High protein prescription in methylmalonic and propionic acidemia patients and its negative association with long-term outcome.

BACKGROUND AND OBJECTIVE: Methylmalonic acidemia (MMA) and propionic acidemia (PA) are inborn errors of metabolism. While survival of MMA and PA patients has improved in recent decades, long-term outcome is still unsatisfactory. A protein restricted diet is the mainstay for treatment. Additional amino acid mixtures (AAM) can be prescribed if natural protein is insufficient. It is unknown if dietary treatment can have an impact on outcome. DESIGN: We performed a nationwide retrospective cohort study and evaluated both longitudinal dietary treatment and clinical course of Dutch MMA and PA patients. Protein prescription was compared to the recommended daily allowances (RDA); the safe level of protein intake as provided by the World Health Organization. The association of longitudinal dietary treatment with long-term outcome was evaluated. RESULTS: The cohort included 76 patients with a median retrospective follow-up period of 15 years (min-max: 0-48 years) and a total of 1063 patient years on a protein restricted diet. Natural protein prescription exceeded the RDA in 37% (470/1287) of all prescriptions and due to AAM prescription, the total protein prescription exceeded RDA in 84% (1070/1277). Higher protein prescriptions were associated with adverse outcomes in severely affected patients. In PA early onset patients a higher natural protein prescription was associated with more frequent AMD. In MMA vitamin B12 unresponsive patients, both a higher total protein prescription and AAM protein prescription were associated with more mitochondrial complications. A higher AAM protein prescription was associated with an increased frequency of cognitive impairment in the entire. CONCLUSION: Protein intake in excess of recommendations is frequent and is associated with poor outcome.

The etiological evaluation of sensorineural hearing loss in children.

This study aims to evaluate the etiology of pediatric sensorineural hearing loss (SNHL). A total of 423 children with SNHL were evaluated, with the focus on the determination of causative genetic and acquired etiologies of uni- and bilateral SNHL in relation to age at diagnosis and severity of the hearing loss. We found that a stepwise diagnostic approach comprising of imaging, genetic, and/or pediatric evaluation identified a cause for SNHL in 67% of the children. The most common causative finding in children with bilateral SNHL was causative gene variants (26%), and in children with unilateral SNHL, a structural anomaly of the temporal bone (27%). The probability of finding an etiologic diagnosis is significantly higher in children under the age of 1 year and children with profound SNHL.Conclusions: With our stepwise diagnostic approach, we found a diagnostic yield of 67%. Bilateral SNHL often has a genetic cause, whereas in unilateral SNHL structural abnormalities of the labyrinth are the dominant etiologic factor. The diagnostic yield is associated with the age at detection and severity of hearing loss: the highest proportion of causative abnormalities is found in children with a young age at detection or a profound hearing loss. What is Known: • Congenital sensorineural hearing loss is one of the most common congenital disorders • Determination of the cause is important for adequate management and prognosis and may include radiology, serology, and DNA analysis What is New: • Using a stepwise diagnostic approach, causative abnormalities are found in 67% both in uni- and bilateral SNHL, with the highest diagnostic yield in very young children and those suffering from profound hearing loss • Bilateral SNHL often has a genetic cause, whereas in unilateral SNHL structural abnormalities of the labyrinth are the dominant etiologic factor.

Evaluation of the outcome of CT and MR imaging in pediatric patients with bilateral sensorineural hearing loss.

OBJECTIVE: To evaluate the clinically relevant abnormalities as visualized on CT and MR imaging in children with symmetric and asymmetric bilateral sensorineural hearing loss (SNHL), in relation to age and the severity of hearing loss. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary referral otology and audiology center. PATIENTS AND DIAGNOSTIC INTERVENTIONS: From January 2006 until January 2016, a total of 207 children diagnosed with symmetric and asymmetric bilateral SNHL were included. They underwent CT and/or MR imaging for the evaluation of the etiology of their hearing loss. MAIN OUTCOME MEASURES: Radiologic abnormalities associated with SNHL. RESULTS: 302 scans were performed in 207 children (median age of 0.8 years old) with bilateral SNHL. The most frequently identified cause of bilateral SNHL was a malformation of the labyrinth. The combined diagnostic yield of CT and MR imaging was 32%. The diagnostic yield of MR (34%) was considerably higher than that of CT (20%). We found a higher rate of abnormalities in children with profound hearing loss (41%) compared to milder hearing loss (8-29%), and in asymmetric SNHL (52%) compared to symmetric SNHL (30%). CONCLUSION: Imaging is essential in the etiologic evaluation of children with bilateral SNHL. The highest diagnostic yield is found in children with bilateral asymmetric SNHL or profound SNHL. Based on our findings, MR is the primary imaging modality of choice in the etiological evaluation of children with bilateral SNHL because of its high diagnostic yield.

High prevalence of abnormalities on CT and MR imaging in children with unilateral sensorineural hearing loss irrespective of age or degree of hearing loss.

OBJECTIVE: Evaluation of causal abnormalities identified on CT and MR imaging in children with unilateral sensorineural hearing loss (USNHL), and the association with age and severity of hearing loss. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary referral otology/audiology center. PATIENTS AND DIAGNOSTIC INTERVENTIONS: 102 children diagnosed with USNHL between 2006 and 2016 were included. They underwent CT and/or MR imaging for the evaluation of the etiology of their hearing loss. MAIN OUTCOME MEASURES: Radiologic abnormalities of the inner ear and brain associated with USNHL. RESULTS: Using CT and/or MR imaging, causal abnormalities were identified in 49%, which is higher than previously reported (25-40%). The most frequently affected site was the labyrinth (29%), followed by the cochlear nerve (9%) and brain (7%). No significant difference in the number or type of abnormalities was found for the degree of hearing loss or age categories. CONCLUSIONS: Imaging is essential in the etiologic analysis of USNHL because of the high prevalence of causative abnormalities that can be identified with radiology, irrespective of the patients' age or degree of hearing loss. CT and MR imaging are complementary imaging options. The ideal imaging algorithm is controversial. Based on our findings, we conclude that there is limited additional diagnostic value of simultaneous dual modality imaging over sequential diagnostics. We therefore perform a stepwise radiological workup in order to maximize the diagnostic yield while minimizing impact and costs. If the primary imaging modality does not identify a cause for USNHL, performing the alternative imaging modality should be considered. LEVEL OF EVIDENCE: Retrospective cohort study 2b.

Growth in patients with mucopolysaccharidosis type III (Sanfilippo disease).

BACKGROUND: Mucopolysaccharidosis III (MPS III), known as Sanfilippo disease, is a lysosomal storage disorder mainly characterized by progressive neurodegeneration with cognitive decline and relatively attenuated somatic signs and symptoms. Although short stature is invariably present in patients with the other mucopolysaccharidoses, it has not been sufficiently addressed in MPS III. The aim of this study was to investigate growth data of a large Dutch MPS III cohort in order to construct growth charts for MPS III patients. METHODS: Height, weight, head circumference (HC), and body mass index (BMI) data from 118 MPS III patients were used to construct reference curves, using the lambda, mu, sigma (LMS) method. Genotype-group comparisons for height standard deviation scores (SDS) were performed by Kruskal-Wallis analysis for different age groups. RESULTS: Birth weight and length were within normal ranges for gestational age and showed a significantly stunted growth from age 6 years onward. Mean final heights were 169.7 cm (-2.0 SDS) and 165.4 cm (-0.84 SDS) for adult male and female, patients, respectively. Phenotypic severity, as assessed by genotyping, correlated with growth pattern and final height. In addition, mean BMI and HC SDS were significantly higher when compared with Dutch standards for both boys and girls. CONCLUSIONS: Growth in MPS III is stunted mainly in patients with the severe phenotype. We provide disease-specific growth references that can be used for clinical management of MPS III patients and may be of value for future treatment studies.

Acid sphingomyelinase (Asm) deficiency patients in The Netherlands and Belgium: disease spectrum and natural course in attenuated patients.

Niemann-Pick disease (NPD) is a neurovisceral lysosomal storage disorder caused by acid sphingomyelinase (ASM) deficiency, which can be categorized as either Niemann-Pick disease type A [NPD-A], with progressive neurological disease and death in early childhood, or as Niemann-Pick disease type B [NPD-B], with a more variable spectrum of manifestations. Enzyme replacement therapy (ERT) with recombinant sphingomyelinase is currently studied as potential treatment for NPD-B patients. The objective of this study is to characterize the clinical features of patients with ASM deficiency in the Netherlands and Belgium with focus on the natural disease course of NPD-B patients. Prospective and retrospective data on ASM deficient patients were collected in The Netherlands and part of Belgium. Patients with NPD-B that could be followed prospectively were evaluated every 6-12 months for pulmonary function tests, 6 minute walk test (6 MWT), imaging (bone marrow infiltration measured by QCSI, organ volumes by MRI and CT scan of the lungs) and biochemical markers. Twenty-five patients with ASM deficiency were identified (13 males, 12 females, median age 13years, range 1-59 years). Nine patients had died at the time of the study, including four NPD-A patients at the age of 1,1, 2, 3 and five NPDB patents at the age of 5, 6, 43, 56 and 60 years. There was a high prevalence of homozygosity and compound heterozygosity for the common p.Arg608del mutation in 43% and 19% of NPD-B patients, respectively. In NPD-B patients, thrombocytopenia was present in most, while anemia and leucopenia were less common (33% and 6 % respectively). HDL cholesterol was reduced in most patients. Pulmonary disease was severe in several patients. Follow-up up to 11 years revealed a gradual decrease in platelet count. Detailed investigations in 6 NPD-B patients with follow-up in 4 patients revealed remarkable stable disease parameters up to 6 years, with some decline in pulmonary function and 6 MWT. Bone marrow fat fractions were decreased, indicating the presence of storage macrophages. Lung involvement was not related to the extent of visceromegaly, cytopenia or bone marrow involvement. In conclusion, in NPD-B patients pulmonary disease is the most debilitating feature. Disease manifestations are mostly stable in attenuated patients. Bone marrow infiltration is a less prominent feature of the disease.

4-Hydroxybutyric aciduria associated with catheter usage: a diagnostic pitfall in the identification of SSADH deficiency.

Succinic semialdehyde dehydrogenase deficiency is a slowly progressive to static neurological disorder featuring elevated concentrations of 4-hydroxybutyric acid in body fluids. We present two patients with elevated 4-hydroxybutyric acid in urine which was later shown to be linked to catheter usage.

Phenylalanine tolerance can already reliably be assessed at the age of 2 years in patients with PKU.

BACKGROUND: The clinical severity of phenylalanine hydroxylase deficiency is usually defined by either pre-treatment phenylalanine (Phe) concentration or Phe tolerance at 5 years of age. So far, little is known about the course of Phe tolerance or the ability of both pre-treatment Phe and Phe tolerance at early age to predict Phe tolerance at later age. AIM: This study was conducted to investigate the course of the individual Phe tolerance and to assess the predictive value of both the pre-treatment Phe concentration and Phe tolerance at 1 and 6 months and 1, 2, 3 and 5 years for Phe tolerance at 10 years of age. METHOD: Data on blood Phe concentration, prescribed Phe intake and weight of 213 early and continuously treated Dutch PKU patients up to 10 years of age were collected. Data acquired under good metabolic control were used in the study. Tolerance was expressed in mg/day and mg/kg per day. RESULTS: Data at 1 and 6 months and at 1, 2, 3 and 5 years of 61, 58, 59, 57, 56 and 59 patients were included for comparison with the Phe tolerance at 10 years. Phe tolerances (mg/kg per day) at 2, 3 and 5 years showed a clear correlation with the tolerance at 10 years of age (r = 0.608, r = 0.725 and r = 0.661). Results for tolerance expressed as mg/day were comparable. Pre-treatment Phe concentrations did not correlate significantly with the tolerance. CONCLUSION: Pre-treatment Phe is unreliable but Phe tolerance is a reliable predictor of the tolerance at 10 years of age, starting at 2 years of age.

The intake of total protein, natural protein and protein substitute and growth of height and head circumference in Dutch infants with phenylketonuria.

In a previous study, Dutch children with phenylketonuria (PKU) were found to be slightly shorter than their healthy counterparts. In the literature, it has been hypothesized that a higher protein intake is necessary to optimize growth in PKU patients. The study aimed to investigate whether protein intake (total, natural and protein substitute) in this group might be an explanatory factor for the observed growth. Growth of height and head circumference and dietary data on protein intake (total, natural and protein substitute) from 174 Dutch PKU patients born between 1974 and 1996 were analysed retrospectively for the patients' first 3 years of life. Analyses were corrected for energy intake during the first year of life and for the clinical severity of the deficiency of phenylalanine hydroxylase by means of plasma phenylalanine concentration at birth. Neither protein nor energy intake correlated with height growth. A positive, statistically significant relation between head circumference growth and natural protein and total protein intake was found, but not with the intake of the protein substitute or energy. Therefore, this study suggests that improvement of the protein substitute rather than an increase of total protein intake may be important in optimizing head circumference growth in PKU patients.

Clearance of maternal leukaemic cells in a neonate.

A 36-week pregnant woman was diagnosed with acute lymphoblastic leukaemia. Delivery was initiated prematurely, and a healthy child was born. Cord blood and peripheral blood samples from the neonate (obtained at 6 weeks, 3 months and 6 months) were analysed for the presence of minimal residual disease by polymerase chain reaction analysis of a leukaemia-specific IGH gene rearrangement and the E2A--PBX1 fusion gene transcript. In the cord blood sample, a tumour load of approximately 4 x 10(-4) was found, whereas all later blood samples were negative. Our data indicate that the maternal leukaemic cells did not engraft in the neonate.

The fall of cardiac output in endotoxemic rats cannot explain all changes in organ blood flow: a comparison between endotoxin and low venous return shock.

During endotoxin shock mean arterial pressure (MAP) and cardiac output (CO) fall, and the latter is redistributed. To evaluate whether these changes are solely caused by the low output, or are also based on endotoxin itself, we compared regional hemodynamic changes during endotoxemia with those in a nonendotoxemic state of decreased CO in anesthetized rats. In group E (n = 10) endotoxin Escherichia coli O127:B8 (8 mg.kg-1) was infused from t = 0 till t = 60 min. In group B (n = 10) the same decrease of CO and MAP was obtained as in group E by inflating a balloon in the inferior caval vein, distal to the renal veins, from t = 0 till t = 60 min. We measured MAP, CO (thermodilution), central venous pressure, heart rate, organ blood flow, and redistribution of CO (microspheres), arterial lactate and glucose, and hematocrit. MAP and CO decreased (p < .05) in both groups (by 30 and 50%, respectively at t = 60). Heart rate, hematocrit, arterial lactate, and arterial glucose were significantly higher (p < .05) in group E (by 17, 12, 180, and 55%, respectively). Blood flow to most organs had similarly decreased in both groups. The decreased intestinal blood flow lead to macroscopic damage only in group E. Blood flows (absolute or as percentage of CO) to heart, hepatic artery, and diaphragm, however, had significantly increased in group E while blood flows to skin, skeletal muscle, and stomach had decreased more in group E. Except for the heart these differences could be explained by increased work load (detoxification: liver; hyperventilation: diaphragm, muscle) and thus to a more pronounced redistribution at the expense of skin and muscle blood flow. Regional hemodynamic changes during endotoxemia thus could largely be attributed to decrease of CO and redistribution of the circulating blood volume. In the heart, endotoxin seemed to exert effects independent of the hypodynamic state. This was also true for the intestinal damage and the rise in hematocrit and arterial lactate.

Protective role of NO in the regional hemodynamic changes during acute endotoxemia in rats.

The role of NO during the first hour of endotoxemia is still controversial. To evaluate whether NO is protective or detrimental to the regulation of systemic blood pressure, cardiac output (CO), and organ perfusion in rats during acute endotoxemia, we have studied the effects of inhibition of NO synthesis. Thirty minutes after 0.1 mg NG-nitro-L-arginine (L-NNA; group L, n = 7, partial inhibition), 1 mg L-NNA (group H, n = 6, complete inhibition), or saline (group E, n = 7) intravenous infusion, anesthetized volume-loaded rats were infused with endotoxin Escherichia coli O127:B8 (8 mg.kg-1 x h-1) from time (t) = 0 to 60 min. Organ blood flow was measured with radioactive microspheres. In group H, at time 0, CO was lower than in group E (by -29%; P < 0.05), and systemic vascular resistance (SVR) was higher than in groups E and L (by 72 and 51%, respectively; P < 0.05). Perfusion of the pancreas, stomach, intestines, and kidney was lower (P < 0.05) and corresponding organ vascular resistance (OVR) higher (P < 0.05) in group H than in groups E and L (except kidney in group L). At t = 60 min, in groups H and L, CO was lower (by -45 and -26%, respectively; P < 0.05) and SVR was higher (by 112 and 54%, respectively; P < 0.05) than in group E. In group L only blood flow to the heart, pancreas, intestines, and kidney was significantly lower than in group E, and corresponding OVR was higher.(ABSTRACT TRUNCATED AT 250 WORDS)

High-energy phosphates in heart, liver, kidney, and skeletal muscle of endotoxemic rats.

Endotoxemia can affect the storage of high-energy phosphates [ATP, creatine phosphate (CrP)] even in organs in which global blood flow does not fall. If a decrease in this storage is due to an inadequate oxygen supply-to-demand ratio, improving the perfusion should restore it. Therefore, in anesthetized endotoxemic rats we studied organ perfusion and the storage of high-energy phosphates of heart, liver, kidney, and skeletal muscle and measured the effects of improving cardiac output (CO) and organ blood flow with cardiostimulatory drugs [dopexamine (DX) and dobutamine (DB)]. Endotoxin (Escherichia coli O127.B8, 8 mg/kg) was infused from 0 to 60 min in three groups of anesthetized rats: one untreated (saline only) group (ES; n = 10), and two groups in which we infused DX (3 x 10(-8) mol.kg-1.min-1; n = 10) or DB (10(-7) mol.kg-1.min-1; n = 8) from 60 to 135 min. A fourth group served as time-matched controls (C; n = 8). Organ blood flows at 0 and 135 min (end of experiment) were measured with radioactive microspheres. In biopsies (at 135 min) we measured lactate, ATP, and CrP concentrations. Endotoxemia decreased CO (45% at 135 min; P < 0.05), which could be restored by DX and DB. Myocardial and skeletal muscle blood flow and ATP did not differ in the groups at 135 min. Hepatic and renal blood flow decreased in the ES group 44 and 52%, respectively (P < 0.05); DX restored the fall of hepatic and DB of renal blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Systemic and regional hemodynamic changes during endotoxin or platelet activating factor (PAF)-induced shock in rats.

To evaluate the role of platelet activating factor (PAF) during endotoxin shock, we compared its effects with those of endotoxin. We measured arterial pressure (MAP), heart rate (HR), cardiac output (CO; thermodilution), arterial lactate (Calact), organ blood flow (radioactive microspheres), and organ vascular resistance in four groups of anesthetized (pentobarbital) male Wistar rats (n = 7 per group), infused from t = 0 to t = 60 min with saline (group C: time matched control), endotoxin Escherichia coli O127:B8, 8 mg.kg-1 (group E), a "low PAF dose" (1 microgram.kg-1) to cause the same decrease in MAP as in group E (group PL), or a "high PAF dose" (3 micrograms.kg-1) to cause the same decrease in CO as in group E (group PH). At t = 60 min, MAP had decreased by 33% in E and PL, and by 55% in PH group. CO had decreased by 41% in the E and PH group. Calact had increased in the E and PH group by 300 and 200%, respectively. In the E, PL and PH group, coronary vascular resistance decreased. In the splanchnic organs, endotoxin caused a decrease in blood flow due to vasoconstriction, whereas PAF (both concentrations) caused vasodilation (except for spleen). Renal vascular resistance decreased (P < 0.05) in the PL group. In all groups, vascular resistance had increased (P < 0.05) in skin, and not changed in skeletal muscle (P < 0.05). Thus, hemodynamic changes after PAF infusion were partially similar to those after endotoxin infusion (coronary vasodilation and vasoconstriction in spleen and skin).(ABSTRACT TRUNCATED AT 250 WORDS)

Organ blood flow and distribution of cardiac output in dopexamine- or dobutamine-treated endotoxemic rats.

Endotoxemia causes a decrease of blood flow to most organs. If this could be prevented, chances of survival might improve. In endotoxemic rats, we studied the effect of a therapeutic infusion of dopexamine (dopaminergic, beta 2-adrenergic) on blood flow and percentage of the cardiac output distributed to heart, brain, hepatic artery, stomach, intestines, spleen, pancreas, kidneys, adrenals, diaphragm, skeletal muscle, and skin. Dopexamine action was compared with that of dobutamine (beta 1-adrenergic). Endotoxin shock was induced in 28 rats with infusion of 8 mg/kg Escherichia coli O127:B8 endotoxin from 0 to 60 minutes; the rats were then divided into 3 groups, which received from 60 to 135 minutes of an infusion of saline (ES; n = 10), dopexamine hydrochloride (DX, 3 x 10(-8) mol/kg.min; n = 10) or dobutamine (DB, 10(-7) mol/kg.min; n = 8). A fourth group served as time-matched controls (C, saline from 0 to 135 minutes; n = 8). In the untreated endotexemic rats, cardiac output decreased and organ blood flow decreased except in the diaphragm, heart, and brain; the percentage of the cardiac output to those organs increased. Dopexamine and dobutamine similarly improved cardiac output in endotoxemic rats. All organs benefitted to the same extent from the increased cardiac output. Therapeutic infusion of dopexamine during endotoxemia did not favor flow to any particular organ; redistribution of cardiac output changed little after administration of dopexamine, and its effects were not significantly different from those of dobutamine.

[The effect of age and activity on arterial oxygen pressure and arterial oxygen saturation in hospitalized patients]. / Het effect van leeftijd en activiteit op arteriële zuurstofspanning en arteriële zuurstofsaturatie bij gehospitaliseerde patiënten.

In order to obtain adequate normal values for arterial blood gas values, the effect of aging and activity was investigated by cross-sectional selection in an in-patient population of 108 patients aged between 20 and 90 years. The patients were free of pulmonary, cardiac and metabolic disease. Smoking and obesity were tolerated up to specified limits. Arterial blood was obtained during standardised resting and active states. The results show a clinically important and highly significant (p less than 0.001) decline of the oxygen tension (PaO2) with age and also a considerable effect of minor activity (p less than 0.01) on blood gas values. However, the relationship of both oxygen tension and oxygen saturation with age is not a linear function as suggested in previous studies. For the interpretation of arterial oxygen tension values or to define hypoxaemia, only normal values related to age and activity should be used. In the elderly, low levels of PaO2 are encountered regularly. Determination of the oxygen saturation may be helpful, especially in differentiating between a normal and a pathological state.