Maple Syrup Urine Disease

Organic Acidemias.

Plasma amino acid and urine organic acid profiles of Filipino patients with maple syrup urine disease (MSUD) and correlation with their neurologic features

Maple syrup urine disease (MSUD) is an inherited disorder of branched-chain amino acid metabolism presenting with life-threatening cerebral oedema and dysmyelination in affected individuals. Treatment requires life-long dietary restriction and monitoring of branched-chain amino acids to avoid brain injury. Despite careful management, children commonly suffer metabolic decompensation in the context of catabolic stress associated with non-specific illness. The mechanisms underlying this decompensation and brain injury are poorly understood. Using recently developed mouse models of classic and intermediate maple syrup urine disease, we assessed biochemical, behavioural and neuropathological changes that occurred during encephalopathy in these mice. Here, we show that rapid brain leucine accumulation displaces other essential amino acids resulting in neurotransmitter depletion and disruption of normal brain growth and development. A novel approach of administering norleucine to heterozygous mothers of classic maple syrup urine disease pups reduced branched-chain amino acid accumulation in milk as well as blood and brain of these pups to enhance survival. Similarly, norleucine substantially delayed encephalopathy in intermediate maple syrup urine disease mice placed on a high protein diet that mimics the catabolic stress shown to cause encephalopathy in human maple syrup urine disease. Current findings suggest two converging mechanisms of brain injury in maple syrup urine disease including: (i) neurotransmitter deficiencies and growth restriction associated with branched-chain amino acid accumulation and (ii) energy deprivation through Krebs cycle disruption associated with branched-chain ketoacid accumulation. Both classic and intermediate models appear to be useful to study the mechanism of brain injury and potential treatment strategies for maple syrup urine disease. Norleucine should be further tested as a potential treatment to prevent encephalopathy in children with maple syrup urine disease during catabolic stress.

Maple Syrup Urine Disease (MSUD) and Type 1 Diabetes Mellitus (T1DM) are two distinct metabolic disorders with unique dietary management requirements. While MSUD necessitates strict restriction of branched-chain amino acids (BCAAs), T1DM requires precise carbohydrate counting to maintain optimal glycemic control. We report two cases of patients diagnosed with both MSUD and T1DM, highlighting the challenges and strategies in dietary management. Case 1, a 5-year-old girl, was diagnosed with T1DM after presenting with hyperglycemia and metabolic acidosis, despite previously stable MSUD management. The dietary regimen was modified to include a leucine-free amino acid formula and controlled carbohydrate intake to stabilize both leucine and glucose levels. Case 2, an 11-year-old boy with the diagnosis of MSUD, presented with hyperglycemia during a routine follow-up. Dietary management involved increasing the leucine-free formula while reducing carbohydrate intake to maintain metabolic control. Both cases emphasize the importance of individualized dietary plans, integrating BCAA restriction and carbohydrate regulation to prevent metabolic crises and achieve optimal glycemic control. These cases also underscore the need for a multidisciplinary approach involving pediatric endocrinologists, metabolic specialists, and dietitians to navigate the complexities of dual metabolic disorders effectively. Further studies are warranted to explore long-term outcomes and potential therapeutic targets in patients with concurrent MSUD and T1DM.

After completing this article, readers should be able to: 1. List the major categories of diseases detectable by expanded newborn screening. 2. Give examples of the benefits and limitations of screening by tandem mass spectrometry. 3. Describe the appropriate follow-up for an abnormal screening result. The screening of newborns for inherited metabolic disorders is a well-established public health activity, first implemented in the early 1960s for the presymptomatic identification of patients who have phenylketonuria (PKU). Since then, significant technological advances, most importantly the development of tandem mass spectrometry (MS/MS), have enabled the detection of an increasing number of metabolic disorders in newborn blood. This article reviews the basic technology of MS/MS and its application to newborn screening, with the aim of highlighting the benefits and pointing out some limitations of this powerful technology. Early screening for PKU used the bacterial inhibition assay of Guthrie, in which inhibition of bacterial growth on an agar medium, introduced by the addition of a phenylalanine analog, was overcome by the presence of dried blood discs containing high levels of phenylalanine (such as from a PKU patient). This approach later was adapted for the detection of leucine in patients who have maple syrup urine disease (MSUD), methionine in patients who have classic homocystinuria, and tyrosine in patients who have tyrosinemia. Over the years, other techniques have been implemented to screen for additional disorders, including congenital hypothyroidism, biotinidase deficiency, galactosemia, hemoglobinopathies, and congenital adrenal hyperplasia. The classic criteria used to determine whether a disorder is suitable for screening include: 1) the disorder is clinically and biochemically well defined, 2) it is associated with significant morbidity or mortality, 3) an effective treatment is available, and 4) there is a simple and safe screening test. (1) By the early 1990s, all states offered screening for at least PKU and congenital hypothyroidism, …

Leucinosis (maple syrup urine disease - MSUD) is an inherited aminoacidopathy and organic aciduria caused by severe enzyme defect in the metabolic pathway of amino acids: leucine, isoleucine, and valine. The classical variant of the disease is characterized by accumulation of both amino and α-keto acids, particulary the most toxic rapid elevation of circulating leucine and its ketoacid, α-ketoisocaproate, which cause encephalopathy and life-threatening brain swelling. However, patients with the most severe form, classical maple syrup urine disease, may appear normal at birth, but develop acute metabolic decompensation within the first weeks of life with typical symptoms: poor feeding, vomiting, poor weight gain, somnolence and burnt sugar-smelling urine, reminiscent of maple syrup. Early diagnosis and dietary intervention improve the patient’s condition, prevent severe complications, and may allow normal intellectual development. We present a 4-month old infant with leucinosis dignosed 3 months earlier, due to elevated levels of amino acids: leucine, isoleucine and valine. The patient was full-term neonate with an uncomplecated delivery, without any family history of metabolic disorder or consanguinity. The infant was referred to a dermatologist, because of maculopapular exanthema on the scalp, trunk, upper and lower extremities, and exfoliative dermatitis of the perioral, particularly anogenital regions, associated with diarrhea. Skin involvement was associated with poor general condition of the infant exhibiting severe hypotension, anemic syndrome, dyspepsia and neurological symptoms. Exanthema developed a few days after the initiation of nutritional therapy for MSUD: isoleucine-, leucine-, and valine-free powdered medical food (MSUD-2) supplemented with iron. Zink levels were within normal ranges. Rapid skin improvement occurred after adequate branched-chain amino acids supplementation was commenced under regular laboratory control (normal zinc serum level with deficiencies of leucine and valine), skin hygiene with antiseptics, emollients and low potent topical corticosteroids. Treatment of acute metabolic decompensation and dietary restriction of branched-chain amino acids are the main aspects in the management of maple syrup urine disease. Common findings in patients with MSUD include: plasma amino acid imbalance, particularly of essential amino acids, failure to thrive attributed to restriction of particular precursor amino acids and natural proteins, micronutrient deficiencies or higher energy requirement due to chronic illness or inflammation. Due to low intake of branched-chain amino acids, some patients develop skin lesions known as acrodermatitis enteropathica-like syndrome. Here we report a case of an infant who developed acrodermatitis enteropathica-like skin eruptions due to branched-chain amino acid deficiency during treatment of maple syrup urine disease. According to available world literature, this is the first report of acrodermatitis enteropathica-like syndrome in an infant with maple syrup urine disease (leucinosis) in the Republic of Bulgaria.

Maple syrup urine disease (MSUD) is an inborn error of metabolism characterized by the accumulation of branched-chain amino acids (leucine, isoleucine, and valine) caused by a defect in the branched-chain alpha-keto acid dehydrogenase complex. Liver transplant is an effective therapy for MSUD, and patients can usually tolerate a regular diet after transplant without symptomatic metabolic decompensation. Most post-transplant patients do not follow a sick-day diet. We report a case of a 7-year-old male with MSUD Type IA, status post-liver transplant at 2 years of age, who presented with profound encephalopathy following poor oral intake and vomiting for 3 days. Broad laboratory workup was significant for hyperleucinosis and an unrevealing infectious workup. We conducted a review of eight post-liver transplant MSUD patients followed at Washington University in St. Louis. The review revealed that plasma amino acids were generally not checked during intercurrent illnesses in this patient cohort. While most of our patients have not had documented encephalopathy, one of the patients with epilepsy had a seizure during a gastrointestinal illness. Based on the review of the literature and from our center's experience, acute metabolic decompensation with intercurrent illnesses in MSUD patients after liver transplant appears to be rare. This case report raises awareness that patients with MSUD are still at risk of developing metabolic crisis post-liver transplant and provides additional insight into the risk factors associated with metabolic decompensation in this patient cohort.

Maple Syrup Urine Disease (MSUD) is an autosomal recessive disorder caused by defects in the branched-chain α-ketoacid dehydrogenase complex resulting in accumulation of branched-chain amino acids (BCAAs) and corresponding branched-chain ketoacids (BCKAs) in tissues and plasma, which are neurotoxic. Early diagnosis and subsequent nutritional modification management can reduce the morbidity and mortality. Prior to 1990s, the diagnosis of MSUD and other inborn errors of metabolism (IEM) in Malaysia were merely based on clinical suspicion and qualitative one-dimensional thin layer chromatography technique. We have successfully established specific laboratory diagnostic techniques to diagnose MSUD and other IEM. We described here our experience in performing high-risk screening for IEM in Malaysia from 1999 to 2006. We analysed the clinical and biochemical profiles of 25 patients with MSUD. A total of 12,728 plasma and urine samples from patients suspected of having IEM were received from physicians all over Malaysia. Plasma amino acids quantitation using fully automated amino acid analyzer and identification of urinary organic acids using Gas Chromatography Mass Spectrometry (GCMS). Patients' clinical information were obtained from the request forms and case records Results: Twenty-five patients were diagnosed MSUD. Nineteen patients (76%) were affected by classical MSUD, whereas six patients had non-classical MSUD. Delayed diagnosis was common among our case series, and 80% of patients had survived with treatment with mild-to-moderate learning difficulties. Our findings suggested that MSUD is not uncommon in Malaysia especially among the Malay and early laboratory diagnosis is crucial.

ABSTRACT:Maple syrup urine disease (MSUD) is an inborn error of amino acid metabolism secondary to enzyme defect that breaks down branched-chain amino acid (BCAA). Accumulation of these amino acids and their corresponding ketoacids in the body progresses to neurodegenerative disorders and encephalopathy in undiagnosed infants. We report a case of 46 days old baby with classical clinical and biochemical findings consistent with MSUD. Baby was investigated for inborn error of metabolism after he developed lethargy and his oral intake reduced on fifth day of life. A diagnosis of MSUD was established after analysis of plasma and CSF amino acid profile. Baby was treated accordingly and improvement in his condition was seen afterwards. KEYWORDS:Maple Syrup Urine Disease (MeSH); Amino Acids (MeSH); Amino Acids, Branched-Chain (MeSH); Infant (MeSH), Cerebrospinal Fluid (MeSH).

Purpose – The purpose of this paper is a single-center six-month follow-up study to determine nutritional status of children with maple syrup urine disease (MSUD). Prolonged restriction on essential amino acid could cause malnutrition. By far, there is no study reported in the context of nutritional status among children with maple syrup urine disease (MSUD), who required life-long protein restriction. Design/methodology/approach – A total of 22 children with MSUD, aged from 1 to 12 years (6.54 ± 3.27) undergoing regular treatment in Institute of Pediatrics, Hospital Kuala Lumpur, were recruited. Body height, weight and head circumference were measured for anthropometry, whereas total protein, albumin and plasma branched-chain amino acid were measured for biochemical aspects. Clinical features diagnosed by pediatrician were recorded from children’s medical record. The 24-hour dietary recall was conducted to measure their nutrients intake. All assessments were repeated at six-month interval except clinical profile. Findings – There were no significant differences in all nutritional parameters from baseline to end of the visit. There was a prominence (particular noticeable of) of growth stunting (68; 64 per cent), undernutrition (35; 32 per cent) and microcephalic (57; 57 per cent) among children with MSUD. Nevertheless, children showed no significant improvement of anthropometric variables from baseline and after 6-month follow-up visit. Nearly all biochemical indicators were significantly (p < 0.05) higher than the reference value except valine. Intellectual disability was the most frequently (71 per cent) presenting symptoms among them. The finding also did not show any macro- or micronutrients fail to achieve above recommended nutrient intake in both visits. In conclusion, it is clear that no significant nutritional deficiency was induced by the use of MSUD dietary therapy; however, the findings indicated that MSUD children are at risk of malnutrition and regular nutritional assessment and monitoring should always be emphasized for optimal linear growth without affecting their amino acid profiles. Research limitations/implications – Multiple 24-hour recalls instead of single 24-hour recall should be used in this study for a better estimate of intake. Originality/value – Although there are retrospective studies targeted in presenting the clinical and biochemical profile of MSUD children which has been extensively examined, limited research has focused on prospective aspect of nutritional status of these children who are undergoing active and regular diet and medical nutrition therapy because of the absence of comprehensive reliable nutritional assessment data.

The branched-chain α-ketoacid dehydrogenase phosphatase (BDP) component of the human branched-chain α-ketoacid dehydrogenase complex (BCKDC) has been expressed in Escherichia coli and purified in the soluble form. The monomeric BDP shows a strict dependence on Mn(2+) ions for phosphatase activity, whereas Mg(2+) and Ca(2+) ions do not support catalysis. Metal binding constants for BDP, determined by competition isothermal titration calorimetry, are 2.4 nm and 10 μm for Mn(2+) and Mg(2+) ions, respectively. Using the phosphorylated decarboxylase component (p-E1b) of BCKDC as a substrate, BDP shows a specific activity of 68 nmol/min/mg. The Ca(2+)-independent binding of BDP to the 24-meric transacylase (dihydrolipoyl transacylase; E2b) core of BCKDC results in a 3-fold increase in the dephosphorylation rate of p-E1b. However, the lipoyl prosthetic group on E2b is not essential for BDP binding or E2b-stimulated phosphatase activity. Acidic residues in the C-terminal linker of the E2b lipoyl domain are essential for the interaction between BDP and E2b. The BDP structure was determined by x-ray crystallography to 2.4 Å resolution. The BDP structure is dominated by a central β-sandwich. There are two protrusions forming a narrow cleft ∼10 Å wide, which constitutes the active site. The carboxylate moieties of acidic residues Asp-109, Asp-207, Asp-298, and Asp-337 in the active-site cleft participate in binding two metal ions. Substitutions of these residues with alanine nullify BDP phosphatase activity. Alteration of the nearby Arg-104 increases the K(m) for p-E1b peptide by 60-fold, suggesting that this residue is critical for the recognition of the native p-E1b protein.

Maple syrup urine disease (MSUD) is an autosomal recessive inherited metabolic disorder, caused by branched-chain alpha-ketoacid dehydrogenase (BCKD) deficiency, leading to toxic accumulation of branched-chain amino acids (BCAAs) including leucine, isoleucine and valine and their corresponding a-ketoacids. The diagnosis of MSUD is based on elevated BCAAs and allo-isoleucine in plasma, and branched-chain hydroxyacids and ketoacids in urine. The identification of alloisoleucine >5 µmol/L is considered pathognomonic. Moreover, brain magnetic resonance imaging (MRI) showing atypical signal intensity and oedema is characteristic of MSUD. Recognition of the classical neuro-radiological findings of MSUD is particularly useful in local settings as many healthcare facilities lack the resources to measure Plasma Amino Acids (PAA). We report three cases of MSUD, in whom the disorder was strongly suspected at presentation, based on classical brain MRI findings, which was urgently confirmed by PAA analysis.

The treatment for Maple Syrup Urine Disease (MSUD) consists of a hypoproteic diet with integration therapy to limit leucine intake, ensuring adequate energy, macronutrients, and micronutrients to prevent catabolism and promote anabolism. We conducted a retrospective cross-sectional study at the Metabolic Rare Disease Unit, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy. Patients with MSUD who were over 3 years old, not treated with liver transplantation, and who provided written consent, were included. The study aimed to describe the dietary treatment of patients with MSUD, evaluate growth data, and analyze the effect of a low-protein and semi-synthetic diet on body composition. Data on height, weight, BMI, waist circumference, food intake, physical activity, and DEXA scans were collected. Thirteen subjects (11 classic MSUD, 2 intermediate MSUD) were included, of which 5 < 18 years old. Results indicated that patients with MSUD follow a balanced diet and have body compositions like healthy subjects in terms of fat and lean mass. A high incidence of osteopenia was observed from a young age, with a positive correlation between protein intake and lean mass and a negative correlation between BCAA-free mixture consumption and bone mineral density z-score. The study highlights the positive effects and potential consequences of the semi-synthetic diet on the body composition of patients with MSUD. A similar study involving all Italian metabolic centers treating MSUD is recommended.

Maple syrup urine disease (MSUD) is an autosomal recessive genetic disorder caused by defects in the catabolism of the branched-chain amino acids (BCAAs). However, the clinical and metabolic screening is limited in identifying all MSUD patients, especially those patients with mild phenotypes or are asymptomatic. This study aims to share the diagnostic experience of an intermediate MSUD case who was missed by metabolic profiling but identified by genetic analysis. This study reports the diagnostic process of a boy with intermediate MSUD. The proband presented with psychomotor retardation and cerebral lesions on magnetic resonance imaging scans at 8 mo of age. Preliminary clinical and metabolic profiling did not support a specific disease. However, whole exome sequencing and subsequent Sanger sequencing at 1 year and 7 mo of age identified bi-allelic pathogenic variants of the BCKDHB gene, confirming the proband as having MSUD with non-classic mild phenotypes. His clinical and laboratory data were retrospectively analyzed. According to his disease course, he was classified into an intermediate form of MSUD. His management was then changed to BCAAs restriction and metabolic monitoring conforming to MSUD. In addition, genetic counseling and prenatal diagnosis were provided to his parents. Our work provides diagnostic experience of an intermediate MSUD case, suggesting that a genetic analysis is important for ambiguous cases, and alerts clinicians to avoid missing patients with non-classic mild phenotypes of MSUD.

BackgroundMaple Syrup Urine Disease (MSUD) is an inborn error of metabolism caused by a deficiency of branched-chain keto acid dehydrogenase. MSUD has several clinical phenotypes depending on the degree of enzyme deficiency. Current treatments are not satisfactory and require new approaches to combat this disease. A major hurdle in developing new treatments has been the lack of a suitable animal model.MethodsTo create a murine model of classic MSUD, we used gene targeting and embryonic stem cell technologies to create a mouse line that lacked a functional E2 subunit gene of branched-chain keto acid dehydrogenase. To create a murine model of intermediate MSUD, we used transgenic technology to express a human E2 cDNA on the knockout background. Mice of both models were characterized at the molecular, biochemical, and whole animal levels.ResultsBy disrupting the E2 subunit gene of branched-chain keto acid dehydrogenase, we created a gene knockout mouse model of classic MSUD. The homozygous knockout mice lacked branched-chain keto acid dehydrogenase activity, E2 immunoreactivity, and had a 3-fold increase in circulating branched-chain amino acids. These metabolic derangements resulted in neonatal lethality. Transgenic expression of a human E2 cDNA in the liver of the E2 knockout animals produced a model of intermediate MSUD. Branched-chain keto acid dehydrogenase activity was 5–6% of normal and was sufficient to allow survival, but was insufficient to normalize circulating branched-chain amino acids levels, which were intermediate between wildtype and the classic MSUD mouse model.ConclusionThese mice represent important animal models that closely approximate the phenotype of humans with the classic and intermediate forms of MSUD. These animals provide useful models to further characterize the pathogenesis of MSUD, as well as models to test novel therapeutic strategies, such as gene and cellular therapies, to treat this devastating metabolic disease.