, as assessed by intermediate endpoints. Confirmation that this approach delays or even prevents renal failure and cardiac events requires another decade of follow-up.

Differences in faecal microbiome composition between adult patients with UCD and PKU and healthy control subjects.

Urea cycle disorders (UCDs) are a group of rare inherited metabolic diseases causing hyperammonemic encephalopathy. Despite intensive dietary and pharmacological therapy, outcome is poor in a subset of UCD patients. Reducing ammonia production by changing faecal microbiome in UCD is an attractive treatment approach. We compared faecal microbiome composition of 10 UCD patients, 10 healthy control subjects and 10 phenylketonuria (PKU) patients. PKU patients on a low protein diet were included to differentiate between the effect of a low protein diet and the UCD itself on microbial composition. Participants were asked to collect a faecal sample and to fill out a 24 h dietary journal. DNA was extracted from faecal material, taxonomy was assigned and microbiome data was analyzed, with a focus on microbiota involved in ammonia metabolism.In this study we show an altered faecal microbiome in UCD patients, different from both PKU and healthy controls. UCD patients on dietary and pharmacological treatment had a less diverse faecal microbiome, and the faecal microbiome of PKU patients on a protein restricted diet with amino acid supplementation showed reduced richness compared to healthy adults without a specific diet. The differences in the microbiome composition of UCD patients compared to healthy controls were in part related to lactulose use. Other genomic process encodings involved in ammonia metabolism, did not seem to differ. Since manipulation of the microbiome is possible, this could be a potential treatment modality. We propose as a first next step, to study the impact of these faecal microbiome alterations on metabolic stability. TAKE HOME MESSAGE: The faecal microbiome of UCD patients was less diverse compared to PKU patients and even more compared to healthy controls.

Standardising clinical outcomes measures for adult clinical trials in Fabry disease: A global Delphi consensus.

BACKGROUND: Recent years have witnessed a considerable increase in clinical trials of new investigational agents for Fabry disease (FD). Several trials investigating different agents are currently in progress; however, lack of standardisation results in challenges to interpretation and comparison. To facilitate the standardisation of investigational programs, we have developed a common framework for future clinical trials in FD. METHODS AND FINDINGS: A broad consensus regarding clinical outcomes and ways to measure them was obtained via the Delphi methodology. 35 FD clinical experts from 4 continents, representing 3389 FD patients, participated in 3 rounds of Delphi procedure. The aim was to reach a consensus regarding clinical trial design, best treatment comparator, clinical outcomes, measurement of those clinical outcomes and inclusion and exclusion criteria. Consensus results of this initiative included: the selection of the adaptative clinical trial as the ideal study design and agalsidase beta as ideal comparator treatment due to its longstanding use in FD. Renal and cardiac outcomes, such as glomerular filtration rate, proteinuria and left ventricular mass index, were prioritised, whereas neurological outcomes including cerebrovascular and white matter lesions were dismissed as a primary or secondary outcome measure. Besides, there was a consensus regarding the importance of patient-related outcomes such as general quality of life, pain, and gastrointestinal symptoms. Also, unity about lysoGb3 and Gb3 tissue deposits as useful surrogate markers of the disease was obtained. The group recognised that cardiac T1 mapping still has potential but requires further development before its widespread introduction in clinical trials. Finally, patients with end-stage renal disease or renal transplant should be excluded unless a particular group for them is created inside the clinical trial. CONCLUSION: This consensus will help to shape the future of clinical trials in FD. We note that the FDA has, coincidentally, recently published draft guidelines on clinical trials in FD and welcome this contribution.

Defining tetrahydrobiopterin responsiveness in phenylketonuria: Survey results from 38 countries.

BACKGROUND: A subset of patients with phenylketonuria benefit from treatment with tetrahydrobiopterin (BH4), although there is no consensus on the definition of BH4 responsiveness. The aim of this study therefore was to gain insight into the definitions of long-term BH4 responsiveness being used around the world. METHODS: We performed a web-based survey targeting healthcare professionals involved in the treatment of PKU patients. Data were analysed according to geographical region (Europe, USA/Canada, other). RESULTS: We analysed 166 responses. Long-term BH4 responsiveness was commonly defined using natural protein tolerance (95.6%), improvement of metabolic control (73.5%) and increase in quality of life (48.2%). When a specific value for a reduction in phenylalanine concentrations was reported (n = 89), 30% and 20% were most frequently used as cut-off values (76% and 19% of respondents, respectively). When a specific relative increase in natural protein tolerance was used to define long-term BH4 responsiveness (n = 71), respondents most commonly reported cut-off values of 30% and 100% (28% of respondents in both cases). Respondents from USA/Canada (n = 50) generally used less strict cut-off values compared to Europe (n = 96). Furthermore, respondents working within the same center answered differently. CONCLUSION: The results of this study suggest a very heterogeneous situation on the topic of defining long-term BH4 responsiveness, not only at a worldwide level but also within centers. Developing a strong evidence- and consensus-based definition would improve the quality of BH4 treatment.

Antibodies against recombinant alpha-galactosidase A in Fabry disease: Subclass analysis and impact on response to treatment.

BACKGROUND: Treatment of Fabry disease (FD) with recombinant alpha-galactosidase A (r-αGAL A) is complicated by the formation of anti-drug antibodies in the majority of male patients with the classical disease phenotype. Detailed information regarding antibody subtypes, onset and persistence of antibody development and their effect on treatment efficacy is sparse. METHODS: A retrospective study was carried out in 39 male patients with classical FD, treated with either agalsidase-alfa or agalsidase-beta (mean follow up of 10 years). With six to twelve months intervals plasma-induced in vitro inhibition of enzyme activity, lysoglobotriaosylsphingosine (lysoGb3) levels and renal function were assessed. In a subset of 12 patients, additionally anti- r-αGAL A IgM, IgA and IgG1, 2, 3 and 4 levels were analyzed. RESULTS: In 23 out of 39 patients, plasma-induced in vitro inhibition of r-αGAL A activity was observed (inhibition-positive). The inhibition titer was strongly negatively correlated to the decrease in lysoGb3: agalsidase-alfa (FElog10(inhibition) = -10.3, P ≤.001), agalsidase-beta (FElog10(inhibition) = -4.7, P ≤.001). Inhibition-positive patients had an accelerated decline in renal function (FE = 1.21, p = .042). During treatment IgG1 anti-r-αGAL A levels increased only in inhibition-positive patients (p = .0045). IgG4 anti-r-αGAL A antibodies developed in 7 out of 9 inhibition-positive patients. Other antibody subclasses were either not present or too low to quantify. CONCLUSION: Development of inhibiting antibodies against r-αGAL A negatively affects the biochemical response to ERT and resulted in an accelerated decline in renal function. The presence of IgG1 and IgG4 anti-r-αGAL A antibodies is associated with in vitro αGAL A activity inhibition.

Bone health in patients with inborn errors of metabolism.

Inborn errors of metabolism encompass a wide spectrum of disorders, frequently affecting bone. The most important metabolic disorders that primarily influence calcium or phosphate balance, resulting in skeletal pathology, are hypophosphatemic rickets and hypophosphatasia. Conditions involving bone marrow or affecting skeletal growth and development are mainly the lysosomal storage disorders, in particular the mucopolysaccharidoses. In these disorders skeletal abnormalities are often the presenting symptom and early recognition and intervention improves outcome in many of these diseases. Many disorders of intermediary metabolism may impact bone health as well, resulting in higher frequencies of osteopenia and osteoporosis. In these conditions factors contributing to the reduced bone mineralization can be the disorder itself, the strict dietary treatment, reduced physical activity or sunlight exposure and/or early ovarian failure. Awareness of these primary or secondary bone problems amongst physicians treating patients with inborn errors of metabolism is of importance for optimization bone health and recognition of skeletal complications.

Osteoporosis in patients with erythropoietic protoporphyria.

BACKGROUND: Erythropoietic protoporphyria (EPP) is a rare metabolic disease with painful photosensitivity due to protoporphyrin IX accumulation. OBJECTIVES: To evaluate bone mineral density (BMD) and known osteoporosis risk factors in patients with EPP. METHODS: Patients with EPP attending the Erasmus MC outpatient clinic who had undergone BMD measurements were included. Plasma 25 hydroxy (OH) vitamin D, alkaline phosphatase, parathyroid hormone and total protoporphyrin IX levels were measured; information on lifestyle, sunlight exposure and a bone-relevant physical exercise index [Bone Physical Activity Questionnaire (BPAQ) score] was obtained via questionnaires. BMD scores and the prevalence of osteopenia and osteoporosis in the EPP population were compared with a reference population. RESULTS: Forty-four patients with EPP (23 female, 21 male; mean age 37·6 years) were included. The mean SDs of the T-scores were -1·12 for the lumbar spine and -0·82 for the femoral neck (both P < 0·001). Osteopenia was present in 36%; osteoporosis in 23%. Based on the reference population the expected prevalence was 15% and 1%, respectively. Prevalence of vitamin D deficiency was 50% (defined as a 25-OH vitamin D level < 50 nmol L-1 ). Mean self-reported BPAQ score was 19·4 units (reference interval 19-24). Multiple linear regression analysis showed a significant influence of vitamin D deficiency and bone-relevant physical exercise score on BMD in patients with EPP. CONCLUSIONS: The prevalence of osteoporosis and osteopenia is greatly increased in patients with EPP. Alkaline phosphatase (related to vitamin D deficiency) and amount of weight-bearing exercise are significantly correlated with low BMD in this population.

Management of an LCHADD Patient During Pregnancy and High Intensity Exercise.

In this report we describe a female Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (LCHADD) patient who suffered from severe exercise intolerance. At age 34, the patient became pregnant for the first time. After an uneventful first 32 weeks of pregnancy she developed sinus tachycardia (resting heart rate 120-134 bpm) and lactate and creatinine kinase levels increased (3.3 mmol/L and 264 U/L, respectively). Increasing MCT supplementation (dose and frequency of administration) lowered heart rate and improved biochemical parameters. At 34 weeks the heart rate rose again and it was decided to deliver the child by caesarean section. Postpartum both mother and child did well.Prior to pregnancy, she performed exercise tests with different doses of medium chain triglycerides (MCTs) to establish a safe and effective exercise program (baseline test, second test with 10 g MCTs and third test with 20 g of MCTs). In the MCT supplemented tests the maximal power output was 23% (second test) and 26% (third test) higher, while cardiac output at maximal power output was the same in all three tests (~15.8 L/min).In conclusion, this is the first report of pregnancy in an LCHADD patient, with favourable outcome for both mother and child. Moreover, in the same patient, MCT supplementation improved cardiac performance and metabolic parameters during high intensity exercise. Using impedance cardiography, we got a clear indication that this benefit was due to improved muscle energy generation at high intensity exercise, since at the same cardiac output a higher power output could be generated.

Severe tracheal and bronchial collapse in adults with type II mucopolysaccharidosis.

BACKGROUND: Mucopolysaccharidosis type II (MPSII) patients frequently suffer from dyspnoea caused by restrictive airway disease due to skeletal abnormalities as well as glycosaminoglycans (GAG) accumulation at different levels of the airway, including the trachea. In this study we describe the extent of the tracheal and bronchial narrowing, the changes in airway diameter during respiration and the effects of these obstructions on respiratory function in adult MPSII patients. METHODS: Five adult MPSII patients (mean age 40 years) were included. Pulmonary function tests and in- and expiratory chest CT scans were obtained. Cross-sectional areas of trachea and main bronchi were measured at end-inspiration and -expiration and percentage collapse was calculated. RESULTS: There was diffuse narrowing of the entire intra-thoracic trachea and main bronchi and severe expiratory collapse of the trachea in all patients. At 1 cm above the aortic arch the median % collapse of the trachea was 68 (range 60 to 77%), at the level of the aortic arch 64 (range 21-93%), for the main bronchi this was 58 (range 26-66%) on the left and 44 (range 9-76%) on the right side. The pulmonary function tests showed that this airway collapse results in obstructive airway disease in all patients, which was severe (forced expiratory volume <50% of predicted) in four out of five patients. CONCLUSION: In adult MPS II patients, central airways diameters are strikingly reduced and upon expiration there is extensive collapse of the trachea and main bronchi. This central airways obstruction explains the severe respiratory symptoms in MPSII patients.

Mild cold effects on hunger, food intake, satiety and skin temperature in humans.

BACKGROUND: Mild cold exposure increases energy expenditure and can influence energy balance, but at the same time it does not increase appetite and energy intake. OBJECTIVE: To quantify dermal insulative cold response, we assessed thermal comfort and skin temperatures changes by infrared thermography. METHODS: We exposed healthy volunteers to either a single episode of environmental mild cold or thermoneutrality. We measured hunger sensation and actual free food intake. After a thermoneutral overnight stay, five males and five females were exposed to either 18°C (mild cold) or 24°C (thermoneutrality) for 2.5 h. Metabolic rate, vital signs, skin temperature, blood biochemistry, cold and hunger scores were measured at baseline and for every 30 min during the temperature intervention. This was followed by an ad libitum meal to obtain the actual desired energy intake after cold exposure. RESULTS: We could replicate the cold-induced increase in REE. But no differences were detected in hunger, food intake, or satiety after mild cold exposure compared with thermoneutrality. After long-term cold exposure, high cold sensation scores were reported, which were negatively correlated with thermogenesis. Skin temperature in the sternal area was tightly correlated with the increase in energy expenditure. CONCLUSIONS: It is concluded that short-term mild cold exposure increases energy expenditure without changes in food intake. Mild cold exposure resulted in significant thermal discomfort, which was negatively correlated with the increase in energy expenditure. Moreover, there is a great between-subject variability in cold response. These data provide further insights on cold exposure as an anti-obesity measure.

A monozygotic twin pair with highly discordant Gaucher phenotypes.

We describe monozygotic twin sisters, born to consanguineous Moroccan parents, who are highly discordant for the manifestations of Gaucher disease. Both carry Gaucher genotype N188S/N188S. One has severe visceral involvement, epilepsy, and a cerebellar syndrome. Her twin does not manifest any symptoms or signs of Gaucher disease but suffers from type 1 diabetes mellitus. The concurrence of a mild Gaucher mutation with a severe phenotype, as well as the occurrence of highly discordant phenotypes in a pair of monozygotic twins, is discussed.

Low HDL cholesterol levels in type I Gaucher disease do not lead to an increased risk of cardiovascular disease.

OBJECTIVE: A low plasma high-density lipoprotein cholesterol (HDL-c) concentration is an important risk factor for the development of atherosclerotic cardiovascular disease. HDL-c levels are abnormally low in type I Gaucher disease (GD) patients. The aim of this study was to determine whether GD is associated with premature atherosclerosis. METHODS: Lipid profiles, apolipoproteins, and carotid artery intima-media thickness (cIMT) were analyzed in 40 type I GD patients, 34 carriers and 41 control subjects. cIMT is a non-invasive validated biomarker for the status of atherosclerosis and present and future cardiovascular disease risk. RESULTS: Compared to control subjects, patients showed decreased HDL-c (1.1+/-0.3 mmol/L) as well as mildly decreased low-density lipoprotein cholesterol (LDL-c) levels (2.8+/-0.7 mmol/L), with an increased ApoB/ApoA1 ratio. In carriers, HDL-c levels were normal, but LDL-c levels were decreased (2.7+/-0.8 mmol/L). Mean cIMT measurements were not different in the three study groups (patients: 0.63+/-0.1mm versus carriers: 0.64+/-0.1mm versus control subjects: 0.65+/-0.1 mm). CONCLUSION: In Gaucher disease low HDL-c levels do not lead to premature atherosclerosis as assessed by cIMT measurement. This indicates that the inverse relationship between levels of HDL-c and risk of cardiovascular disease in the general population may not be present in all conditions characterised by low HDL-c levels.

Overweight, insulin resistance and type II diabetes in type I Gaucher disease patients in relation to enzyme replacement therapy.

Type I Gaucher disease, a lysosomal storage disorder is associated with metabolic abnormalities such as high resting energy expenditure, low circulating adiponectin and peripheral insulin resistance. Treatment with enzyme replacement therapy (enzyme therapy) leads to a decrease in resting energy expenditure, but its influence on weight and risk of development of type II diabetes is unknown. We studied the BMI, prevalence of overweight, insulin resistance and type II diabetes in untreated and enzyme therapy treated Gaucher patients before and after several years of follow-up and compared this to data on healthy subjects from literature. We established that in untreated Gaucher patients the prevalence of overweight is lower than in the general population. Long-term treatment with enzyme therapy induces a larger than average weight gain leading to a similar prevalence of overweight in enzyme therapy treated patients and the general population. The prevalence of type II diabetes increases significantly during treatment with enzyme therapy, resulting in a comparable prevalence of type II diabetes in enzyme therapy treated patients and the general population.

Hypermetabolism in Gaucher disease type I is not associated with altered thyroid hormone levels.

Type I Gaucher disease (OMIM 231000) is an inherited storage disorder in which deficiency of the enzyme glucocerebrosidase (EC 32145) leads to accumulation of glucocerebroside in lysosomes of macrophages. These storage cells are present in liver, spleen and bone marrow resulting in hepatosplenomegaly, cytopenia and bone complications. Metabolic abnormalities in Gaucher patients include hypermetabolism, possibly caused by elevated levels of pro-inflammatory cytokines. Nonthyroidal illness (NTI) is a combination of changes in circulating thyroid hormone levels (decreased T(3), elevated rT(3), normal or mildly depressed TSH) present in different illnesses and might be an adaptation to protect the organism from harmful catabolic effects of hypermetabolism. The hypermetabolism and the elevated cytokine levels in Gaucher disease led us to hypothesize that the alterations in thyroid hormone levels as seen in NTI might also occur in Gaucher patients. We studied thyroid hormone levels before and during treatment in 22 adult type I Gaucher patients and resting energy expenditure (REE) and correlations with thyroid hormone levels in 12 patients. Baseline thyroid hormone levels were normal in the majority (17) of patients. No cases of nonthyroidal illness were detected. Baseline REE (kcal/kg per 24 h) was not correlated with circulating levels of T(3), rT(3) or fT(4). Treatment of Gaucher disease with enzyme replacement therapy for several years resulted in a decrease in circulating fT(4) levels. After several months of treatment most patients showed a decrease in REE. There was no correlation between the changes in REE and changes in fT(4) and T(3).

T-lymphocyte subset distribution in human spleen.

BACKGROUND: When analyzing human cellular immune responses, most focus is placed on the peripheral blood (PB) and, to a lesser extent, the lymph nodes. To date the spleen has not been analyzed with regard to its role in adaptive cellular immunity and more notably not with respect to T-cell immune responses. MATERIALS AND METHODS: We analyzed the splenic lymphocyte compartment in comparison with the PB lymphocyte compartment regarding the number of NK cells, B cells, CD4(+), CD8(+) T cells and CMV-specific CD8(+) T cells. Furthermore, we analyzed the distribution of naive, memory and effector subsets of CD4(+) and CD8(+) T cells in these compartments. RESULTS: The spleen contains proportionally more B cells and less CD4(+) and CD8(+) T cells than PB. The percentage of CD8(+) T cells is greater in the spleen, leading to an inverse CD4/CD8 ratio. Both splenic CD4(+) and CD8(+) T-cell populations show a greater number of activated cells, and splenic CD8(+) T cells show a more differentiated cytotoxic CD27(-)CD45RA(+) memory phenotype. CONCLUSIONS: Our findings show that the distribution of the different lymphocyte subsets is markedly different between the spleen and the PB, thus inferring an important and distinct role for the spleen in CD4(+) and CD8(+) T-cell activation.

Isolation and biodiversity of hitherto undescribed soil bacteria related to Bacillus niacini.

The hitherto largely not described phylogenetic neighborhood of Bacillus niacini has been explored by a comprehensive cultivation experiment and genomic variety studies. Previous culture-independent studies demonstrated that approximately 15% of all Bacillus 16S rDNA directly extracted from soils worldwide was affiliated to B. niacini. Seven different media were inoculated with soil suspensions in serial dilutions and incubated at different temperatures. Then, bacterial colonies were picked and analyzed by sequencing. A mineral medium with acetate as carbon source yielded a B. niacini rate of >3% of all picked colonies. Other media were less efficient but also successful. Applying this culturing approach, we succeeded in obtaining 64 isolates from different Dutch soils. The isolates turned out to be diverse, although closely related to B. niacini as revealed by 16S rDNA sequencing. Close matches with environmental clones were also found, thus demonstrating much more diversity beyond previously known 16S rDNA sequences. The rep-PCR fingerprinting method revealed a high genomic variety, redundancy could not be observed among our isolates. Hence, the hitherto neglected B. niacini lineage, apparently among the most abundant soil Bacillus, was accessible to our cultivation approach.