Branched-chain Organic Acidurias Research Articles

Clinical utility of low branched-chain amino acid modular diets in patients with isovaleric aciduria and maple syrup urine disease

Introduction: Modular diets (MDs) with low amount of offending amino acids have been developed using locally available food ingredients as alternatives to commercial formulas for the treatment of branched-chain organic acidurias (BCOAs). Herein, we conducted a clinical investigation of MDs in patients with BCOAs. Methods: Modular diet A (MDA), with low leucine was produced for maple syrup urine disease (MSUD), and modular diet B (MDB) products, MDB-1, -2, -3, and -4, with low leucine, valine, methionine and threonine were made for isovaleric aciduria (IVA)/methylmalonic aciduria (MMA)/propionic aciduria (PA). Children aged 4-18 years, with MSUD, IVA, PA or MMA were invited to participate in the study. The research subjects switched from metabolic formula protocol to modular diet protocol. They were followed-up at 0, 1, 2, 4, and 6 months. Clinical efficacies of MDs were determined by completion of study, compliance to MDs, clinical outcomes and complications, and parental satisfaction. Results: Six children (2 MSUD and 4 IVA) participated and completed the study. Compliance to MDA was 100% in MSUD subjects with G-tube feeding, while compliance to MDB varied among self-fed individuals with IVA. One subject with MSUD was clinically stable throughout the study, while the other experienced metabolic instability. All IVA individuals showed clinical and laboratory stability during the study. One MSUD and three IVA families preferred the metabolic formula, whereas the other IVA family reported no preference and the other MSUD subject preferred MDs. Conclusion: We provided a proof of concept in developing modular diets for BCOAs, and showed favourable outcomes when using MDs in IVA and varying clinical benefits in MSUD.

Development of Modular Diet for Children with Branched‐chain Organic Acidurias Using Locally Available Raw Materials

Branched‐chain organic acidurias resulted from abnormal specific enzymes involving catabolism of branched‐chain amino acids (BCAAs). The common organic acidurias are maple syrup urine disease (MSUD), isovaleric acidemia (IVA), propionic acidemia (PA), and methylmalonic acidemia (MMA). Long‐term management includes certain amino acid restriction and metabolic formulas to provide adequate energy and protein. Due to high cost and shortage of metabolic formula, we aimed to formulate modular diets (MDs) as an alternative treatment product for children with BCAAs disorders aged 4–15 years. Raw materials locally available in Thailand were analyzed and selected. Fish maw and roasted sunflower kernel were used as protein sources due to their proper leucine contents. Carbohydrate source includes maltodextrin and sucrose. Soy bean oil and/or non‐dairy creamer were fat sources. The diets were developed for 2 applications including (i) MD‐A, low in leucine for MSUD, was prepared in powder form, and (ii) MD‐B, low in leucine for IVA, and low in valine for PA and MMA, was prepared in powder form, seasoning powder, instant powder drink, and chocolate flavored snack. The diets were analyzed for macronutrient composition and amino acid profile. Per 100 g, the MD‐A diet provided 512 kcal with 9.9 g protein (P), 59.1 g carbohydrate (CHO), and 26.2 g fat (F). Energy, protein, carbohydrate, and fat contents per 100 g of MD‐B ranged 546–601 kcal, 8.2–12.3 g, 36.7–51 g, and 33.6–51 g, respectively. Energy and macronutrient contents were comparable to the commercial formula. Costs of raw materials in the MDs were US$ 0.42–0.51 per 100 g.Locally available raw materials could be used for developing MDs for children with BCAAs disorders at low cost. The products are useful for low‐income patients in developing countries. The efficacy of these MDs used as an alternative treatment in children with branched‐chain organic acidurias should be further evaluated.Support or Funding InformationThis research work is partially supported by RA scholarship from the Faculty of Graduate Studies, Mahidol University Academic Year 2012

Molecular and phenotypic characteristics of seven novel mutations causing branched-chain organic acidurias.

Specific mitochondrial enzymatic deficiencies in the catabolism of branched-chain amino acids cause methylmalonic aciduria (MMA), propionic acidemia (PA) and maple syrup urine disease (MSUD). Disease-causing mutations were identified in nine unrelated branched-chain organic acidurias (BCOA) patients. We detected eight previously described mutations: p.Asn219Tyr, p.Arg369His p.Val553Glyfs*17 in MUT, p.Thr198Serfs*6 in MMAA, p.Ile144_Leu181del in PCCB, p.Gly288Valfs*11, p.Tyr438Asn in BCKDHA and p.Ala137Val in BCKDHB gene. Interestingly, we identified seven novel genetic variants: p.Leu549Pro, p.Glu564*, p.Leu641Pro in MUT, p.Tyr206Cys in PCCB, p.His194Arg, p.Val298Met in BCKDHA and p.Glu286_Met290del in BCKDHB gene. In silico and/or eukaryotic expression studies confirmed pathogenic effect of all novel genetic variants. Aberrant enzymes p.Leu549Pro MUT, p.Leu641Pro MUT and p.Tyr206Cys PCCB did not show residual activity in activity assays. In addition, activity of MUT enzymes was not rescued in the presence of vitamin B12 precursor in vitro which was in accordance with non-responsiveness or partial responsiveness of patients to vitamin B12 therapy. Our study brings the first molecular genetic data and detailed phenotypic characteristics for MMA, PA and MSUD patients for Serbia and the whole South-Eastern European region. Therefore, our study contributes to the better understanding of molecular landscape of BCOA in Europe and to general knowledge on genotype-phenotype correlation for these rare diseases.

Chronic pancreatitis in branched-chain organic acidurias—a case of methylmalonic aciduria and an overview of the literature

A severe rare complication in patients with branched-chain organic acidurias (BCOA) is pancreatitis with a limited number of patients published so far. Here, we report on a patient with methylmalonic aciduria (MMA) who developed chronic pancreatitis after several episodes of acute pancreatitis. In addition, an overview is given about some previous published cases with BCOA who developed pancreatitis in the course of the disease. In half of the published MMA patients with pancreatitis, an acute pancreatitis was reported while the rest suffered from a chronic form of this disease. Acute pancreatitis in BCOA patients can clinically present in the context of recurrent vomiting and an impaired general physical condition even without typical signs of pancreatitis. Any form of pancreatitis should be ruled out in the assessment of acutely ill patients with BCOA.

Management of West Syndrome in a Patient With Methylmalonic Aciduria

Infantile spasms (or West syndrome) occur occasionally in patients with branched-chain organic acidurias. We describe a patient diagnosed with methylmalonic aciduria at 4.5 months of age during an episode of metabolic decompensation. The child was developmentally delayed and hypotonic; his electroencephalography (EEG) showed hypsarrythmia and brain magnetic resonance imaging (MRI) demonstrated moderate abnormalities in the globi pallidi. Following the failure of vigabatrin and lamotrigine to control the spasms, hydrocortisone was introduced. Methylmalonic acid excretion increased at the onset of steroid therapy but was rapidly corrected with transient protein restriction and initiation of metronidazole therapy. Full control of spasms and hypsarrythmia permitted the discontinuation of hydrocortisone therapy a year following its initiation. Tone and development improved although the latter remained delayed. This case illustrates the importance of screening for inborn errors of metabolism in seizure disorders, and that, although challenging, the management of methylmalonic aciduria with concurrent steroid therapy is possible and beneficial.

Spondylocostal Dysostosis Associated with Methylmalonic Aciduria

Spondylocostal dysostosis (SCD) is a genetic disorder characterized by vertebral segmentation and formation defects associated with changes of the ribs. Autosomal dominant and recessive modes of inheritance have been reported. Methylmalonic aciduria (MMA) is an inborn error of propionate or cobalamin metabolism. It is an autosomal recessive disorder and one of the most frequent forms of branched-chain organic acidurias. Here we report on a case of a Brazilian boy with both diseases. As we know, it is the first case in the literature with the occurrence of both SCD and MMA--the first a skeletal disease and the latter an inborn error of metabolism.

Methylmalonic and propionic aciduria

Methylmalonic and propionic aciduria (PA) are the most frequent forms of branched-chain organic acidurias. These autosomal recessive disorders result from deficient activity of methylmalonyl-CoA mutase and propionyl-CoA carboxylase, respectively. Clinically, acute or chronic neurologic signs are caused by the accumulation of toxic compounds proximal to the metabolic block. Phenotype varies from severe neonatal-onset forms with high mortality and poor outcome to milder forms with a later onset. In both cases the clinical course is dominated by the risk of relapses of life-threatening episodes of metabolic decompensation and of severe organ failure. Despite improvement of treatment, the overall outcome remains disappointing with no major differences between the two diseases. The diagnosis is based on the presence of characteristic compounds in body fluids as detected by organic acid analysis in urine and acylcarnitine profile in blood. Therapy is based on low-protein high-energy diet, carnitine supplementation, and metronidazole. Some patients with methylmalonic aciduria (MMA) respond to pharmacological doses of vitamin B12. Given the poor long-term prognosis, liver transplantation has been recently attempted as an alternative therapy to conventional medical treatment to cure the underlying metabolic defect. Nevertheless, the overall experience to date does not clearly demonstrate its effectiveness in preventing further deterioration or improving survival and quality of life. The recent implementation of neonatal screening by electrospray tandem mass spectrometry has decreased early mortality and improved the short-term outcome, without changing the detection rate of both diseases in the screening population compared to clinically detected cases. However, the limited number of patients and the short duration of their follow-up do not yet permit drawing final conclusions on its effect on the long-term outcome of methylmalonic and propionic acidemia.

Severe hypoglycaemia in isolated 3‐methylcrotonyl‐CoA carboxylase deficiency; a rare, severe clinical presentation

Since the introduction of neonatal screening for branched-chain organic acidurias, it has been noted that isolated 3-methylcrotonyl-CoA carboxylase deficiency is probably one of the most frequent organic acidurias. Only a few cases with severe clinical presentation have been described. Profound hypoglycaemia is an uncommon but life-threatening complication.

Branched-chain organic acidurias

Branched chain organic acidurias are a group of disorders that result from an abnormality of specific enzymes involving the catabolism of branched chain amino acids (leucine, isoleucine, valine). Maple syrup urine disease (MSUD), isovaleric acidaemia (IVA), propionic aciduria (PA) and methylmalonic aciduria (MMA) represent the most commonly encountered abnormal organic acidurias. All these four disorders present in neonates as a neurologic distress of the intoxication type with either ketosis or ketoacidosis and hyperammonaemia. There is a free interval between birth and clinical symptoms. MMA, PA and IVA present with a severe dehydration, leuconeutropenia and thrombopenia which can mimic sepsis. All these disorders can be diagnosed by identifying acylcarnitine and other organic acid compounds in plasma and urine by gas chromatography mass spectrometry or tandem MS-MS. These disorders are amenable to treatment by removing toxic compounds and by using special diets and carnitine.

Management and emergency treatments of neonates with a suspicion of inborn errors of metabolism

During the neonatal period, inborn errors of metabolism mostly present with an overwhelming illness that requires prompt diagnosis and both supportive and specific treatments. The most frequent situations are due to branched-chain organic acidurias that present with ketoacidosis and urea cycle defects that are characterized by hyperammonaemia. During both situations, toxin removal procedures and nutritional support with a free-protein and high-energy diet are pivotal treatments. In patients presenting with hypoglycaemia blood glucose levels must be corrected. Progress following glucose provision is useful in recognizing the disorders that are mainly implicated. Hyperinsulinism requires high-glucose infusion. Glycogen storage diseases and gluconeogenesis defects are easily treated with a permanent glucose provision while hypoglycaemias quickly recur. In patients with galactosaemia, hereditary fructose intolerance or tyrosinaemia type I, the presentation is dominated by a liver failure requiring galactose and fructose exclusion associated with a low-protein diet. Many patients with β-oxidation defects may present with hypoglycaemia that is usually easily corrected. The precise diagnosis can be easily missed in those patients that do well in the following weeks but may develop cardiac failure, arrhythmia and/or liver failure. Patients presenting with intractable convulsions, vitamin responsiveness to biotin, pyridoxine and folate must be considered.