Cystathionine beta-synthase (CBS) deficiency is a rare inherited disorder in the methionine catabolic pathway, in which the impaired synthesis of cystathionine leads to accumulation of homocysteine. ...Patients can present to many different specialists and diagnosis is often delayed. Severely affected patients usually present in childhood with ectopia lentis, learning difficulties and skeletal abnormalities. These patients generally require treatment with a low-methionine diet and/or betaine. In contrast, mildly affected patients are likely to present as adults with thromboembolism and to respond to treatment with pyridoxine. In this article, we present recommendations for the diagnosis and management of CBS deficiency, based on a systematic review of the literature. Unfortunately, the quality of the evidence is poor, as it often is for rare diseases. We strongly recommend measuring the plasma total homocysteine concentrations in any patient whose clinical features suggest the diagnosis. Our recommendations may help to standardise testing for pyridoxine responsiveness. Current evidence suggests that patients are unlikely to develop complications if the plasma total homocysteine concentration is maintained below 120 μmol/L. Nevertheless, we recommend keeping the concentration below 100 μmol/L because levels fluctuate and the complications associated with high levels are so serious.
The presence of typical clinical signs may lead to a suspicion of CβS deficiency, but definitive diagnosis depends on a severely raised total homocysteine (tHcy; >100-400μmol/L) with low methionine ...and cystine levels. 3 Intellectual abilities as reported on sibling 1 as having developmental delay is at odds with a further statement which makes the assumption of probable "B 6 responsive type0" in the siblings based on the "mild systemic involvement and normal intelligence."
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Medium chain acyl-CoA dehydrogenase deficiency (MCADD) is a rare metabolic disorder, and commonly now part of newborn screening programs. Those diagnosed at birth are now progressing from childhood ...to adulthood. The study aim was to explore young people’s experiences of living with MCADD and managing their condition. A descriptive qualitative study design involving semi-structured interviews with 12 participants aged 10 to 15 years, recruited from one regional pediatric metabolic disorder service in England. Data were analyzed using thematic analysis. The two major themes were “Eating for energy” and “Growing into a self-management role.” Self-monitoring and self-management skills had been nurtured from early childhood by parents and healthcare providers. Young people’s anxieties concerned having to maintain adequate energy input to stay safe and the associated burden of responsibility. Growing up with MCADD presents specific challenges. Self-management and ongoing support are important for dealing with those challenges.
Background and Objective
Methylmalonic aciduria (MMA) and propionic aciduria (PA) are organic acidurias characterised by the accumulation of toxic metabolites and hyperammonaemia related to secondary ...N-acetylglutamate deficiency. Carglumic acid, a synthetic analogue of N-acetylglutamate, decreases ammonia levels by restoring the functioning of the urea cycle. However, there are limited data available on the long-term safety and effectiveness of carglumic acid. Here, we present an interim analysis of the ongoing, long-term, prospective, observational PROTECT study (NCT04176523), which is investigating the long-term use of carglumic acid in children and adults with MMA and PA.
Methods
Individuals with MMA or PA from France, Germany, Italy, Norway, Spain, Sweden and the UK who have received at least 1 year of carglumic acid treatment as part of their usual care are eligible for inclusion. The primary objective is the number and duration of acute metabolic decompensation events with hyperammonaemia (ammonia level >159 µmol/L during a patient’s first month of life or >60 µmol/L thereafter, with an increased lactate level > 1.8 mmol/L and/or acidosis pH < 7.35) before and after treatment with carglumic acid. Peak plasma ammonia levels during the last decompensation event before and the first decompensation event after carglumic acid initiation, and the annualised rate of decompensation events before and after treatment initiation are also being assessed. Secondary objectives include the duration of hospital stay associated with decompensation events. Data are being collected at approximately 12 months’ and 18 months’ follow-up.
Results
Of the patients currently enrolled in the PROTECT study, data from ten available patients with MMA (
n
= 4) and PA (
n
= 6) were analysed. The patients had received carglumic acid for 14–77 (mean 36) months. Carglumic acid reduced the median peak ammonia level of the total patient population from 250 µmol/L (range 97–2569) before treatment to 103 µmol/L (range 97–171) after treatment. The annualised rate of acute metabolic decompensations with hyperammonaemia was reduced by a median of – 41% (range − 100% to + 60%) after treatment with carglumic acid. Of the five patients who experienced a decompensation event before treatment and for whom a post-treatment rate could be calculated, the annualised decompensation event rate was lower after carglumic acid treatment in four patients. The mean duration of hospital inpatient stay during decompensation events was shorter after than before carglumic acid treatment initiation in four of five patients for whom length of stay could be calculated.
Conclusions
In this group of patients with MMA and PA, treatment with carglumic acid for at least 1 year reduced peak plasma ammonia levels in the total patient population and reduced the frequency of metabolic decompensation events, as well as the duration of inpatient stay due to metabolic decompensations in a subset of patients.
Clinical Trial Registration
ClinicalTrials.gov, NCT04176523. Registered 25 November, 2019, retrospectively registered,
https://clinicaltrials.gov/ct2/show/NCT04176523
.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Newborn screening has enabled the early diagnosis of Glutaric aciduria type 1, with the possibility of improving neurological outcomes in affected children. Achieving those outcomes requires parents ...to effectively manage their child's condition by adherence to a strict dietary regime and responding to situations that may trigger decompensation. The specific information and support needs of this group of parents are unknown.
A focus group with five parents was conducted to gain insights into the information that parents needed and the ways in which they accessed and used information to manage their child's condition. A topic guide was used to direct the discussion which was recorded and fully transcribed. All participants gave informed consent. Data were analysed using thematic analysis, a structured approach that contributes to transparency and validity of results while allowing the integration of predetermined and emerging themes. To ensure rigour, two researchers were involved in initial coding of data and key analytic decisions.
Two main themes were identified. 'Understanding the condition' explored parent's needs to understand the scientific complexity of the condition and to be aware of the worst case scenario associated with loss of metabolic control. 'Managing the condition' explained how parents co-ordinated and controlled the involvement of other carers and parents' need to be active partners in medical management to feel in control of the situation.
The study highlights the importance of addressing parents' initial and ongoing informational needs so they can fulfil their role and protect their child from metabolic harm.
Newborn screening enabling early diagnosis of medium chain acyl-CoA dehydrogenase deficiency (MCADD) has dramatically improved health outcomes in children with MCADD. Achieving those outcomes depends ...on effective management by parents. Understanding parental management strategies and associated anxieties and concerns is needed to inform provision of appropriate care and support. Semistructured interviews were conducted with a purposive sample of parents of children aged 2 to 12 years. Thematic analysis identified two main themes. Managing dietary intake examined how parents managed day-to-day dietary intake to ensure adequate intake and protection of safe fasting intervals. Managing and preventing illness events explored parental experiences of managing illness events and their approach to preventing these events. Management strategies were characterized by caution and vigilance and influenced by a lack of confidence in others to manage the condition. The study identifies the need for increased awareness of the condition, particularly in relation to emergency treatment.
N‐carbamoyl‐l‐glutamate (NCG), the N‐acetyl‐l‐glutamate analogue used to treat N‐acetylglutamate synthase deficiency, has been proposed as potential therapy of carbamoyl phosphate synthetase 1 ...deficiency (CPS1D). Previous findings in five CPS1D patients suggest that NCG‐responsiveness could be mutation‐specific. We report on a patient with CPS1D, homozygous for the novel p.(Pro1211Arg) CPS1 mutation, who presented at 9 days of life with hyperammonemic coma which was successfully treated with emergency measures. He remained metabolically stable on merely oral NCG, arginine, and modest protein restriction. Ammonia scavengers were only added after poor dietary compliance following solid food intake at age 1 year. The patient received a liver transplantation at 3.9 years of age, having normal cognitive, motor, and quality of life scores despite repeated but successfully treated episodes of hyperammonemia. Studies using recombinantly produced mutant CPS1 confirmed the partial nature of the CPS1D triggered by the p.(Pro1211Arg) mutation. This mutation decreased the solubility and yield of CPS1 as expected for increased tendency to misfold, and reduced the thermal stability, maximum specific activity (Vmax; ~2‐fold reduction), and apparent affinity (~5‐fold reduction) for ATP of the purified enzyme. By increasing the saturation of the NAG site in vivo, NCG could stabilize CPS1 and minimize the decrease in the effective affinity of the enzyme for ATP. These observations, together with prior experience, support the ascertainment of clinical responsiveness to NCG in CPS1 deficient patients, particularly when decreased stability or lowered affinity for NAG of the mutant enzyme are suspected or proven.
The presentation of cerebral venous sinus thrombosis may be acute or chronic with a progressive clinical course. The diagnosis can be challenging, and there are several clinical syndromes associated ...with the disease. It is also an uncommon but recognised complication of homocystinuria. We describe a case where early anticoagulation, together with dietary intervention, was associated with a favourable clinical outcome.
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.
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