Roshni Vara

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.

Liver transplantation for propionic acidemia in children

Propionic acidemia (PA) is a rare inherited disorder of branched chain amino acid metabolism; despite improvements in conventional medical management, the long‐term outcome remains disappointing. Liver transplantation (LT) has been proposed to minimize the risk of further metabolic decompensations and to improve the quality of life. We performed a retrospective review of all children with PA who underwent LT between 1987 and 2008. Five children were identified with a median age of 1.2 years (range = 0.7‐4.1 years) at referral. Four of the children presented clinically at 3 weeks of age or less, and 1 child was diagnosed prenatally. All had metabolic acidosis and hyperammonemia. Two had seizures and required intensive care; this care included inotropic support and continuous venovenous hemofiltration in 1 child. The children were considered for elective LT for the following reasons: frequent metabolic decompensations (2), previous sibling death (2), and elective management (1). One child underwent auxiliary LT, and 4 children received orthotopic grafts (1 living related graft). The median age at LT was 1.5 years (range = 0.8‐7.0 years). There was 1 retransplant 3 months after LT due to hepatic artery thrombosis. One year after LT, 1 patient suffered a metabolic stroke with minimal residual neurology. After a median follow‐up of 7.3 years (range = 2.2‐15.0 years), all the children had normal graft function and a good quality of life with a protein‐unrestricted diet and no further metabolic decompensations. In conclusion, LT has a role in the management of PA: it reduces the risk of metabolic decompensation and improves the quality of life. The potential for the development of metabolic sequelae is not completely eliminated. Liver Transpl 17:661‐667, 2011.

Recurrent De Novo Dominant Mutations in SLC25A4 Cause Severe Early-Onset Mitochondrial Disease and Loss of Mitochondrial DNA Copy Number

Mutations in SLC25A4 encoding the mitochondrial ADP/ATP carrier AAC1 are well-recognized causes of mitochondrial disease. Several heterozygous SLC25A4 mutations cause adult-onset autosomal-dominant progressive external ophthalmoplegia associated with multiple mitochondrial DNA deletions, whereas recessive SLC25A4 mutations cause childhood-onset mitochondrial myopathy and cardiomyopathy. Here, we describe the identification by whole-exome sequencing of seven probands harboring dominant, de novo SLC25A4 mutations. All affected individuals presented at birth, were ventilator dependent and, where tested, revealed severe combined mitochondrial respiratory chain deficiencies associated with a marked loss of mitochondrial DNA copy number in skeletal muscle. Strikingly, an identical c.239G>A (p.Arg80His) mutation was present in four of the seven subjects, and the other three case subjects harbored the same c.703C>G (p.Arg235Gly) mutation. Analysis of skeletal muscle revealed a marked decrease of AAC1 protein levels and loss of respiratory chain complexes containing mitochondrial DNA-encoded subunits. We show that both recombinant AAC1 mutant proteins are severely impaired in ADP/ATP transport, affecting most likely the substrate binding and mechanics of the carrier, respectively. This highly reduced capacity for transport probably affects mitochondrial DNA maintenance and in turn respiration, causing a severe energy crisis. The confirmation of the pathogenicity of these de novo SLC25A4 mutations highlights a third distinct clinical phenotype associated with mutation of this gene and demonstrates that early-onset mitochondrial disease can be caused by recurrent de novo mutations, which has significant implications for the application and analysis of whole-exome sequencing data in mitochondrial disease.

A single center experience of donation after cardiac death liver transplantation in pediatric recipients

Bartlett A, Vara R, Muiesan P, Mariott P, Dhawan A, Mieli‐Vergani G, Rela M, Heaton N. A single center experience of donation after cardiac death liver transplantation in pediatric recipients.
Pediatr Transplantation 2010:14: 388–392.

Age at disease onset and peak ammonium level rather than interventional variables predict the neurological outcome in urea cycle disorders

BackgroundPatients with urea cycle disorders (UCDs) have an increased risk of neurological disease manifestation.AimsDetermining the effect of diagnostic and therapeutic interventions on the neurological outcome.MethodsEvaluation of baseline, regular follow-up and emergency visits of 456 UCD patients prospectively followed between 2011 and 2015 by the E-IMD patient registry.ResultsAbout two-thirds of UCD patients remained asymptomatic until age 12 days [i.e. the median age at diagnosis of patients identified by newborn screening (NBS)] suggesting a potential benefit of NBS. In fact, NBS lowered the age at diagnosis in patients with late onset of symptoms (>28 days), and a trend towards improved long-term neurological outcome was found for patients with argininosuccinate synthetase and lyase deficiency as well as argininemia identified by NBS. Three to 17 different drug combinations were used for maintenance therapy, but superiority of any single drug or specific drug combination above other combinations was not demonstrated. Importantly, non-interventional variables of disease severity, such as age at disease onset and peak ammonium level of the initial hyperammonemic crisis (cut-off level: 500 μmol/L) best predicted the neurological outcome.ConclusionsPromising results of NBS for late onset UCD patients are reported and should be re-evaluated in a larger and more advanced age group. However, non-interventional variables affect the neurological outcome of UCD patients. Available evidence-based guideline recommendations are currently heterogeneously implemented into practice, leading to a high variability of drug combinations that hamper our understanding of optimised long-term and emergency treatment.

Childhood hepatocellular carcinoma: a clinicopathological study of 12 cases with special reference to EpCAM

To elucidate the characteristics of hepatocellular carcinoma (HCC) in children.

Leukaemia presenting with fulminant hepatic failure in a child

In all children with fulminant hepatic failure, the differential diagnosis of leukaemia should be considered, particularly if there is hepatosplenomegaly, pancytopenia and a high lactate dehydrogenase. Early bone marrow aspiration should be performed to confirm diagnosis, as peripheral blood smears may often be normal. Hepatomegly is a common feature of leukaemia but acute liver failure as the first presentation is extremely uncommon [1, 2].We report a 4-year-old girl with a 2-week history of lethargy, vomiting and fluctuating sensorium for 2 days. There was no history of drug or toxin ingestion. She was icteric with liver 15 cm and spleen 9 cm below the costal margin respectively. Due to grade 3 encephalopathy, she was mechanically ventilated on the liver intensive care unit. Laboratory investigations revealed the following: haemoglobin 91 g/l (reference range 115–155 g/l), WBC 0.85·10/l (reference range 5.5–15.5·10/l), neutrophil count 0.5·10/l (reference range 3–5.8·10/l), platelet count 29·10/l (reference range 150–400·10/l) and no blasts were seen in the peripheral smear. Furthermore, INR 2.6 (reference range 0.8–1.2), D-dimer 1925 ng/ml, AST 714 IU/l (reference range 15–55 IU/l), total bilirubin 6 mg/dl (103 lmol/l; reference range 3.4–17 lmol/ l), LDH 4289 IU/l (reference range 150–500 IU/l), ammonia 102 lmol/l (reference range 34–47 lmol/l), lactate 9 mmol/l (reference range 0.9–1.7 mmol/l) and creatinine 94 lmol/l (reference range 27–62 lmol/l). Ultrasonography revealed a heterogeneous liver with multiple hypoechoic areas. Viral screen was negative. Bcell ALL, type L3 (Burkitt) was diagnosed from bone marrow examination done at 12 h. Early haemofiltration was started because of fulminant hepatic failure (FHF) and to prevent tumour lysis syndrome. Following pre-hydration and rasburicase, intravenous vincristine (1 mg/m) on days 1 and 8; and oral prednisolone (60 mg/m) daily (day 2 onward) was started. On day 4, after correction of her coagulopathy, a first dose of triple intrathecal chemotherapy (methotrexate 15 mg, cytosine arabinoside 30 mg and hydrocortisone 15 mg) was administered. The cytospin of the CSF was clear of leukaemic cells. By day 7 she was extubated, there was clinical and biochemical improvement with reduction in hepatosplenomegaly. Further chemotherapy was administered according to high-risk protocol for leukaemia and she remains in remission with normal liver function 1 year after starting treatment. Despite presentation as grade 3 hepatic encephalopathy, her survival could be attributed to early diagnosis, measures taken to prevent tumour lysis syndrome and modification of standard induction chemotherapy by the staggered use of vincristine and steroids with delayed introduction of other agents. The initial therapy and the choice of chemotherapeutic agents are complicated because most drugs are hepatotoxic or undergo hepatic metabolism and excretion. A balance has to be struck between effective treatment of the leukaemia and preservation of liver function. Kelleher et al. [3] recommended and justified the use of these agents at relatively higher dose than recommended in hepatic dysfunction to achieve early remission, with the possible advantage of clearing the tumour from the liver quickly and improving the hepatic function. Nevertheless, supportive treatment and specific prophylaxis against tumour lysis syndrome is essential in the presence of FHF. Following recovery of liver function, more intensive chemotherapy can be given.

Neonatal screening for hereditary tyrosinaemia: are we there yet?

McKiernan et al describe their experience with early use of nitisinone, previously known as NTBC (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione), in infants with hereditary tyrosinaemia type 1 (HT1), diagnosed on neonatal screening, or because of an affected sibling. They report the absence of clinical liver disease, no mortality and improved short-to-medium term neurodevelopment in comparison with other affected children, including their own siblings.1 HT1 is a rare liver-based and kidney-based metabolic disease (estimated UK prevalence 1/100 000), leading to acute liver failure in early infancy, hypophosphatemic rickets, neurological crises, liver cirrhosis and potentially to hepatocellular carcinoma. The mechanism of carcinogenesis is subject to intensive research, but likely related to retention of toxic compounds (maleyl-acetoacetate and fumarylacetoacetate) proximal to metabolic defect in fumarylacetoacetate hydratase enzyme, which catalyses the last step of tyrosine degradation.2 Due to the considerable risk of malignancy this condition represented an almost automatic indication for elective operation in the pioneering days of paediatric liver transplantation (LT). In the early 1990 s, nitisinone was proven to effectively block 4-hydroxyphenylpyruvate dioxygenase activity, thereby significantly inhibiting the production of the toxic metabolites and dramatically reducing requirements for LT.2 However, there are reports showing the development of chronic liver disease and hepatocellular carcinoma in children treated …

The times they are a-changin': Editorial

Fifty years in medicine is a long time; since the pioneering work of Thomas Starzl in 1963, dramatic progress has been made in transplantation surgery, has become established as a routine clinical procedure for many end-stage disorders. Fifty years in popular music is not such a long time; after releasing one of his iconic songs in the same year, Bob Dylan is still happily touring the world. Advances in metabolic medicine have been somewhere in between. Many metabolic conditions are now better understood, but real changes in their management have been exceptional. It is no wonder then that metabolic physicians have recently grown disappointed by the unsatisfactory medium-term neurological outcomes, quality of life, and social integration of their chronic patients and have started to explore alternative options, including liver replacement. The idea is that liver grafting can achieve metabolic stabilization, even though some of the biochemical pathways are not exclusive to the liver, and prevent further superimposed neurological insults. These appear to be almost inevitable, despite optimal medical and dietary management. Last year, several interdisciplinary meetings in both Europe and North America (Pittsburgh, Rome, and Birmingham) attracted metabolic specialists, transplant physicians, and surgeons, all hoping to exploit the success of liver transplantation (LT) by applying it more widely and more appropriately in this novel territory (G. Mazariegos, B. Shneider, B. Burton, I. Fox, N. Ha zić, P. Kishnani, et al. unpublished data, 2013). In this issue of Liver Transplantation, using the United Network for Organ Sharing (UNOS) database, Perito et al. present a compilation of the North American experience with LT for urea cycle disorders (UCDs) and organic acidemias. Their report demonstrates the increasing popularity of this indication for LT, which is illustrated by a marked increase in its overall share from 4.3% in 2002-2005 to 7.4% in 2010-2012. The authors report impressive survival figures, including graft survival rates of 89% and 83% at 1 and 5 years, respectively, which compare very favorably with graft survival figures for biliary atresia (88% and 83%, respectively) and other metabolic/cholestatic conditions (86% and 75%, respectively). Their review sends a clear message that LT represents a viable option for this select group of metabolic indications. Studies stemming from the UNOS database are often very valuable and instructive because of their size and inclusiveness; however, their perennial limitation remains their heterogeneity. This report by Perito et al. is not an exception: different centers, different timing for LT, different metabolic regimens, and different metabolic diagnoses. UCDs are hardly comparable with maple syrup urine disease or organic acidemias. Children with UCDs are prone to sudden episodes of hyperammonemia and encephalopathy, the severity and frequency of which differ even between proximal and distal cycle defects. On the other hand, those with organic acidemias tend to decompensate with acidosis, ketosis, and secondary hyperammonemia, again with considerable phenotypic variability. Future studies should aim for a direct comparison of the same conditions and include a more consistent approach to neurocognitive and extrahepatic assessment before and

Cardiac manifestations of inherited metabolic disease in children

Inborn errors of metabolism (IEM) are responsible for around 5% of all cases of cardiomyopathy (CM) and for 15% of non‐idiopathic cases. Storage disorders such as Pompe disease (glycogen storage disease type II) typically cause hypertrophic CM, whereas the accumulation of toxic metabolites, as seen in the organic acidurias, is associated with dilated cardiomyopathy (DCM). Mixed pathology is also possible, particularly in late presentations. IEM such as Barth syndrome, a disorder of cardiolipin stability usually associated with DCM, have been associated with rarer types of CM such as endocardial fibroelastosis and left ventricular non‐compaction. Conduction disturbances can also occur, particularly in disorders of glycogen metabolism associated with PRKAG2 mutations. Cardiac screening of patients with metabolic diseases is important to guide treatment and stratify risk. Supportive cardiac treatment may be required, and although associated myocardial disease may improve or even resolve with correction of the underlying metabolic disturbance, progression to cardiac transplantation has been described. In this article we document all IEM known to be associated with cardiac disease in children, focusing on common and clinically important diagnoses. We also discuss the pathophysiology of the various types of CM, and present a recommended approach to screening in the pediatric population.