Line Borgwardt

Fabry disease in children: agalsidase-beta enzyme replacement therapy

Fabry disease is a rare, multiorgan disease. The most serious complications involve the kidney, brain and heart. This study aims to assess the effect of enzyme replacement therapy (ERT) using agalsidase‐beta in children with Fabry disease. We carried out a nationwide, descriptive and observational retrospective cohort study of 10 children (9–16 years at baseline), who underwent regular systematic investigations for 1–8 years after initiation of ERT with agalsidase‐beta (Fabryzyme®, Genzyme). Ophthalmological, echocardiographic abnormalities and hypohidrosis were found at baseline and during the follow‐up period. Serious kidney, heart or brain involvement had not developed at the last follow‐up examination. For the majority of the patients improvements were found concerning headache, acroparaesthesias and gastrointestinal pain during the follow‐up period. The level of energy and physical activity also increased. Treatment with agalsidase‐beta was associated with a reduction of neuropathic and abdominal pain and headache. Although all aspects of the Fabry pain phenotype cannot be treated with ERT, the observed effects were clinically significant in the lives of the majority of Fabry children and together with the absence of serious Fabry manifestations at last follow‐up, we argue that early initiation of ERT may be considered.

Elective caesarean section increases the risk of respiratory morbidity of the newborn

Elective caesarean section upon maternal request has become more common during the last decades (1). Two surveys in the United Kingdom demonstrated that elective caesarean section upon maternal request increased from 1% in the mid 1970s and 1980s, to 30–38% in the 1990s (2). In Denmark, the overall frequency of caesarean section increased from 11.1% to 20.4% from 1982 to 2004. A Danish study stated that caesarean section upon maternal request is found as one of the main causes to the increase in caesarean section in general (3). This study aims to investigate the association among elective caesarean sections, spontaneous vaginal deliveries and neonatal respiratory morbidity in normal pregnancies expecting a normal uncomplicated birth. This is an important issue and has relevance to paediatricians when evaluating the neonatal infants after elective caesarean sections and to obstetricians when counselling mothers in choosing way of delivery. This is a retrospective study based on information from patient administrative systems and clinical databases at Hvidovre Hospital, Copenhagen University Hospital, Denmark. Information was extracted for all women giving birth in the period 1 January 2003 to 31 December 2005 at Hvidovre Hospital, Copenhagen University Hospital. The patient administrative system is used for registration of admissions and diagnoses and it is used for the economic contribution to the hospital departments. A clinical database of obstetrics keeps information regarding all deliveries at the hospital and is used for research and quality assessments. Database information was extracted, about maternal age, parity, birth weight, gestational age, umbilical cord pH, standard base excess and Apgar score. Based on the infants civil registration number, a search in the clinical database of neonatology and in the patient administrative system was performed. The latter gave information whether the infants had been admitted to a neonatal unit, the length of stay and the diagnosis at discharge. The clinical database of neonatology gave information regarding continuous positive airway pressure (CPAP) and ventilatory treatment. The criteria for inclusion were gestational age from 37 to 38 completed weeks, spontaneous vaginal delivery in cephalic presentation and elective caesarean section due to maternal request, breech presentation or transverse position. The statistical analyses were performed using SPSS 12.0 software (Chicago, IL, USA). Data on interval scales were compared using a t-test, whereas dichotomous variables were compared using a χ2-test. The level of significance was set at 0.05. A total of 16371 infants were born at Hvidovre Hospital during the 3-year period. Among those, 2174 deliveries fulfilled the criteria for inclusion and exclusion. Of these, 1680 was spontaneous vaginal deliveries and 494 elective caesarean sections. Thirty infants delivered by elective caesarean section and 37 delivered by spontaneous vaginal delivery were all transferred from the maternity ward and admitted to the neonatal unit. Overall patient characteristics are presented in Table 1. The primary diagnoses for the infants admitted to the neonatal unit are presented in Table 2. The most frequent diagnosis was respiratory morbidity, defined as persisting pulmonary hypertension of the newborn (PPHN), transient tachypnea of the newborn (TTN), pneumonia, and respiratory distress syndrome. Respiratory morbidity appears 10 times as frequent in the elective caesarean section group compared to the spontaneous vaginal delivery group (4.25% vs. 0.42%, RR 10.2, p < 0.0001) and when admitted to the neonatal unit still occurred more frequent among elective caesarean sections (70% vs. 19%, RR 3.70, p < 0.00001). Hypoglycaemia was

Estimating GFR in children with 99mTc-DTPA renography: a comparison with single-sample 51Cr-EDTA clearance

Glomerular filtration rate (GFR) measurement by 51Cr‐ethylenediaminetetraacetic acid (EDTA) and blood sampling in children is usually cumbersome for the patient, parents and laboratory technicians. We have previously developed a method accurately estimating GFR in adults. The aim of the present study was to evaluate the accuracy of this non‐invasive method in children. We calculated GFR from 99mTc‐diethylene triamine pentaacetic acid (DTPA) renography and compared with 51Cr‐EDTA plasma clearance of 29 children between the age of 1 month and 12 years (mean 4·7 years). The correlation between 99mTc‐DTPA renography and 51Cr‐EDTA plasma clearance was for all children R = 0·96 (n = 29, P<0·0001), for children above 2 years of age R = 0·96 (n = 18, P<0·0001) and for children <2 years R = 0·84 (n = 11, P<0·001). We conclude that assessment of GFR from 99mTc‐DTPA renography is reliable and comparable to GFR calculated from 51Cr‐EDTA plasma clearance. Because our method is non‐invasive and only takes 21 min, it may be preferable in many cases where an assessment of renal function is needed in children especially when renography is performed anyhow.

Alpha-mannosidosis: correlation between phenotype, genotype and mutant MAN2B1 subcellular localisation

BackgroundAlpha-mannosidosis is caused by mutations in MAN2B1, leading to loss of lysosomal alpha-mannosidase activity. Symptoms include intellectual disabilities, hearing impairment, motor function disturbances, facial coarsening and musculoskeletal abnormalities.MethodsTo study the genotype-phenotype relationship for alpha-mannosidosis 66 patients were included. Based on the predicted effect of the mutations and the subcellular localisation of mutant MAN2B1 in cultured cells, the patients were divided into three subgroups.Clinical and biochemical data were collected. Correlation analyses between each of the three subgroups of genotype/subcellular localisation and the clinical and biochemical data were done to investigate the potential relationship between genotype and phenotype in alpha-mannosidosis.Statistical analyses were performed using the SPSS software. Analyses of covariance were performed to describe the genotype-phenotype correlations. The phenotype parameters were modelled by the mutation group and age as a covariate. P values of <0.05 were considered as statistically significant.ResultsComplete MAN2B1 genotypes were established for all patients. We found significantly higher scores in the Leiter-R test, lower concentrations of CSF-oligosaccharides, higher point scores in the Bruininks-Oseretsky Test of Motor Proficiency subtests (BOT-2); Upper limb coordination and Balance, and a higher FVC% in patients in subgroup 3, harbouring at least one variant that allows localisation of the mutant MAN2B1 protein to the lysosomes compared to subgrou 2 and/or subgroup 1 with no lysosomal localization of the mutant MAN2B1 protein.ConclusionOur results indicate a correlation between the MAN2B1 genotypes and the cognitive function, upper limb coordination, balance, FVC% and the storage of oligosaccharides in CSF. This correlation depends on the subcellular localisation of the mutant MAN2B1 protein.

Alpha-mannosidosis: characterization of CNS pathology and correlation between CNS pathology and cognitive function

Alpha‐mannosidosis (AM) (OMIM 248500) is a rare lysosomal storage disease. The understanding of the central nervous system (CNS) pathology is limited. This study is the first describing the CNS pathology and the correlation between the CNS pathology and intellectual disabilities in human AM. Thirty‐four patients, aged 6–35 years, with AM were included. Data from 13 healthy controls were included in the analysis of the magnetic resonance spectroscopy (MRS). Measurements of CNS neurodegeneration biomarkers in cerebrospinal fluid (CSF), CSF‐oligosaccharides, and performance of cerebral magnetic resonance imaging (MRI) and MRS were carried out. On MRI, 5 of 10 patients had occipital white matter (WM) signal abnormalities, and 6 of 10 patients had age‐inappropriate myelination. MRS demonstrated significantly elevated mannose complex in gray matter and WM. We found elevated concentrations of tau‐protein, glial fibrillary acidic protein and neurofilament light protein in 97 patients, 74% and 41% of CSF samples, respectively. A negative correlation between CSF‐biomarkers and cognitive function and CSF‐oligosaccharides and cognitive function was found. The combination of MRS/MRI changes, elevated concentrations of CSF‐biomarkers and CSF‐oligosaccharides suggests gliosis and reduced myelination, as part of the CNS pathology in AM. Our data demonstrate early neuropathological changes, which may be taken into consideration when planning initiation of treatment.

Anesthesia for patients with alpha-mannosidosis – a case series of 10 patients

dogs from bupivacaine-induced cardiac toxicity. Reg Anesth Pain Med 2003; 28: 198–202. 5 Picard J, Harrop-Griffith W. Lipid emulsion to treat drug overdose: past, present and future. Anaesthesia 2009; 64: 785–786. 6 Rosenblatt M. Successful use of a 20%lipid emulsion to resuscitate a patient after a presumed bupivacaine-related cardiac arrest. Anesthesiology 2006; 105: 217–218. 7 Mirtallo J. State of the art review: intravenous fat emulsions: current applications, safety profile, and clinical implications. Ann Pharmacother 2010; 44: 688–700. 8 Christensen RD. Identifying patients, on the first day of life, at high-risk of developing parenteral nutrition–associated liver disease. J Perinatol 2007; 27: 284–290.

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.

Health Related Quality of Life, Disability, and Pain in Alpha Mannosidosis: Long-Term Data of Enzyme Replacement Therapy With Velmanase Alfa (Human Recombinant Alpha Mannosidase)

Alpha-mannosidosis, a rare lysosomal storage disorder caused by deficiency of the lysosomal enzyme alpha-mannosidase, results in accumulation of mannose-rich glycoproteins in the tissues and sequel...