C. Hendriksz

Mortality and cause of death in mucopolysaccharidosis type II—a historical review based on data from the Hunter Outcome Survey (HOS)

SummaryMucopolysaccharidosis type II (MPS II or Hunter syndrome) is a progressive, multisystemic disease caused by a deficiency of iduronate-2-sulfatase. Patients with the severe form of the disease have cognitive impairment and typically die in the second decade of life. Patients with the less severe form do not experience significant cognitive involvement and may survive until the fifth or sixth decade of life. We studied the relationship of both severity of MPS II and the time period in which patients died with age at death in 129 patients for whom data were entered retrospectively into HOS (Hunter Outcome Survey), the only large-scale, multinational observational study of patients with MPS II. Median age at death was significantly lower in patients with cognitive involvement compared with those without cognitive involvement (11.7 versus 14.1xa0years; pu2009=u20090.024). These data indicate that cognitive involvement is indicative of more severe disease and lower life expectancy in patients with MPS II. Median age at death was significantly lower in patients who died in or before 1985 compared with those who died after 1985 (11.3 versus 14.1xa0years; p α 0.001). The difference in age at death between patients dying in or before, relative to after, the selected cut-off date of 1985 may reflect improvements in patient identification, care and management over the past two decades. Data from patients who died after 1985 could serve as a control in analyses of the effects of enzyme replacement therapy with idursulfase on mortality in patients with MPS II.

Gastrointestinal disturbances and their management in miglustat-treated patients

Miglustat (Zavesca®) is approved for the oral treatment of adult patients with mild to moderate type 1 Gaucher disease (GD1) for whom enzyme replacement therapy is unsuitable, and for the treatment of progressive neurological manifestations in adult and paediatric patients with Niemann-Pick disease type C (NP-C). Gastrointestinal disturbances such as diarrhoea, flatulence and abdominal pain/discomfort have consistently been reported as the most frequent adverse events associated with miglustat during clinical trials and in real-world clinical practice settings. These adverse events are generally mild or moderate in severity, occurring mostly during the initial weeks of therapy. The mechanism underlying these gastrointestinal disturbances is the inhibition by miglustat of intestinal disaccharidase enzymes (mainly sucrase and maltase), leading to sub-optimal hydrolysis of carbohydrates and subsequent osmotic diarrhoea and altered colonic fermentation. Transient decreases in body weight, which are often observed during initial miglustat therapy, are considered likely due to gastrointestinal carbohydrate malabsorption and associated negative caloric balance. While most cases of diarrhoea resolve spontaneously during continued miglustat therapy, diarrhoea also responds well to anti-propulsive medications such as loperamide. Dietary modifications such as reduced consumption of dietary sucrose, maltose and lactose have been shown to improve the gastrointestinal tolerability of miglustat and reduce the magnitude of any changes in body weight, particularly if initiated at or before the start of therapy. Miglustat dose escalation at treatment initiation may also reduce gastrointestinal disturbances. This article discusses these aspects in detail, and provides practical recommendations on how to optimize the gastrointestinal tolerability of miglustat.

Does maternal knowledge and parent education affect blood phenylalanine control in phenylketonuria

BACKGROUNDnMetabolic control in phenylketonuria (PKU) may be influenced by parental ability because dietary treatment involves complex food choices. This is an observational study to compare maternal carer (MC) knowledge and parental education with phenylalanine concentrations in children with PKU.nnnMETHODSnChildren (n = 46; 26 boys) aged 1-10 years (median age 6 years) on dietary treatment were recruited. Their median lifetime and median phenylalanine concentrations in the year prior to study were estimated. MC completed a questionnaire to assess dietary knowledge.nnnRESULTSnOverall maternal knowledge on most aspects of diet was good and there was a correlation between annual median blood phenylalanine concentrations, but at the age of 5-6 years of age only, and higher maternal carer scores on PKU knowledge (r = -0.646; P < 0.0001). Three of only four children (12%) with median phenylalanine concentrations above 500 micromol L(-1) in the year prior to study had both parents leave school without educational qualifications. Children who had median phenylalanine concentrations (n = 3; 7%) over the recommended ranges at 3 years of age or earlier continued to have poor control.nnnCONCLUSIONSnBlood phenylalanine control within the first 3 years of age, poor parental educational achievement at school level, and unsatisfactory maternal dietary knowledge may all influence longer-term blood phenylalanine control in children.

Prospective treatment in carnitine–acylcarnitine translocase deficiency

SummaryCarnitine–acylcarnitine translocase (CACT) deficiency is a rare disorder that results in long-chain fatty acids being unavailable for mitochondrial β-oxidation and ketogenesis. It can present in the neonatal period or infancy with a severe clinical form, typically with convulsions, hypothermia, encephalopathy, cardiomyopathy and liver dysfunction, or with a milder phenotype with episodes of hypoglycaemia and hyperammonaemia during intercurrent illness. Investigations show hypoketonaemia, intermittent dicarboxyluria and hypocarnitinaemia with grossly elevated acylcarnitines. Enzyme assay or DNA analysis confirms the diagnosis. The severe phenotype results in severe disability or death. The less severe phenotype can also cause significant disability secondary to hypoglycaemia and/or hyperammonaemia at presentation. We report the outcome of two siblings with CACT deficiency. The index patient presented at the age of 2 months during a respiratory illness with hypoglycaemia, hyperammonaemia and cardiorespiratory collapse. Acylcarnitine profiles showed decreased free carnitine but striking elevations of long-chain acylcarnitines. Urine organic acids showed dicarboxylic aciduria. Fatty acid oxidation studies showed reduced oleate and myristate oxidation. His acylcarnitine profile normalized after he was started on a medium-chain triglyceride (MCT) low-fat diet and carnitine supplementation. Low CACT activity on enzyme assay confirmed the diagnosis. He has resulting profound developmental delay and epilepsy. The sibling was prospectively treated with a low-fat MCT diet and carnitine supplementation. Acylcarnitine profile at birth also showed elevated long-chain acylcarnitines. Fatty acid oxidation studies confirmed the diagnosis. To date he has normal development and has not had any significant periods of hypoglycaemia or hyperammonaemia.

'Ready to drink' protein substitute is easier is for people with phenylketonuria

SummaryIn phenylketonuria (PKU), compliance with taking protein substitute is an issue in teenage and older patients. A ‘ready to drink’ protein substitute may overcome many of the practical issues associated with its administration. Objective To investigate the efficacy of a liquid protein substitute in a 6-week, three-part, randomized, crossover, controlled study. Methods 27 subjects (15 female; 12 male) with PKU with a median age of 30 years (range 8–49 years) were recruited. One subject withdrew from the study. Their median daily dose of protein equivalent was 60 g (range 45--75 g). In parts 1 and 2, subjects were randomized to either a liquid or a powder protein substitute with the same nutritional composition per unit (each 130 ml liquid pouch or 25 g powder sachet contained 15 g protein equivalent). In part 3, subjects chose liquid, powder or a combination of both. Weekly blood phenylalanine (Phe) concentrations were estimated, and during weeks 2, 4 and 6 subjects completed a daily questionnaire on administration issues. Results All but one of 26 subjects chose the liquid in part 3 as either their sole (69%, n = 18) or partial source (28%, n = 7) of protein substitute. Blood Phe concentrations were significantly better on the liquid (p = 0.03). With the liquid protein substitute, subjects were less self-consciousness (p = 0.003) and found it easier to take away from home (p = 0.001). Overall, the liquid was easier (p <u20090.0001), more convenient (p = 0.002) and resulted in less wastage of protein substitute (p = 0.001). Conclusion Liquid protein substitute was popular and efficacious, reduced self-consciousness and overall improved compliance of teenagers and adults with PKU.

Intellectual and neurological functioning in Morquio syndrome (MPS IVa)

Mucopolysaccharidosis type IVa (MPS IVa, Morquio syndrome OMIM #253000) is a lysosomal storage disease caused by deficiency in N-acetylgalactosamine-6-sulfatase (GALNS, EC 3.1.6.4; encoded by GALNS gene at 16q24.3). Unlike other MPS disorders involving excessive heparan and dermatan sulfate, Morquio syndrome has not been associated with neurological involvement nor with intellectual impairment as this disorder of keratan sulfate has been described as a purely visceral and skeletal disorder. Neurocognitive assessment was undertaken of MPS IVa patients with age appropriate intellectual tests as well as a Child Behaviour Checklist as part of clinical follow up. Available neuroimaging studies (MRI and MR spectroscopy) were reviewed. Whilst more than half of the overall IQ scores fell in the average range, scores for 3/8 children fell below average. A number of behavioural problems were highlighted, including anxiety/depression, attention and somatic complaints. Subtle neuroimaging abnormalities were demonstrated in over half of the children. These findings present a challenge to existing assumptions about the nature of Morquio A syndrome. A hypothesis regarding the potential role of calcium signalling is explored.

Expert recommendations for the laboratory diagnosis of MPS VI.

Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease caused by a deficiency of N-acetylgalactosamine 4-sulfatase (arylsulfatase B, ASB). This enzyme is required for the degradation of dermatan sulfate. In its absence, dermatan sulfate accumulates in cells and is excreted in large quantities in urine. Specific therapeutic intervention is available; however, accurate and timely diagnosis is crucial for maximal benefit. To better understand the current practices for diagnosis and to establish diagnostic guidelines, an international MPS VI laboratory diagnostics scientific summit was held in February of 2011 in Miami, Florida. The various steps in the diagnosis of MPS VI were discussed including urinary glycosaminoglycan (uGAG) analysis, enzyme activity analysis, and molecular analysis. The following conclusions were reached. Dilute urine samples pose a significant problem for uGAG analysis and MPS VI patients can be missed by quantitative uGAG testing alone as dermatan sulfate may not always be excreted in large quantities. Enzyme activity analysis is universally acknowledged as a key component of diagnosis; however, several caveats must be considered and the appropriate use of reference enzymes is essential. Molecular analysis supports enzyme activity test results and is essential for carrier testing, subsequent genetic counseling, and prenatal testing. Overall the expert panel recommends caution in the use of uGAG screening alone to rule out or confirm the diagnosis of MPS VI and acknowledges enzyme activity analysis as a critical component of diagnosis. Measurement of another sulfatase enzyme to exclude multiple sulfatase deficiency was recommended prior to the initiation of therapy. When feasible, the use of molecular testing as part of the diagnosis is encouraged. A diagnostic algorithm for MPS VI is provided.

Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) as a cause of liver disease in infants in the UK

SummaryCitrin deficiency is a disorder with two phenotypes: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), and adult-onset type II citrullinaemia (CTLN2). NICCD presents in the first few weeks of life with prolonged cholestasis and metabolic abnormalities including aminoacidaemia (notably citrulline, tyrosine, threonine, arginine and methionine) and galactosuria. Symptoms resolve within the first year of life, thus making a diagnosis difficult after this time. Although patients subsequently remain generally healthy, some may develop more severe symptoms of CTLN2, characterized by neurological changes, one or more decades later. To date more than 400 cases have been reported, almost all from East Asia (mainly Japan). Here we describe the first two cases of NICCD in infants from the UK, one of caucasian origin and one of Pakistani origin. Both showed typical clinical and biochemical changes with a diagnosis confirmed by the presence of previously unreported mutations in the SLC25A13 gene. The presence of citrin deficiency in other ethnic groups means that NICCD needs to be considered in the diagnosis of any neonate with an unexplained cholestasis. We discuss both the difficulties in diagnosing these patients in populations where very few DNA mutations have been identified and the problems faced in the management of these patients. These findings also raise the possibility of adults with CTLN2 in whom a diagnosis has yet to be made.

Bone marrow transplantation in glycogen storage disease type 1b.

We report a case of glycogen storage disease type 1b that was successfully treated with bone marrow transplantation after life-threatening complications related to neutropenia and thrombocytopenia. Concomitant reduction in inflammatory bowel disease-related symptoms and improved metabolic stability were also observed.

Long-term compliance with a novel vitamin and mineral supplement in older people with PKU.

SummaryBackground:The long-term efficacy of vitamin and mineral preparations in dietary-treated adult patients with phenylketonuria (PKU) is unreported. Aim: In an open, intervention trial, the acceptability, safety and impact on biochemical and haematological micronutrient status of a new vitamin and mineral tablet (Phlexy Vits, SHS International) was investigated.Methods:Fifteen subjects with PKU (median age 21xa0years, range 8–33xa0years) on low-phenylalanine diet from two PKU centres were recruited. No vitamins or minerals were added to their protein substitute and for 12xa0months they took their full daily requirements of vitamin and minerals from Phlexy Vits (5 tablets/daily). All but two subjects had taken alternative vitamin and mineral supplements before the trial. Fasting bloods were taken at baseline (week −2 and at week 0), 4 and 12xa0months for a range of biochemical and nutritional measurements.Results:By 4xa0months, serum vitamin B12 (pu2009=u20090.003), serum manganese (p=0.03) and plasma (p=0.03) and red blood cell (p=0.004) glutathionine peroxidase (GSHPx) all significantly increased but remained within normal reference ranges. By 12xa0months, serum vitamin B12 (p<0.05) and plasma GSHPx (p<0.05) remained increased. The Phlexy Vits tablets scored better than conventional vitamin and mineral supplements for overall acceptability (p<0.05), and ease of swallowing (p=0.1) at 4xa0months, although swallowing score deteriorated by 12xa0months (p<0.05). There was a small but significant deterioration in compliance with taking the vitamin and mineral supplements between 4 and 12xa0months (p<0.05).Conclusion:In the long term, these comprehensive vitamin and mineral tablets appeared acceptable and improved biochemical nutritional status, although there were long-term compliance and swallowing issues.