Maple Syrup Disease Research Articles

#1760 Four cases of ADTKD: AFM analysis of urine sediment

Abstract Background and Aims Autosomal Dominant Tubulointerstitial kidney disease (ADTKD) is a rare disease (16 per million), associated with CV events, hypertension, and gout. ADTKD is characterized by interstitial fibrosis, tubular atrophy, microcysts, and progressive CKD. We describe a case of a family with clinical characteristics of ADTKD and provide for the first time a characterization of their urinary sediment. Given the tendency of a specific type of ADTKD caused by UMOD mutation to form tubular crystals, we have also tested the ability of the urine from ADTKD patients to precipitate and form crystals in vitro. Method We examined clinical features and urinary sediment of a family with ADTKD: a 51 years old woman with CKD (eGFR 30 mL/min/1.73 m2, CDK-EPI 2021) and her three sons, a 20 years old male, two daughters of 26 and 24 years old, all with hyperuricemia. Genetic analysis is not yet available. The test of urine precipitation consisted of the analysis of crystals after air-drying a thin layer of urine after enrichment of the organic quota by triple centrifugation for 10 minutes at 1000 rpm. Urinary sediments were also studied by Atomic Force Microscopy (ICSPI nGauge AFM) to achieve a resolution of 20 nm of crystals. Results Clinical data for the four patients are reported in the table. None of the patients showed proteinuria. The urine sediment of all patients showed rare WBC (in greater amounts only in patient 1), rare amorphous granular casts, and rare tubular cells. Three patients showed formations of variably sized crystals in vitro. The precipitation test did not show crystals in patient 1, whereas patients 2-3 showed several rosette-type crystals often with a wagon-wheel concentric contour which resembled leucine crystals or CaCO3. Adding formalin to the samples resulted in a more clear organization of crystals in wagon-wheel structures. AFM imaging of the crystals showed rod-like structures branching with an angle of 35°. Conclusion ADTKD remains a poorly understood genetic condition with no specific treatment options. Our data suggest that patients with this condition may have an enhanced tendency to form crystals in vitro. Speculatively, this might induce tubular injury in vivo. Data from UMOD-ko animal models showed intrarenal crystals (not better specified). Genetic alterations of branched aminoacids metabolism (such as leucine in Maple syrup disease) can also cause tubular diseases, although the systemic manifestations are very different from our patients. Genetic analysis of our family will give further information on the proteins involved in these crystal structures.

Identification of a novel homozygous mutation of the BCKDHB gene in an Iranian patient with maple syrup disease using next-generation sequencing

BackgroundMaple syrup urine disease (MSUD) is an autosomal recessive disorder caused by decreased branched-chain alpha-keto acid dehydrogenase (BCKD) activity in human tissues. The BCKD enzyme is mostly active in the human body in the muscles and the brain; thus, genetic deficiency of the BCKD complex can result in neurological damage in patients. Deleterious mutations in BCKDHB, BCKDHA, DBT, and DLD genes have a significant impact on BCKD activity. MethodsIn this study, we described a case of MSUD in a consanguineous Iranian family without a history of metabolic disorders. A 7-year-old boy was diagnosed 21 days after birth with lethargy, feeding problems, and vomiting. Plasma amino acid concentration and level of ammonia were measured. And then, whole-exome sequencing (WES) 100× was used to identify causative mutation along with some bioinformatics analysis. ResultsA novel pathogenic homozygous mutation, c.552_553insA; P185Tfs*17, was detected in the BCKDHB gene's exon5. This variant was predicted as a pathogenic mutation using bioinformatics tools including Mutationtaster, Fathmm-mkl, Provean, DEOGEN2, SNPs&GO, PhyloP, and PhastCons. This mutation leads to a truncated protein in which conserved regions are lost. Besides, the variant is completely co-segregated with the disease in this family. ConclusionA novel pathogenic mutation c.552_553insA in the BCKDHB gene related to MSUD was diagnosed in an Iranian family. This finding from the present study can be efficient in upgrading mutation databases and recognizing MSUD causes.

Aumento acentuado da leucina como fator de mau prognóstico na doença da urina de xarope de bordo - relato de caso

INTRODUCTION: Leucinosis or Maple Syrup Disease (MSD) is an innate metabolism error caused by a deficiency in the activity of the alpha-keto acid-dehydrogenase enzyme complex, which leads to the accumulation of essential branched-chain amino acids (leucine, valine, and isoleucine), leucine is particularly toxic to the central nervous system (CNS). OBJECTIVES: Report a case of maple syrup disease in a 10-day-old newborn (NB), born to consanguineous parents, with late diagnosis, with high levels of leucine, with an unfavorable prognosis. COMMENTS: MSD is a rare condition, of autosomal recessive origin, which occurs due to the accumulation of essential branched-chain amino acids in tissues(leucine, valine, and isoleucine). The accumulation of amino acids mainly affects the CNS. Studies have shown that the elevated leucine concentration decreases the serum sodium concentration and increases intracellular water, causing cerebral edema. Neurological damage will depend on the degree and time of tissue exposure to metabolites. Despite the unfavorable outcome of the case presented, the prognosis of MSD can be modified with strict diet control and early and aggressive management of metabolic crisis.

Case of steroid-sensitive nephrotic syndrome in a child with orphan disease – leucinosis.

BACKGROUND. The article presents the case of a clinical and laboratory complex of a recurrent hormone-sensitive variant of nephrotic syndrome in a patient with leucinosis (maple syrup disease). THE AIM: to study the clinical laboratory features of nephrotic syndrome in a child with orphan disease – leucinosis. A PATIENT. A 4-year-old child born in a consanguineous marriage, who had previously been diagnosed with a rare genetic disease leucinosis, was examined. The manifestation of leucinosis began from the 8th day of birth. Based on the results of a molecular genetic study the diagnosis was pinpointed as leucinosis with an autosomal recessive mode of inheritance, classic neonatal (maple syrup disease). At the age of 4 the child developed a clinical and laboratory complex of nephrotic syndrome. RESULTS. The onset of nephrotic syndrome was characterized by a hormone-sensitive course. After completion of the course of glucocorticosteroid therapy, there was a relapse because of acute respiratory infection which also turned out to be hormone-sensitive. Kidney function was not impaired. There were no crises of leucinosis due to nephrotic syndrome. CONCLUSION. Taking into account the development of nephrotic syndrome in a child with a genetically determined disease, a molecular genetic examination should be done to exclude the hereditary nature of the developed nephrotic syndrome. The examination is of great clinical importance for determining treatment tactics, cytostatic therapy, doing a kidney biopsy in order to determine the morphological form of glomerulonephritis, prognosis of progression to the end-stage renal failure.

Enteral tube feeding in patients receiving dietary treatment for metabolic diseases: A retrospective analysis in a large French cohort

ContextA strictly controlled diet (often involving enteral tube feeding (ETF)) is part of the treatment of many inherited metabolic diseases (IMDs). ObjectiveTo describe the use of ETF in a large cohort of patients with IMDs. DesignA retrospective analysis of ETF in patients with urea cycle disorders (UCDs), organic aciduria (OA), maple syrup disease (MSUD), glycogen storage diseases (GSDs) or fatty acid oxidation disorders (FAODs) diagnosed before the age of 12 months. SettingThe reference center for IMDs at Necker Hospital (Paris, France). Results190 patients born between January 1991 and August 2017 were being treated for OA (n = 60), UCDs (n = 55), MSUD (n = 32), GSDs (n = 26) or FAODs (n = 17). Ninety-eight of these patients (52%) received ETF (OA subgroup: n = 40 (67%); UCDs: n = 12 (22%); MSUD: n = 9 (28%); GSDs: n = 23 (88%); FAODs: n = 14 (82%)). Indications for ETF were feeding difficulties in 64 (65%) patients, cessation of fasting in 39 (40%), and recurrent metabolic decompensation in 14 (14%). Complications of ETF were recorded in 48% of cases, more frequently with nasogastric tube (NGT) than with gastrostomy. Among patients in whom ETF was withdrawn, the mean duration of ETF was 5.9 (SD: 4.8) years (range: 0.6–19.8 years). The duration of ETF was found to vary from one disease subgroup to another (p = 0.051). While the longest median duration was found in the GSD subgroup (6.8 years), the shortest one was found in the UCD subgroup (0.9 years). ConclusionETF is an integral part of the dietary management of IMDs. The long duration of ETF and the specific risks of NGT highlights the potential value of gastrostomy.In this study at a French tertiary hospital, we documented the indications, modalities, duration and complications of enteral tube feeding in a cohort of patients with inherited metabolic diseases.

Progress of research on Maple syrup disease

Maple syrup disease (MSUD) is a rare autosomal recessive disorder caused primarily by mutations of branched-chain keto acid dehydrogenase complex (BCKDC). BCKDC includes at least four pathogenic genes of BCKDHA, BCKDHB, DLD and DBT. The clinical manifestations of MSUD are complex, and the main symptoms at the early stage include difficulty in feeding, drowsiness, change in muscle tone and special urine flavor of maple syrup. As the disease progresses, convulsion, hypoglycemia, coma and systemic failure may occur. MSUD is easily missed or misdiagnosed during the neonatal period. This paper provides a review for recent progress made in research on MSUD including etiology, physiopathology, clinical manifestation, auxiliary examination and treatment, with a particular emphasis on genetic testing and treatment.

High glucose intake and glycaemic level in critically ill neonates with inherited metabolic disorders of intoxication.

To investigate glycaemic levels in critically ill neonates with inherited metabolic disorders of intoxication. Thirty-nine neonates with a median age of 7days (0-24) were retrospectively included (urea cycle disorders (n = 18), maple syrup disease (n = 13), organic acidemias (n = 8)). Twenty-seven neonates were intubated, 21 were haemodialysed and 6 died. During the first 3days, median total and peak blood glucose (BG) levels were 7.1mmol/L (0.9-50) and 10mmol/L (5.1-50), respectively. The median glucose intake rate was 11mg/kg/min (2.7-15.9). Fifteen and 23 neonates exhibited severe hyperglycaemia (≥2 BG levels >12mmol/L) and mild hyperglycaemia (≥2 BG levels >7 and ≤12mmol/L), respectively. Glycaemic levels and number of hyperglycaemic neonates decreased over the first 3days (p < 0.001) while total glucose intake rate was stable (p = 0.11). Enteral route of glucose intake was associated with a lower number of hyperglycaemic neonates (p = 0.04) and glycaemic level (p = 0.02). Hyperglycaemia is common in critically ill neonates receiving high glucose intake with inherited metabolic disorders of intoxication. Physicians should decrease the rate of total glucose intake and begin enteral feeding as quickly as possible in cases of persistent hyperglycaemia. • The risk of hyperglycaemia in the acute phase of critical illness is high. What is New: • Hyperglycaemia is common in the initial management of critically ill neonates with inherited metabolic disorders of intoxication receiving high glucose intake.

Evolution and Innovations of the National Neonatal and High Risk Screening Program in Costa Rica

We present the evolution, organization and results of the National Neonatal and High Risk Screening Program in Costa Rica (PNT). This program has been working uninterruptedly for more than fourteen years. Costa Rica currently has a literacy rate of 95%. To August 2004 the rate of infant mortality was 9.74 per 1000 births and to 2003, life expectancy was 76.3 years for men and 81.1 years for women. The control of infectious and parasitic diseases, as well as of severe malnutrition, has given room to a prevalence of chronic diseases with a pathology profile similar to that of a developed country. The clinical observation, mainly starting from early 70s, of a growing number of patients with mental retardation and other disabilities caused by congenital hypothyroidism and hereditary metabolic diseases that could have been prevented in many cases with an early diagnosis and opportune treatment, led us to the decision to implement a systematically massive neonatal screening for these diseases. The presence of a single Public System of Social Security in Costa Rica, which currently includes from primary health care up to the hospitals of tertiary attention, with a single Children's Hospital for the whole country, as well as communication facilities, are factors that offered, in principle, favorable conditions for this effort, even for a developing country. To September 2004, 835,217 children have been screened. There is a coverage of 95.1% of the newborns in the country. Also to this date, 259 children with congenital hypothyroidism, 18 with phenylketonuria, 20 with the maple syrup disease, 30 with congenital adrenal hyperplasia and 10 with galactosemia have been detected, confirmed and treated, for a total of 337 children that were spared of mental retardation, other disabilities and even death. Massive neonatal screening for organic acidemias recently started in June of 2004. Cystic fibrosis is under a pilot study and the screening for hemoglobinopathies and toxoplasmosis is planned. The Center for Prevention of Disabilities, which started its functions on September 23, 2002, made feasible to integrate neonatal screening, high risk screening and diagnostic confirmation of the diseases now included in the national screening program as well as those to be added in the future.

Enfermedad de jarabe de arce: una entidad rara que debemos recordar. A propósito de su manejo dietético

Maple syrup disease is secondary to a deficiency of deshydrogenase complex of a cetoacid of branched-chain. This disease has a recessive autosomic inheritance, with an incidence of 1/200,000 newborns, without differences between male and female. Due to clinical presentation and biochemical response to tiamin, these patients can be classified in five clinical entities: classic, intermediate, intermittent, positive response to tiamin and deficiency of dihydrolipoyl deshydrogenase (E3). In these patients, an increase of seric branched-chain aminoacids is detected, it could be detected by (chromatography) during neonatal period. Valine, isoleucine, and aloisoleucine are increased in serum, orine, and cephaloraquideum liquid by ionic changed chromatography, chromatography of high resolution or high voltage electrophoresis. Patients have two phases in this disease (acute phase and maintaining phase). Objectives in acute phase are based in three topics: to eliminate toxic metabolites, nutritional support and to get anabolism. Utilization of hemodialysis/peritoneal dialysis/blood exchange is one of the first treatments. Dietetic support is the second treatment, with a minimum energy intake and controlling blood levels of aminoacids. Modified dietetic formulas is a main device to treat these patients.

Maple syrup disease presenting as paroxysmal dystonia

An apparently normal 22-month-old boy was evaluated because of weekly paroxysmal episodes consisting of curvature of the body (alternating sides). During attacks, which lasted 5 minutes to 8 hours, the patient had extreme irritability. We hypothesized based on the clinical picture that the paroxysmal events might correspond to partial epileptic seizures, hemiplegic migraine, paroxysmal torticollis, or Sandifer’s syndrome. Blood count, hepatic and renal function, ionogram, and glycemia were normal. Electroencephalogram showed left temporal slow waves. Brain computed tomography scan was normal. The patient was put on sodium valproate (30mg/kg/ day PO). Two months later, the patient had similar weekly attacks. These episodes were videotaped, and we were able to diagnose a paroxysmal dystonia accompanied by irritability. Physical and neurological examination was normal between the attacks. Mental age showed a delay of 10 months of global development (Griffiths scale). Brain magnetic resonance imaging (MRI) showed symmetrical hypersignal in T2-weighted images in the brainstem, globus pallidus, thalami, and dentate nuclei (see Fig). Serum and urinary amino acid analysis in the interictal periods disclosed abnormally high leucine (489 mol/L; normal, 109), isoleucine (278 mol/L; normal, 94), valine (500 mol/L; normal, 246), and alloisoleucine (88 mol/L; normal, 3.4) levels. Urinary organic acid chromatography was normal. Serum leucine level was 300 mol/L after 5 days’ treatment with a vegetarian diet and milk substitute. Supplementation with high doses of thiamine did not improve the metabolic picture. Ten months after maple syrup urine disease (MSUD) was diagnosed, the patient had only two mild attacks of dystonia accompanied by metabolic decompensation episodes precipitated by fever. In addition, his psychomotor development improved, particularly verbal capacities. Brain MRI has not shown significant differences, however. Most episodes of paroxysmal dyskinesia in children are idiopathic. Secondary metabolic causes include nonketotic hyperglycinemia, hypoglycemia, hypocalcemia, thyrotoxicosis, kernicterus, cystinuria, and pyruvate carboxylase deficiency. We have presented a patient with episodes of nonkinesigenic paroxysmal dystonia accompanied by marked irritability. This makes this case different from typical idiopathic dystonias. Left temporal electroencephalogram abnormalities suggested a diagnosis of epilepsy, but it was quite improbable given the alternating location of the dystonic attacks and the failure to respond to antiepileptic therapy. Brain MRI pointed to a symptomatic cause (metabolic, toxic, or anoxic). The abnormal levels of branched-chain amino acids in the interictal periods with persistently high alloisoleucine levels have helped us diagnose chronic intermediate MSDU. Nonspecific developmental delay, progressive psychomotor retardation, dementia, and seizures can be observed during the course of this disease. Although age at onset, delayed psychomotor development, and typical brain imaging make this case similar to others, our patient atypically presented with paroxysmal dystonia. MSUD should be considered in the differential diagnosis of secondary causes of childhoodonset paroxysmal dyskinesia.

Branched-chain Ketoacyl Dehydrogenase Deficiency: Maple Syrup Disease.

Classic maple syrup disease can be managed to allow a benign neonatal course, normal growth, and low hospitalization rates. The majority of affected infants that are prospectively managed have good neurodevelopmental outcome; however, acute metabolic intoxication and neurologic deterioration can develop rapidly at any age. Each episode is associated with a risk for cerebral edema, cerebrovascular compromise, and brain herniation. High plasma leucine and, possibly, alpha-ketoisocaproate are the principal neurotoxins in maple syrup disease. Plasma levels rise rapidly in association with net protein catabolism provoked by common infections and injuries. Transient periods of maple syrup disease encephalopathy appear fully reversible, leaving no clinically detectable neurologic sequelae. In contrast, prolonged amino acid imbalance, particularly if occurring during the critical period of brain development, leads to neuronal hypoplasia, a paucity of synapses, and undermyelination. Stagnated maturation and inadequate nutritional maintenance of brain structure have lifelong neurologic and behavioral consequences. Core elements of effective long-term therapy include screening and identification of asymptomatic newborns, frequent plasma amino acid monitoring, careful attention to branched-chain amino acid nurtriture, prevention of cerebral essential amino acid deficiencies, adequate provision of essential omega-3 class fatty acids and micronutrients deficient in commercial formulas, methods for home monitoring of metabolic control, and a commitment to lifelong therapy. Recognizing the risk for acute leucine intoxication depends on anticipating effects of common childhood infection and physiologic stresses on whole body protein turnover. Successful management of metabolic decompensation is based on the use of home sick-day regimens, rapid availability of branched-chain amino acid-free hyperalimentation solutions for hospitalized children, prevention of hyponatremia in patients with leucinosis, and frequent adjustments of intravenous therapies guided by plasma amino acid levels and indices of metabolic and clinical response.

Diagnosis and treatment of maple syrup disease: a study of 36 patients.

To evaluate an approach to the diagnosis and treatment of maple syrup disease (MSD). Family histories and molecular testing for the Y393N mutation of the E1alpha subunit of the branched-chain alpha-ketoacid dehydrogenase allow us to identify infants who were at high risk for MSD. Amino acid concentrations were measured in blood specimens from these at-risk infants between 12 and 24 hours of age. An additional 18 infants with MSD were diagnosed between 4 and 16 days of age because of metabolic illness. A treatment protocol for MSD was designed to 1) inhibit endogenous protein catabolism, 2) sustain protein synthesis, 3) prevent deficiencies of essential amino acids, and 4) maintain normal serum osmolarity. Our protocol emphasizes the enhancement of protein anabolism and dietary correction of imbalances in plasma amino acids rather than removal of leucine by dialysis or hemofiltration. During acute illnesses, the rate of decrease of the plasma leucine level was monitored as an index of net protein synthesis. The treatment protocol for acute illnesses included the use of mannitol, furosemide, and hypertonic saline to maintain or reestablish normal serum sodium and extracellular osmolarity and thereby prevent or reverse life-threatening cerebral edema. Similar principles were followed for both sick and well outpatient management, especially during the first year, when careful matching of branched-chain amino acid intake with rapidly changing growth rates was necessary. Branched-chain ketoacid excretion was monitored frequently at home and branched-chain amino acid levels were measured within the time of a routine clinic visit, allowing immediate diagnosis and treatment of metabolic derangements. 1) Eighteen neonates with MSD were identified in the high-risk group (n = 39) between 12 and 24 hours of age using amino acid analysis of plasma or whole blood collected on filter paper. The molar ratio of leucine to alanine in plasma ranged from 1.3 to 12.4, compared with a control range of 0.12 to 0.53. None of the infants identified before 3 days of age and managed by our treatment protocol became ill during the neonatal period, and 16 of the 18 were managed without hospitalization. 2) Using our treatment protocol, 18 additional infants who were biochemically intoxicated at the time of diagnosis recovered rapidly. In all infants, plasma leucine levels decreased to <400 micromol/L between 2 to 4 days after diagnosis. Rates of decrease of the plasma leucine level using a combination of enteral and parenteral nutrition were consistently higher than those reported for dialysis or hemoperfusion. Prevention of acute isoleucine, valine, and other plasma amino acid deficiencies by appropriate supplements allowed a sustained decrease of plasma leucine levels to the therapeutic range of 100 to 300 micromol/L, at which point dietary leucine was introduced. 3) Follow-up of the 36 infants over >219 patient years showed that, although common infections frequently cause loss of metabolic control, the overall rate of hospitalization after the neonatal period was only 0.56 days per patient per year of follow-up, and developmental outcomes were uniformly good. Four patients developed life-threatening cerebral edema as a consequence of metabolic intoxication induced by infection, but all recovered. These 4 patients each showed evidence that acutely decreased serum sodium concentration and decreased serum osmolarity were associated with rapid progression of cerebral edema during their acute illnesses. Classical MSD can be managed to allow a benign neonatal course, normal growth and development, and low hospitalization rates. However, neurologic function may deteriorate rapidly at any age because of metabolic intoxication provoked by common infections and injuries. Effective management of the complex pathophysiology of this biochemical disorder requires integrated management of general medical care and nutrition, as well as control of several variables that influence endogenous protein anabolism and catabolism, plasma amino acid concentrations, and serum osmolarity.

Maple Syrup Disease: Diagnosis and Therapy

Infants at high risk for maple syrup disease (MSD) were identified by family history and molecular testing for the Y393N mutation of the E1a subunit of the branched chain a-ketoacid dehydrogenase in a study at Johns Hopkins University School of Medicine, Baltimore, MD.

Which Organic Acids does Hemofiltrate Contain in the Presence of Acute Renal Failure?

It is not generally possible to measure most organic acids in the serum of critically ill patients, due to rapid metabolism and methodological problems. Only the regular measurement of lactic acid and the arterial ketone body ratio (acetoacetate/beta-hydroxybutyrate, AKBR) have been introduced in clinical practice, but these parameters can represent only a part of the disturbed metabolism. In pediatric patients, a chromatographical urine analysis has been established for detection of inborn errors of metabolism, which allows the determination of more than 50 organic acids simultaneously (gas chromatographic (GC) analysis in combination with mass spectrometry (MS)]. In continuous treatment of acute renal failure, hemofiltrate is always available, but it contains only low protein concentrations and after the filtration process, metabolism is rapidly stopped. The sieving coefficient of lactic acid is nearly one in hemofiltration. The aim of our study was to compare results of the regular and CG/MS methods in blood and hemofiltrate for lactic acid, and to find other organic acids of possible clinical importance. We investigated serum (lactic acid) and hemofiltrate of 40 critically ill patitens, similar to the urine analysis method for infants. All patients suffered from acute renal failure and were treated by continuous veno-venous hemofiltration (CVVH). The conditions of treatment were standardized (spontaneous ultrafiltration in the first hour), and the material (blood/hemofiltrate) was taken one hour after the beginning of extracorporeal circulation. Statistical methods included correlation analysis, nonparametric ANOVA with Wilcoxon scores (ranks of data), and stepwise discriminant analysis. Regular and GC/MS methods in hemofiltrate showed a good correlation for lactic acid. The best correlation with lactic acid was found for 4-hydroxy-phenyllactic acid (n=20, r=0.866), 2-hydroxy-valeric acid (n=22, r=0.7491) and 2-hydroxybutyric acid (n=32, r=0.5148). Age, sex, diagnosis, and APACHE II score play a subordinate role, but the presence of glyceric and citric acid possibly have prognostic importance [nonparimetric ANOVA with Wilcoxon scores (ranks of data)], as does the combination of 3-hydroxypropionic acid, glyceric acid, and threonic-acid-4-lacton (stepwise discriminant analysis). It can be concluded that in acute renal failure, the measurement of lactic acid and AKBR can reflect only a small part of disturbed metabolism. Hemofiltrate can be a useful medium in describing metabolic processes in critically ill patients with acute renal failure. Some inherited metabolic diseases in infants (phenylketonuria, maple syrup disease) and ketoacidosis show similar metabolic modifications.

Neonatal screening for inborn errors of metabolism in Switzerland

Neonatal screening for inborn errors of metabolism in Switzerland began in 1965 at the Children’s Hospital in Zurich with screening for phenylketonuria (PKU) by assaying for phenylalanine on dried spots of blood. In 1967, this screening was also initiated at the Central Laboratory of the Swiss Red Cross in Berne. The program then rapidly expanded. Screening for maple syrup disease (MSUD) by the Guthrie leucine assay, for homocystinuria by the Guthrie methionine assay, and for galactosemia with first the galactose assay (modified Guthrie test according to Paigen) and then for galactose-l-phosphate uridyltransferase activity (Beutler and Baluda) were added. Over the years some modifications of the program occurred: in 1973, the enzyme fluorimetric test according to Wiedemann that measures galactose was introduced in Berne for galactosemia screening and in 1974 TSH screening by RIA for congenital hypothyroidism (CH) was begun. In 1986, the enzyme immunoassay (Delfia) became the method for CH screening. Histidinemia screening with the Guthrie histidine assay was conducted as a pilot study for one year but a low prevalence, inadequate treatment and the large number of untreated cases described with normal development prompted abandonment of this screening. In 198 1 methionine screening was also abandoned, since no case of homocystinuria was identified during the 16 year screening period. However, four cases of hypermethioninemia, among them patients with fructose intolerance, were discovered with this screening. Biotinidase screening was added 1986. In 1987 leucine screening was also stopped, due to the low prevalance of MSUD and the fact that screening specimens collected on day 4 might be too late for the very early newborn diagnosis required in this

Abnormalities of muscle fibers in maple syrup urine disease.

Muscle fiber abnormalities are described in three cases of neonatal maple syrup disease. There were important variations in fiber diameters. Lesions consisted in focal or diffuse destruction of myofibrils. In view of recent biochemical and clinical data, a direct relation between elevated branched-chain amino acid levels and the muscular abnormalities seems improbable.

Mammalian α-Keto Acid Dehydrogenase Complexes: IV. Substrate Specificities and Kinetic Properties of the Pig Heart Pyruvate and 2-Oxoglutarate Dehydrogenase Complexes

Abstract It was found that the pig heart pyruvate dehydrogenase complex is capable of oxidatively decarboxylating α-ketobutyrate at about the rate of 62% of that of pyruvate in the over-all reaction assay and about 79% in the dehydrogenase assay. The complex also shows some activities with α-ketovalerate, α-ketoisocaproate, and α-ketocaproate. These activities were associated with this complex throughout the purification process. The 2-oxoglutarate dehydrogenase complex is highly specific for 2-oxoglutarate, but does also show some activity with α-ketoadipate. The pig heart pyruvate dehydrogenase complex was inhibited competitively by α-ketoisovalerate and α-keto-β-methylvalerate with pyruvate, α-ketobutyrate, and α-ketoisocaproate. The 2-oxoglutarate dehydrogenase complex exhibited mixed inhibition by α-ketoisovalerate, α-keto-β-methylvalerate, and α-ketoisocaproate with 2-oxoglutarate. The significances of the results relative to maple syrup disease are discussed.

Maple syrup disease. Effects of dietary therapy on cerebral lipids.

MAPLE syrup disease is a rapidly progressive familial cerebral degenerative condition marked by the excretion of a urine possessing a sweet, maple syrup-like odor. 1 The enzymatic basis for this disease is a failure in the oxidative decarboxylation of three branched-chain keto acids, the derivatives of leucine, valine, and isoleucine. As a consequence of the defect, these compounds and their amino acid analogues are excreted in large amounts, and plasma levels of branched-chain amino acids are many times higher than normal. 2 Hypertonia, disturbances in respiration, and seizures appear shortly after birth and prove to be fatal within a few weeks or months in a majority of children. In analogy to the therapy for phenylketonuria, Holt et al first suggested regulating the abnormal blood levels of branchedchain amino acids by means of a completely synthetic diet in which the intake of leucine, isoleucine, valine, and methionine could be carefully

Serotonin Depletion by Dietary Leucine

MAPLE syrup disease (branched-chain ketonuria) is an apparently familial disease associated with mental retardation and biochemically characterized by enhanced urinary excretion of branched-chain amino-acids and their products.

Cerebral lipids in maple syrup disease

A combined neuropathological and neurochemical study of a patient who succumbedto maple syrup disease is presented. The principal anatomic abnormalities were in the white matter and included generalized cerebral edema, astrocytosis, oligodendroglial swelling, and a decreased amount of myelin. On chemical analysis the concentrations of all major lipid fractions were within normal limits for the patient's age. Cerebrosides, sulfatides, and ceramides were isolated and their structure verified. Although the relative amounts of long-chain fatty acids in all three glycolipids was markedly reduced as compared with that of adult tissues, the fatty acid pattern was similar to that of control specimens of comparable age.