UK guideline on the transition and management of childhood liver diseases in adulthood.

INTRODUCTION: Improved outcomes of liver disease in childhood and young adulthood have resulted in an increasing number of young adults (YA) entering adult liver services. The adult hepatologist therefore requires a working knowledge in diseases that arise almost exclusively in children and their complications in adulthood. AIMS: To provide adult hepatologists with succinct guidelines on aspects of transitional care in YA relevant to key disease aetiologies encountered in clinical practice. METHODS: A systematic literature search was undertaken using the Pubmed, Medline, Web of Knowledge and Cochrane database from 1980 to 2023. MeSH search terms relating to liver diseases ('cholestatic liver diseases', 'biliary atresia', 'metabolic', 'paediatric liver diseases', 'autoimmune liver diseases'), transition to adult care ('transition services', 'young adult services') and adolescent care were used. The quality of evidence and the grading of recommendations were appraised using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS: These guidelines deal with the transition of YA and address key aetiologies for the adult hepatologist under the following headings: (1) Models and provision of care; (2) screening and management of mental health disorders; (3) aetiologies; (4) timing and role of liver transplantation; and (5) sexual health and fertility. CONCLUSIONS: These are the first nationally developed guidelines on the transition and management of childhood liver diseases in adulthood. They provide a framework upon which to base clinical care, which we envisage will lead to improved outcomes for YA with chronic liver disease.

Liver transplantation in ornithine transcarbamylase deficiency: A retrospective multicentre cohort study.

Ornithine transcarbamylase deficiency (OTCD) is an X-linked defect of ureagenesis and the most common urea cycle disorder. Patients present with hyperammonemia causing neurological symptoms, which can lead to coma and death. Liver transplantation (LT) is the only curative therapy, but has several limitations including organ shortage, significant morbidity and requirement of lifelong immunosuppression. This study aims to identify the characteristics and outcomes of patients who underwent LT for OTCD. We conducted a retrospective study for OTCD patients from 5 UK centres receiving LT in 3 transplantation centres between 2010 and 2022. Patients' demographics, family history, initial presentation, age at LT, graft type and pre- and post-LT clinical, metabolic, and neurocognitive profile were collected from medical records. A total of 20 OTCD patients (11 males, 9 females) were enrolled in this study. 6/20 had neonatal and 14/20 late-onset presentation. 2/20 patients had positive family history for OTCD and one of them was diagnosed antenatally and received prospective treatment. All patients were managed with standard of care based on protein-restricted diet, ammonia scavengers and supplementation with arginine and/or citrulline before LT. 15/20 patients had neurodevelopmental problems before LT. The indication for LT was presence (or family history) of recurrent metabolic decompensations occurring despite standard medical therapy leading to neurodisability and quality of life impairment. Median age at LT was 10.5 months (6-24) and 66 months (35-156) in neonatal and late onset patients, respectively. 15/20 patients had deceased donor LT (DDLT) and 5/20 had living related donor LT (LDLT). Overall survival was 95% with one patient dying 6 h after LT. 13/20 had complications after LT and 2/20 patients required re-transplantation. All patients discontinued dietary restriction and ammonia scavengers after LT and remained metabolically stable. Patients who had neurodevelopmental problems before LT persisted to have difficulties after LT. 1/5 patients who was reported to have normal neurodevelopment before LT developed behavioural problems after LT, while the remaining 4 maintained their abilities without any reported issues. LT was found to be effective in correcting the metabolic defect, eliminates the risk of hyperammonemia and prolongs patients' survival.

Safety, efficacy, and timing of transplantation(s) in propionic and methylmalonic aciduria.

Propionic (PA) and methylmalonic aciduria (MMA) share many clinical similarities, which include the risk of acute metabolic encephalopathies, and some long-term complications, such as optic neuropathy, pancreatic involvement, developmental disability, and similar management approaches, but they also represent distinct clinical and biochemical entities. In the severe forms of PA and MMA, most long-term complications cannot be prevented with conventional clinical management. Organ transplantation represents a form of partial enzyme replacement to improve the long-term outlook for these disorders. There is evidence that early liver transplant in both disorders greatly improves metabolic stability and reduces the risk of long-term complications. For MMA, early liver transplant reduces methylmalonic acid levels which in turns reduces its effects on kidneys, and therefore slows progression of chronic kidney disease. However, established organ damage cannot be reversed. For patients with MMA who present with chronic kidney disease, consideration should be given for combined liver and kidney transplants. Transplantation in PA and MMA carries a high risk of complications and requires highly specialised pre-operative and peri-operative management. Involvement of a multidisciplinary team is essential and should include metabolic team, nephrologist, hepatologist, hepatobiliary and renal transplant surgeons, anaesthesiologists, cardiologists, intensive care team, dieticians and specialist nurses. These patients require life-long multidisciplinary follow-up. There is increasing evidence in the literature on excellent short to medium-term patient and allograft survival following transplantation when patients are managed by a multidisciplinary team in a specialist centre. Improved early diagnosis and reductions in transplant-related mortality and morbidity have allowed early transplantation to be used electively to further improve the outcome.

Neurocognitive outcome and mental health in children with tyrosinemia type 1 and phenylketonuria: A comparison between two genetic disorders affecting the same metabolic pathway.

Tyrosinemia type 1 (TT1) and phenylketonuria (PKU) are both inborn errors of phenylalanine-tyrosine metabolism. Neurocognitive and behavioral outcomes have always featured in PKU research but received less attention in TT1 research. This study aimed to investigate and compare neurocognitive, behavioral, and social outcomes of treated TT1 and PKU patients. We included 33 TT1 patients (mean age 11.24 years; 16 male), 31 PKU patients (mean age 10.84; 14 male), and 58 age- and gender-matched healthy controls (mean age 10.82 years; 29 male). IQ (Wechsler-subtests), executive functioning (the Behavioral Rating Inventory of Executive Functioning), mental health (the Achenbach-scales), and social functioning (the Social Skills Rating System) were assessed. Results of TT1 patients, PKU patients, and healthy controls were compared using Kruskal-Wallis tests with post-hoc Mann-Whitney U tests. TT1 patients showed a lower IQ and poorer executive functioning, mental health, and social functioning compared to healthy controls and PKU patients. PKU patients did not differ from healthy controls regarding these outcome measures. Relatively poor outcomes for TT1 patients were particularly evident for verbal IQ, BRIEF dimensions "working memory", "plan and organize" and "monitor", ASEBA dimensions "social problems" and "attention problems", and for the SSRS "assertiveness" scale (all p values <0.001). To conclude, TT1 patients showed cognitive impairments on all domains studied, and appeared to be significantly more affected than PKU patients. More attention should be paid to investigating and monitoring neurocognitive outcome in TT1 and research should focus on explaining the underlying pathophysiological mechanism.

Liver Disease and Risk of Hepatocellular Carcinoma in Children With Mutations in TALDO1.

Mutations in the transaldolase 1 (TALDO1) gene have been described in a limited number of cases. Several organs can be affected and clinical manifestations are variable, but often include liver dysfunction and/or hepatosplenomegaly. We report 4 patients presenting with liver disease: 2 with early-onset hepatocellular carcinoma (HCC). Patients with cholestasis and mutations in TALDO1 were identified by next-generation sequencing. Clinical, laboratory, and histological data were collected. Four (1 male) patients were identified with variants predicted to be damaging in TALDO1. Three patients were homozygous (two protein truncating/one missense mutations), 1 one was compound heterozygous (two missense mutations). Median age at presentation was 4 months (range, 2-210 days) with jaundice (3), hepatosplenomegaly (3), and pancytopaenia (1). The diagnosis was corroborated by detection of minimal transaldolase enzyme activity in skin fibroblasts in two cases and raised urine polyols in the third. Three patients underwent liver transplantation (LT), 2 of whom had confirmed HCC on explanted liver. One patient suddenly died shortly after LT. The nontransplanted case has a chronic liver disease with multiple dysplastic liver nodules, but normal liver biochemistry and alpha-fetoprotein. Median follow-up was 4 years (range, 1-21). Conclusion: Transaldolase deficiency can include early-onset normal gamma-glutamyltransferase liver disease with multisystem involvement and variable progression. Patients with this disease are at risk of early-onset HCC and may require early LT.

Long-term safety and outcomes in hereditary tyrosinaemia type 1 with nitisinone treatment: a 15-year non-interventional, multicentre study.

BACKGROUND: Since the EU approval of nitisinone in 2005, prognosis for patients with hereditary tyrosinaemia type 1 has changed dramatically, with patients living with the disease now reaching adulthood for the first time in history. This study aimed to assess the long-term safety and outcomes of nitisinone treatment in patients with hereditary tyrosinaemia type 1. METHODS: We did a non-interventional, non-comparative, multicentre study in 77 sites across 17 countries in Europe and collected retrospective and prospective longitudinal data in patients with hereditary tyrosinaemia type 1 who were treated with oral nitisinone during the study period (Feb 21, 2005, to Sept 30, 2019). There were no specific exclusion criteria. Patients were followed-up with an investigator at least annually for as long as they were treated, or until the end of the study. The primary endpoints, occurrence of adverse events related to hepatic, renal, ophthalmic, haematological, or cognitive or developmental function, were assessed in the complete set (all patients already receiving treatment at the index date [Feb 21, 2005] or starting treatment thereafter) and the index set (the subset of patients who had their first dose on the index date or later only). FINDINGS: 315 patients were enrolled during the study period (complete set). Additionally, data from 24 patients who had liver transplantation or died during the post-marketing surveillance programme were retrieved (extended analysis set; 339 patients). Median treatment duration was 11·2 years (range 0·7-28·4); cumulative nitisinone exposure was 3172·7 patient-years. Patients who were diagnosed by neonatal screening started nitisinone treatment at median age 0·8 months versus 8·5 months in those who presented clinically. Incidences of hepatic, renal, ophthalmic, haematological, or cognitive or developmental adverse events were low. Occurrence of liver transplantation or death was more frequent the later that treatment was initiated (none of 70 patients who started treatment at age <28 days vs 35 [13%] of 268 patients who started treatment at age ≥28 days). 279 (89%) of 315 patients were assessed as having either very good or good nitisinone treatment compliance. Treatment and diet compliance declined as patients aged. Suboptimal plasma phenylalanine and tyrosine levels were observed. The majority of patients were reported to have good overall clinical condition throughout treatment; 176 (87%) of 203 during the entire study, 98% following 1 year of treatment. INTERPRETATION: Long-term nitisinone treatment was well tolerated and no new safety signals were revealed. Life-limiting hepatic disease appears to have been prevented by early treatment start. Neonatal screening was the most effective way of ensuring early treatment. Standardised monitoring of blood tyrosine, phenylalanine, and nitisinone levels has potential to guide individualised therapy. FUNDING: Swedish Orphan Biovitrum (Sobi).

Study of Acute Liver Failure in Children Using Next Generation Sequencing Technology.

OBJECTIVE: To use next generation sequencing (NGS) technology to identify undiagnosed, monogenic diseases in a cohort of children who suffered from acute liver failure (ALF) without an identifiable etiology. STUDY DESIGN: We identified 148 under 10 years of age admitted to King's College Hospital, London, with ALF of indeterminate etiology between 2000 and 2018. A custom NGS panel of 64 candidate genes known to cause ALF and/or metabolic liver disease was constructed. Targeted sequencing was carried out on 41 children in whom DNA samples were available. Trio exome sequencing was performed on 4 children admitted during 2019. A comparison of the clinical characteristics of those identified with biallelic variants against those without biallelic variants was then made. RESULTS: Homozygous and compound heterozygous variants were identified in 8 out of 41 children (20%) and 4 out of 4 children (100%) in whom targeted and exome sequencing were carried out, respectively. The genes involved were NBAS (3 children); DLD (2 children); and CPT1A, FAH, LARS1, MPV17, NPC1, POLG, SUCLG1, and TWINK (1 each). The 12 children who were identified with biallelic variants were younger at presentation and more likely to die in comparison with those who did not: median age at presentation of 3 months and 30 months and survival rate 75% and 97%, respectively. CONCLUSIONS: NGS was successful in identifying several specific etiologies of ALF. Variants in NBAS and mitochondrial DNA maintenance genes were the most common findings. In the future, a rapid sequencing NGS workflow could help in reaching a timely diagnosis and facilitate clinical decision making in children with ALF.

New insights into carnitine-acylcarnitine translocase deficiency from 23 cases: Management challenges and potential therapeutic approaches.

Carnitine acyl-carnitine translocase deficiency (CACTD) is a rare autosomal recessive disorder of mitochondrial long-chain fatty-acid transport. Most patients present in the first 2 days of life, with hypoketotic hypoglycaemia, hyperammonaemia, cardiomyopathy or arrhythmia, hepatomegaly and elevated liver enzymes. Multi-centre international retrospective chart review of clinical presentation, biochemistry, treatment modalities including diet, subsequent complications, and mode of death of all patients. Twenty-three patients from nine tertiary metabolic units were identified. Seven attenuated patients of Pakistani heritage, six of these homozygous c.82G>T, had later onset manifestations and long-term survival without chronic hyperammonemia. Of the 16 classical cases, 15 had cardiac involvement at presentation comprising cardiac arrhythmias (9/15), cardiac arrest (7/15), and cardiac hypertrophy (9/15). Where recorded, ammonia levels were elevated in all but one severe case (13/14 measured) and 14/16 had hypoglycaemia. Nine classical patients survived longer-term-most with feeding difficulties and cognitive delay. Hyperammonaemia appears refractory to ammonia scavenger treatment and carglumic acid, but responds well to high glucose delivery during acute metabolic crises. High-energy intake seems necessary to prevent decompensation. Anaplerosis utilising therapeutic d,l-3-hydroxybutyrate, Triheptanoin and increased protein intake, appeared to improve chronic hyperammonemia and metabolic stability where trialled in individual cases. CACTD is a rare disorder of fatty acid oxidation with a preponderance to severe cardiac dysfunction. Long-term survival is possible in classical early-onset cases with long-chain fat restriction, judicious use of glucose infusions, and medium chain triglyceride supplementation. Adjunctive therapies supporting anaplerosis may improve longer-term outcomes.

Liver histology in children with glycogen storage disorders type VI and IX.

BACKGROUND: Glycogen storage diseases (GSD) type VI and IX are caused by liver phosphorylase system deficiencies and the two types are clinically indistinguishable. AIM: As the role of liver biopsy is increasingly questioned, we aim to assess its current value in clinical practice. METHODS: We retrospectively reviewed children with diagnosis of GSD VI and IX at a paediatric liver centre between 2001 and 2018. Clinical features, molecular analysis and imaging were reviewed. Liver histology was reassessed by a single histopatologist. RESULTS: Twenty-two cases were identified (9 type VI, 9 IXa, 1 IXb and 3 IXc). Features at presentation were hepatomegaly (95%), deranged AST (81%), short stature (50%) and failure to thrive (4%). Liver biopsy was performed in 19 patients. Fibrosis varied in GSD IXa with METAVIR score between F1-F3 and ISHAK score of F2-F5. METAVIR score was F2-F3 in GSD VI and F3-F4 in GSD IXc. Hepatocyte glycogenation, mild steatosis, lobular inflammatory activity and periportal copper binding protein staining were also demonstrated. CONCLUSIONS: Although GSD VI and IX are considered clinically mild, chronic histological changes of varying severity could be seen in all liver biopsies. Histopathological assessment of the liver involvement is superior to biochemical parameters, but definitive classification requires a mutational analysis.

Fatal metabolic stroke in a child with propionic acidemia 11 years post liver transplant.

Propionic acidemia is a rare autosomal recessive inborn error of metabolism caused by a deficiency of propionyl CoA carboxylase which often manifests with frequent metabolic decompensations and risk of neurological injury. Outcomes with medical therapy remain suboptimal. Liver transplantation has been shown to be a therapeutic option for patients and results in a milder phenotype of the disease and partial correction of the enzyme defect. Liver transplantation has been increasingly reported over the last decade and experience in managing these patients is improving. Long-term outcomes are generally good; however, the risk of complications still exists despite transplantation. We report a child who presented with a fatal metabolic stroke 11 years post liver transplant without any biochemical evidence of decompensation. We highlight the need to closely monitor these patients lifelong despite liver transplantation and maintain multidisciplinary working between hepatology and metabolic clinicians.

Dietary Management, Clinical Status and Outcome of Patients with Citrin Deficiency in the UK.

BACKGROUND: Little is known about the optimal dietary treatment for citrin deficiency. Our aim is to describe the management of UK citrin deficiency patients. METHODS: A longitudinal retrospective review was performed. Data were collected from medical records on presenting signs and symptoms, dietary management and clinical outcome. RESULTS: data were collected on 32 patients from 21 families. 50% were females (16/32). Median age at diagnosis was 4 y (5 days-35 y) with 12 patients diagnosed in the neonatal period with neonatal intrahepatic cholestasis (NICCD), eight later in childhood (FTTDCD) and 12 by family screening based on index cases from five families. No patient had adult-onset type II citrullinemia. The patient age at the time of data collection was a median of 11 y (1-44 y). 91% (29/32) of patients had normal physical and neurological development, 47% (15/32) experienced recurrent unexplained abdominal pain and 9% (3/32) episodes of hypoglycaemia. Siblings had different phenotypes (5 families had > 1 affected patient). Most patients preferred high protein foods, limiting sugar-containing foods. Only 41% (13/32) were prescribed a low CHO, high protein, high fat diet (restriction varied) and two used medium chain triglyceride (MCT) supplements. No patient was prescribed drug therapy. Twenty-five per cent (8/32) of patients were underweight and 41% (13/32) had height <-1 z-scores. CONCLUSIONS: patients presented with various phenotypes, symptoms and suboptimal growth. Symptoms and biochemical markers improved with age, but height remained low in some. More research is necessary to assess the effectiveness of dietary approaches in improving clinical outcomes and symptoms in citrin deficiency.

Clinical utilization of dried blood spot nitisinone (NTBC) and succinylacetone (SA) concentrations in hereditary tyrosinaemia type 1 - A UK centre experience.

BACKGROUND: Dried blood spot monitoring of nitisinone and succinylacetone in hereditary tyrosinaemia type 1 patients is not widely available in the United Kingdom. Currently, biochemical monitoring utilizes urinary succinylacetone, blood spot tyrosine and phenylalanine monitoring, which can lack in convenience and accuracy, respectively. METHODS: We report the development of a dried blood spot assay for nitisinone and succinylacetone and analysed retrospective clinical and biochemical data for hereditary tyrosinaemia type 1 patients from a single UK centre. RESULTS: A total of 13 hereditary tyrosinaemia type 1 patients were evaluated. Eleven presented with liver dysfunction (two with associated renal tubulopathy) and two were detected by early sibling screening. All patients (age 0.03-22 months) were commenced on a tyrosine-/phenylalanine-restricted diet and nitisinone at diagnosis. Ten patients were on twice daily dosing and three were on single daily dosing at the start of monitoring. One patient from each dosing group swapped between dosing regimens at 20 years of age and 8 months of age, respectively. A total of 684 dried blood spot samples were analysed; 80% of nitisinone concentrations were between 9.2 and 27 µmol/L when succinylacetone was <0.3 µmol/L. Patients on twice daily dosing regimens had significantly higher nitisinone concentration compared with those on once daily dosing (P < 0.0001). The median dose required in the twice daily doing group was significantly lower when compared with once daily dosing. CONCLUSIONS: Dried blood spot monitoring for nitisinone and succinylacetone concentrations in hereditary tyrosinaemia type 1 patients is a rapid and convenient method which allows physicians to individualize treatment plans and observe adherence to treatment.

Post-transplantation Outcomes in Patients with PA or MMA: A Review of the Literature.

INTRODUCTION: Liver transplantation is recognised as a treatment option for patients with propionic acidemia (PA) and those with methylmalonic acidemia (MMA) without renal impairment. In patients with MMA and moderate-to-severe renal impairment, combined liver-kidney transplantation is indicated. However, clinical experience of these transplantation options in patients with PA and MMA remains limited and fragmented. We undertook an overview of post-transplantation outcomes in patients with PA and MMA using the current available evidence. METHODS: A literature search identified publications on the use of transplantation in patients with PA and MMA. Publications were considered if they presented adequate demographic and outcome data from patients with PA or MMA. Publications that did not report any specific outcomes for patients or provided insufficient data were excluded. RESULTS: Seventy publications were identified of which 38 were full papers. A total of 373 patients underwent liver/kidney/combined liver-kidney transplantation for PA or MMA. The most typical reason for transplantation was recurrent metabolic decompensation. A total of 27 post-transplant deaths were reported in patients with PA [14.0% (27/194)]. For patients with MMA, 18 post-transplant deaths were reported [11% (18/167)]. A total of 62 complications were reported in 115 patients with PA (54%) with cardiomyopathy (n = 12), hepatic arterial thrombosis (HAT; n = 14) and viral infections (n = 12) being the most commonly reported. A total of 52 complications were reported in 106 patients with MMA (49%) with viral infections (n = 14) and renal failure/impairment (n = 10) being the most commonly reported. CONCLUSIONS: Liver transplantation and combined liver-kidney transplantation appears to benefit some patients with PA or MMA, respectively, but this approach does not provide complete correction of the metabolic defect and some patients remain at risk from disease-related and transplantation-related complications, including death. Thus, all treatment avenues should be exhausted before consideration of organ transplantation and the benefits of this approach must be weighed against the risk of perioperative complications on an individual basis.

RBCK1-related disease: A rare multisystem disorder with polyglucosan storage, auto-inflammation, recurrent infections, skeletal, and cardiac myopathy-Four additional patients and a review of the current literature.

In this article, we report four new patients, from three kindreds, with pathogenic variants in RBCK1 and a multisystem disorder characterised by widespread polyglucosan storage. We describe the clinical presentation of progressive skeletal and cardiac myopathy, combined immunodeficiencies and auto-inflammation, illustrate in detail the histopathological findings in multiple tissue types, and report muscle MRI findings.

Liver Transplantation in Children With Propionic Acidemia: Medium-Term Outcomes.

Liver transplantation (LT) for patients with propionic acidemia (PA) is an emerging therapeutic option. We present a retrospective review of patients with PA who underwent LT at a tertiary liver center between 1995 and 2015. A total of 14 children were identified (8 males) with median age at initial presentation of 3 days (range, 0-77 days). Pretransplant median protein restriction was 1 g/kg/day (range, 0.63-1.75 g/kg/day), 71% required supportive feeding, and 86% had developmental delay. Frequent metabolic decompensations (MDs) were the main indication for LT with a median age at transplantation of 2.4 years (range, 0.8-7.1 years). Only 1 graft was from a living donor, and 13 were from deceased donors (4 auxiliary). The 2-year patient survival was 86%, and overall study and graft survival was 79% and 69%, respectively. Three patients died after LT: at 43 days (biliary peritonitis), 225 days (acute-on-chronic rejection with multiorgan failure), and 13.5 years (posttransplant lymphoproliferative disease). Plasma glycine and propionylcarnitine remained elevated but reduced after transplant. Of 11 survivors, 5 had at least 1 episode of acute cellular rejection, 2 sustained a metabolic stroke (with full recovery), and 3 developed mild cardiomyopathy after LT. All have liberalized protein intake, and 9 had no further MDs: median episodes before transplant, 4 (range, 1-30); and median episodes after transplant, 0 (range, 0-5). All survivors made some developmental progress after LT, and none worsened at a median follow-up of 5.8 years (range, 2-23 years). LT in PA significantly reduces the frequency of MDs, can liberalize protein intake and improve quality of life, and should continue to be considered in selected cases.

Emotional and behavioral problems, quality of life and metabolic control in NTBC-treated Tyrosinemia type 1 patients.

BACKGROUND: Treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) and dietary phenylalanine and tyrosine restriction improves physical health and life expectancy in Tyrosinemia type 1 (TT1). However, neurocognitive outcome is suboptimal. This study aimed to investigate behavior problems and health-related quality of life (HR-QoL) in NTBC-dietary-treated TT1 and to relate this to phenylalanine and tyrosine concentrations. RESULTS: Thirty-one TT1 patients (19 males; mean age 13.9 ± 5.3 years) were included in this study. Emotional and behavioral problems, as measured by the Achenbach System of Empirically Based Assessment, were present in almost all domains. Attention and thought problems were particularly evident. HR-QoL was assessed by the TNO AZL Children's and Adults QoL questionnaires. Poorer HR-QoL as compared to reference populations was observed for the domains: independent daily functioning, cognitive functioning and school performance, social contacts, motor functioning, and vitality. Both internalizing and externalizing behavior problems were associated with low phenylalanine (and associated lower tyrosine) concentrations during the first year of life. In contrast, high tyrosine (and associated higher phenylalanine) concentrations during life and specifically the last year before testing were associated with more internalizing behavior and/or HR-QoL problems. CONCLUSIONS: TT1 patients showed several behavior problems and a lower HR-QoL. Associations with metabolic control differed for different age periods. This suggests the need for continuous fine-tuning and monitoring of dietary treatment to keep phenylalanine and tyrosine concentrations within target ranges in NTBC-treated TT1 patients.

Ocorrência concomitante de deficiência de cobalamina C e Síndrome de Beckwith-Wiedemann: um relato de caso / Concomitant occurrence of deficiency of cobalamin C and Beckwith-Wiedemann syndrome: a case report

Objetivo: descrever caso raro de concomitância de síndrome de Beckwith-Wiedemann e deficiência de cobalamina C. Relato: menina, 4 anos, 19,5kg, 1,17m. Nasceu de cesariana, com 39+5 semanas e 3660g. Diagnosticada onfalocele intra-útero, corrigida no período neonatal. Realizada detecção genética neonatal de síndrome de Beckwith-Wiedemann. Com 2 meses, apresentou crises de ausência, eletroencefalograma anormal e ressonância evidenciando coleções subdurais crônicas e diminuição de substância branca. Apresentou hiper-homocisteinemia e aumento de ácido metilmalônico, confirmando deficiência de cobalamina C. Com 6 meses, crises convulsivas mudaram de padrão, apresentou acidose metabólica e hemorragias retinianas. Com 2 anos, diagnosticado autismo. Apresenta tônus central diminuído, tônus periférico normal, déficit neuropsicomotor, deficiência visual, nistagmo, microcefalia leve, macroglossia e crescimento excessivo. Em uso de hidroxicobalamina, betaína e ácido fólico. Conclusão: relatamos a concomitância de condições raras, sendo as complicações mais graves os déficits visuais e neuropsicomotores pela deficiência de cobalamina C

Objective: To describe a case of a patient presenting concomitantly with Beckwith-Wiedemann syndrome and cobalamin C deficiency. Report: Girl, 4 years old, 19.5kg, 1.17m. Born from cesarean section, with 39+5 weeks of gestation and weighing 3,660g. Diagnosed intra-uterus with omphalocele, which was repaired in the neonatal period. Neonatal Beckwith-Wiedemann syndrome detection was performed by genetic testing. With 2 months of age, she presented absence seizures, with abnormal electroencephalogram and MRI, evidencing chronic subdural collections and white matter decrease. She presented hyperhomocysteinemia and increased methylmalonic acid, with a subsequent diagnosis of cobalamin C deficiency. At 6 months of age, her seizures changed pattern, she presented metabolic acidosis and superficial retinal haemorrhages. At 2 years of age, she was diagnosed with autism. She presents reduced central tone, normal peripheral tonus, preserved reflexes, neuropsychomotor deficit, visual deficiency, nystagmus, mild microcephaly, macroglossia and excessive growth. In use of hydroxocobalamin, betaine and folic acid. Conclusion: in the case presented, rare conditions occurred concomitantly, with the most severe complications including visual and neuropsychomotor deficits, due to cobalamin C deficiency

Transatlantic combined and comparative data analysis of 1095 patients with urea cycle disorders-A successful strategy for clinical research of rare diseases.

BACKGROUND: To improve our understanding of urea cycle disorders (UCDs) prospectively followed by two North American (NA) and European (EU) patient cohorts. AIMS: Description of the NA and EU patient samples and investigation of the prospects of combined and comparative analyses for individuals with UCDs. METHODS: Retrieval and comparison of the data from 1095 individuals (NA: 620, EU: 475) from two electronic databases. RESULTS: The proportion of females with ornithine transcarbamylase deficiency (fOTC-D), particularly those being asymptomatic (asfOTC-D), was higher in the NA than in the EU sample. Exclusion of asfOTC-D resulted in similar distributions in both samples. The mean age at first symptoms was higher in NA than in EU patients with late onset (LO), but similar for those with early (≤ 28 days) onset (EO) of symptoms. Also, the mean age at diagnosis and diagnostic delay for EO and LO patients were similar in the NA and EU cohorts. In most patients (including fOTC-D), diagnosis was made after the onset of symptoms (59.9%) or by high-risk family screening (24.7%), and less often by newborn screening (8.9%) and prenatal testing (3.7%). Analysis of clinical phenotypes revealed that EO patients presented with more symptoms than LO individuals, but that numbers of symptoms correlated with plasma ammonium concentrations in EO patients only. Liver transplantation was reported for 90 NA and 25 EU patients. CONCLUSIONS: Combined analysis of databases drawn from distinct populations opens the possibility to increase sample sizes for natural history questions, while comparative analysis utilizing differences in approach to treatment can evaluate therapeutic options and enhance long-term outcome studies.

Liver transplantation for neonatal-onset citrullinemia.

Citrullinemia or ASS deficiency in its classical form presents in the neonatal period with poor feeding, hyperammonemia, encephalopathy, seizures, and if untreated can be fatal. Despite advances in medical therapy, neurocognitive outcomes remain suboptimal. LT has emerged as a potential management option. A retrospective single-center review identified 7 children with a median age of 1.1 years (range, 0.6-5.8) at referral. Five children presented clinically, and 2 were treated prospectively from birth due to positive family history. All patients received standard medical and dietary therapy prior to LT. The indications for LT were frequent metabolic decompensations in 4, elective in 2, and ALF in 1. The median age at LT was 2.4 years (range, 1.3-6.5). Five patients received 6 left lateral segment grafts, one a live unrelated donor left lateral segment as an APOLT graft, and one a cadaveric whole liver graft as APOLT. One child required retransplantation due to hepatic artery thrombosis. Graft and patient survival were 86% and 100%, respectively. Median follow-up is 3.1 years (range, 0.1-4.1), and the median age at follow-up is 5.5 years (range, 4.0-9.8). There have been no metabolic decompensations in 6 children, while 1 patient (with APOLT) developed asymptomatic hyperammonemia with no clinical or histological signs of liver injury, requiring additional medical therapy. Our medium-term experience following LT in citrullinemia is favorable, demonstrating a positive transformation of the clinical phenotype.