Anupam Chakrapani

Suggested guidelines for the diagnosis and management of urea cycle disorders

Urea cycle disorders (UCDs) are inborn errors of ammonia detoxification/arginine synthesis due to defects affecting the catalysts of the Krebs-Henseleit cycle (five core enzymes, one activating enzyme and one mitochondrial ornithine/citrulline antiporter) with an estimated incidence of 1:8.000. Patients present with hyperammonemia either shortly after birth (~50%) or, later at any age, leading to death or to severe neurological handicap in many survivors. Despite the existence of effective therapy with alternative pathway therapy and liver transplantation, outcomes remain poor. This may be related to underrecognition and delayed diagnosis due to the nonspecific clinical presentation and insufficient awareness of health care professionals because of disease rarity. These guidelines aim at providing a trans-European consensus to: guide practitioners, set standards of care and help awareness campaigns. To achieve these goals, the guidelines were developed using a Delphi methodology, by having professionals on UCDs across seven European countries to gather all the existing evidence, score it according to the SIGN evidence level system and draw a series of statements supported by an associated level of evidence. The guidelines were revised by external specialist consultants, unrelated authorities in the field of UCDs and practicing pediatricians in training. Although the evidence degree did hardly ever exceed level C (evidence from non-analytical studies like case reports and series), it was sufficient to guide practice on both acute and chronic presentations, address diagnosis, management, monitoring, outcomes, and psychosocial and ethical issues. Also, it identified knowledge voids that must be filled by future research. We believe these guidelines will help to: harmonise practice, set common standards and spread good practices with a positive impact on the outcomes of UCD patients.

The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation.

BackgroundThe clinical presentation of patients with organic acidurias (OAD) and urea cycle disorders (UCD) is variable; symptoms are often non-specific.Aims/methodsTo improve the knowledge about OAD and UCD the E-IMD consortium established a web-based patient registry.ResultsWe registered 795 patients with OAD (nu2009=u2009452) and UCD (nu2009=u2009343), with ornithine transcarbamylase (OTC) deficiency (nu2009=u2009196), glutaric aciduria type 1 (GA1; nu2009=u2009150) and methylmalonic aciduria (MMA; nu2009=u2009149) being the most frequent diseases. Overall, 548 patients (69xa0%) were symptomatic. The majority of them (nu2009=u2009463) presented with acute metabolic crisis during (nu2009=u2009220) or after the newborn period (nu2009=u2009243) frequently demonstrating impaired consciousness, vomiting and/or muscular hypotonia. Neonatal onset of symptoms was most frequent in argininosuccinic synthetase and lyase deficiency and carbamylphosphate 1 synthetase deficiency, unexpectedly low in male OTC deficiency, and least frequently in GA1 and female OTC deficiency. For patients with MMA, propionic aciduria (PA) and OTC deficiency (male and female), hyperammonemia was more severe in metabolic crises during than after the newborn period, whereas metabolic acidosis tended to be more severe in MMA and PA patients with late onset of symptoms. Symptomatic patients without metabolic crises (nu2009=u200994) often presented with a movement disorder, mental retardation, epilepsy and psychiatric disorders (the latter in UCD only).ConclusionsThe initial presentation varies widely in OAD and UCD patients. This is a challenge for rapid diagnosis and early start of treatment. Patients with a sepsis-like neonatal crisis and those with late-onset of symptoms are both at risk of delayed or missed diagnosis.

Treatment of infantile Pompe disease with alglucosidase alpha: the UK experience

Treatment of infantile Pompe disease with recombinant human acid α-glucosidase has shown substantial improvement in survival, and in cardiac, motor and respiratory functions. We analyzed the outcome of all patients with infantile Pompe disease treated in the United Kingdom since the availability of the enzyme, using a questionnaire-based survey circulated to all treating centres. A total of 20 infants were treated from 2000 to 2009. Median ages at diagnosis and treatment were 5.75 months (range 0.25–31xa0months) and 6.5xa0months (0.5–32xa0months), respectively. Median duration of treatment was 31 months (1–102xa0months). Overall ventilator-free survival was 35% (7/20 infants), while 35% (7/20) died at a median age of 10 months (5.75–15xa0months) and 30% (6/20) were alive but ventilator-dependent. Endotracheal intubation for acute deterioration carried a high risk of failure of extubation and progression to long-term ventilation (LTV), but elective general anaesthesia, in contrast, was well tolerated. Overall outcome was worse than in the pivotal clinical trials; possible causes include later diagnosis and treatment in our patients and a higher incidence of infants at the severe end of the clinical spectrum. Careful consideration must be given to all possible outcomes, including LTV, before commencing enzyme replacement therapy in newly diagnosed infants.

The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: the evolving clinical phenotype

BackgroundThe disease course and long-term outcome of patients with organic acidurias (OAD) and urea cycle disorders (UCD) are incompletely understood.AimsTo evaluate the complex clinical phenotype of OAD and UCD patients at different ages.ResultsAcquired microcephaly and movement disorders were common in OAD and UCD highlighting that the brain is the major organ involved in these diseases. Cardiomyopathy [methylmalonic (MMA) and propionic aciduria (PA)], prolonged QTc interval (PA), optic nerve atrophy [MMA, isovaleric aciduria (IVA)], pancytopenia (PA), and macrocephaly [glutaric aciduria type 1 (GA1)] were exclusively found in OAD patients, whereas hepatic involvement was more frequent in UCD patients, in particular in argininosuccinate lyase (ASL) deficiency. Chronic renal failure was often found in MMA, with highest frequency in mut0 patients. Unexpectedly, chronic renal failure was also observed in adolescent and adult patients with GA1 and ASL deficiency. It had a similar frequency in patients with or without a movement disorder suggesting different pathophysiology. Thirteen patients (classic OAD: 3, UCD: 10) died during the study interval, ten of them during the initial metabolic crisis in the newborn period. Male patients with late-onset ornithine transcarbamylase deficiency were presumably overrepresented in the study population.ConclusionsNeurologic impairment is common in OAD and UCD, whereas the involvement of other organs (heart, liver, kidneys, eyes) follows a disease-specific pattern. The identification of unexpected chronic renal failure in GA1 and ASL deficiency emphasizes the importance of a systematic follow-up in patients with rare diseases.

Disorders of Tyrosine Metabolism

Five inherited disorders of tyrosine catabolism are known and depicted in Fig. 15.1. Hereditary tyrosinaemia type I is characterized by progressive liver disease and renal tubular dysfunction with rickets. Hereditary tyrosinaemia type II (Richner-Hanhart syndrome) presents with keratitis and blisterous lesions of the palms and soles. Tyrosinaemia type III may be asymptomatic or associated with mental retardation. Hawkinsinuria may be asymptomatic or presents with failure to thrive and metabolic acidosis in infancy. In alkaptonuria symptoms of osteoarthritis usually appear at an advanced age. Other inborn errors of tyrosine metabolism include oculocutaneous albinism caused by a deficiency of melanocyte-specific tyrosinase, converting tyrosine into DOPA-quinone; the deficiency of tyrosine hydroxylase, the first enzyme in the synthesis of dopamine from tyrosine; and the deficiency of aromatic l-amino acid decarboxylase, which also affects tryptophan metabolism. The latter two disorders are covered in Chap. 26.

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.

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.

Trifunctional protein deficiency: three families with significant maternal hepatic dysfunction in pregnancy not associated with E474Q mutation.

We report five families with trifunctional protein deficiency in which, during pregnancy, three mothers experienced significant hepatic disease when carrying an affected fetus. Diagnoses were based on increased levels of long-chain hydroxyacylcarnitines and deficiencies of 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and 3-ketoacyl-CoA thiolase activity in fibroblasts. All affected infants lacked the common E474Q mutation associated with isolated LCHAD deficiency. This mutation is thought to be a predisposing factor for maternal hepatic disease in pregnancy. Our findings suggest that other defects in this enzyme complex might be responsible for maternal hepatic complications in pregnancy.