Abnormalities In Amino Acid Metabolism Research Articles

Quo vadis ureagenesis disorders? A journey from 90 years ago into the future.

The pathway of ammonia disposal in the mammalian organism has been described in 1932 as a metabolic cycle present in the liver in different compartments. In 1958, the first human disorder affecting this pathway was described as a genetic condition leading to cognitive impairment and constant abnormalities of amino acid metabolism. Since then, defects in all enzymes and transporters of the urea cycle have been described, referring to them as primary urea cycle disorders causing primary hyperammonemia. In addition, there is a still increasing list of conditions that impact on the function of the urea cycle by various mechanisms, hereby leading to secondary hyperammonemia. Despite great advances in understanding the molecular background and the biochemical specificities of both primary and secondary hyperammonemias, there remain many open questions: we do not fully understand the pathophysiology in many of the conditions; we do not always understand the highly variable clinical course of affected patients; we clearly appreciate the need for novel and improved diagnostic and therapeutic approaches. This study does look back to the beginning of the urea cycle (hi)story, briefly describes the journey through past decades, hereby illustrating advancements and knowledge gaps, and gives examples for the extremely broad perspective imminent to some of the defects of ureagenesis and allied conditions.

Amino acid transporters in neurological disorders and neuroprotective effects of cysteine derivatives

For most diseases and disorders occurring in the brain, the full causes behind them are yet unknown, but many show signs of dysfunction of amino acid transporters or abnormalities in amino acid metabolism. The blood-brain barrier (BBB) plays a key role in supporting the function of the central nervous system (CNS). Because of its unique structure, the BBB can maintain the optimal environment for CNS by controlling the passage of hydrophilic molecules from blood to the brain. Nutrients, such as amino acids, can cross the BBB via specific transporters. Many amino acids are essential for CNS function, and dysfunction of these amino acid transporters can lead to abnormalities in amino acid levels. This has been linked to causes behind certain genetic brain diseases, such as schizophrenia, autism spectrum disorder, and Huntington's disease (HD). One example of crucial amino acids is L-Cys, the rate-limiting factor in the biosynthesis of an important antioxidant, glutathione (GSH). Deficiency of L-Cys and GSH has been linked to oxidative stress and has been shown as a plausible cause behind certain CNS diseases, like schizophrenia and HD. This review presents the current status of potential L-Cys therapies and gives future directions that can be taken to improve amino acid transportation related to distinct CNS diseases.

Serum Amino Acid Profiling in Children with Autistic Spectrum Disorder: Insights from a Single-Center Study in Southern Romania.

The objective of this study was to analyze the serum amino acid profile in children diagnosed with autistic spectrum disorder (ASD) in southern Romania. The analysis aimed to provide insights into the underlying metabolic dysregulations associated with ASD. ASD is a neurodevelopmental disorder characterized by impaired social interaction, communication deficits, and restricted repetitive behaviors. Although the exact cause of ASD is largely unknown, recent evidence suggests that abnormalities in amino acid metabolism may contribute to its pathogenesis. Therefore, studying the amino acid profile in children with ASD could offer valuable information for understanding the metabolic disturbances associated with this complex disorder. This single-center study examined serum samples from children diagnosed with ASD, utilizing advanced analytical techniques to quantify the levels of different amino acids, amino acid derivatives, and amino acid-like substances. The results showed a lower level of taurine and a higher level of asparagine and leucine in the ASD group versus the control group. In the ASD group, we observed significant differences in tryptophan and alpha-aminobutyric acid levels based on age, with higher tryptophan levels in children older than 7 years when compared to children younger than 7 years; however, no significant correlations were found with the ASD group older than 7 years old. Additionally, younger children with ASD exhibited higher levels of alpha-aminobutyric acid than older children with ASD. The findings from this study contribute to the growing body of knowledge on the metabolic aspects of ASD, highlighting potential biomarkers and therapeutic targets for improving the management and treatment of ASD in children.

Adaptation to Protein Restriction Is Impaired in Insulin-Dependent Diabetes Mellitus ,

Although mild abnormalities of amino acid metabolism frequently exist in conventionally treated insulin-dependent diabetes mellitus (IDDM), their physiologic and nutritional importance is uncertain. We tested whether a tendency toward body N loss can be either masked or revealed in insulin-treated IDDM by changing the level of protein in the diet. After adaptation to a protein-free diet adequate in all other nutrients, obligatory urinary N excretion of intensively treated IDDM subjects was significantly greater than normal, indicating an impaired ability to recycle endogenous amino acids during protein restriction. When the preceding diet was high in protein, urea N production after consumption of a mixed test meal matched the amount of N consumed for both normal and diabetic subjects. However, when the test meal was preceded by 5 d of protein restriction, conventionally treated IDDM subjects failed to adaptively reduce postprandial urea production as effectively as normal or intensively treated IDDM subjects. Thus, even during insulin treatment, the ability to maximally recycle endogenous amino acids is impaired in IDDM, as is the ability to adaptively increase dietary amino acid retention in response to protein restriction.

Effects of pharmacological treatment on metabolomic alterations in animal models of depression

Numerous studies have investigated metabolite alterations resulting from pharmacological treatment in depression models although few quantitative studies explored metabolites exhibiting constant alterations. This study aimed to identify consistently dysregulated metabolites across such studies using a knowledgebase-driven approach. This study was based on 157 studies that identified an assembly of 2757 differential metabolites in the brain, blood, urine, liver, and feces samples of depression models with pharmacological medication. The use of a vote-counting approach to identify consistently upregulated and downregulated metabolites showed that serotonin, dopamine, norepinephrine, gamma-aminobutyric acid, anandamide, tryptophan, hypoxanthine, and 3-methoxytyramine were upregulated in the brain, while quinolinic acid, glutamic acid, 5-hydroxyindoleacetic acid, myo-inositol, lactic acid, and the kynurenine/tryptophan ratio were downregulated. Circulating levels of trimethylamine N-oxide, isoleucine, leucine, tryptophan, creatine, serotonin, valine, betaine, and low-density lipoprotein were elevated. In contrast, levels of alpha-d-glucose, lactic acid, N-acetyl glycoprotein, glutamine, beta-d-glucose, corticosterone, alanine, phenylacetylglycine, glycine, high-density lipoprotein, arachidonic acid, myo-inositol, allantoin, and taurine were decreased. Moreover, 12 metabolites in urine and nine metabolites in the liver were dysregulated after treatment. Pharmacological treatment also increased fecal levels of butyric acid, acetic acid, propionic acid, and isovaleric acid. Collectively, metabolite disturbances induced by depression were reversed by pharmacological treatment. Pharmacological medication reversed the reduction of brain neurotransmitters caused by depression, modulated disturbance of the tryptophan-kynurenine pathway and inflammatory activation, and alleviated abnormalities of amino acid metabolism, energy metabolism, lipid metabolism, and gut microbiota-derived metabolites.

Altered Fecal Metabolomics and Potential Biomarkers of Psoriatic Arthritis Differing From Rheumatoid Arthritis.

Psoriatic arthritis (PsA) is a chronic inflammatory joint disease, and the diagnosis is quite difficult due to the unavailability of reliable clinical markers. This study aimed to investigate the fecal metabolites in PsA by comparison with rheumatoid arthritis (RA), and to identify potential diagnostic biomarkers for PsA. The metabolic profiles of the fecal samples from 27 PsA and 29 RA patients and also 36 healthy controls (HCs) were performed on ultra-high-performance liquid chromatography coupled with hybrid triple quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS). And differentially altered metabolites were screened and assessed using multivariate analysis for exploring the potential biomarkers of PsA. The results showed that 154 fecal metabolites were significantly altered in PsA patients when compared with HCs, and 45 metabolites were different when compared with RA patients. A total of 14 common differential metabolites could be defined as candidate biomarkers. Furthermore, a support vector machines (SVM) model was performed to distinguish PsA from RA patients and HCs, and 5 fecal metabolites, namely, α/β-turmerone, glycerol 1-hexadecanoate, dihydrosphingosine, pantothenic acid and glutamine, were determined as biomarkers for PsA. Through the metabolic pathways analysis, we found that the abnormality of amino acid metabolism, bile acid metabolism and lipid metabolism might contribute to the occurrence and development of PsA. In summary, our research provided ideas for the early diagnosis and treatment of PsA by identifying fecal biomarkers and analyzing metabolic pathways.

Gallic Acid Alleviates Gut Dysfunction and Boosts Immune and Antioxidant Activities in Puppies Under Environmental Stress Based on Microbiome-Metabolomics Analysis.

Early-life exposure to environmental stress disrupts the gut barrier and leads to inflammatory responses and changes in gut microbiota composition. Gallic acid (GA), a natural plant polyphenol, has received significant interest for its antioxidant, anti-inflammatory, and antimicrobial properties that support the maintenance of intestinal health. To assess whether dietary supplementation of GA alleviates environmental stress, a total of 19 puppies were randomly allocated to the following three dietary treatments for 2 weeks: 1) basal diet (control (CON)); 2) basal diet + transportation (TS); and 3) basal diet with the addition of 500 mg/kg of GA + transportation (TS+GA). After a 1-week supplementation period, puppies in the TS and TS+GA groups were transported from a stressful environment to another livable location, and puppies in the CON group were then left in the stressful environment. Results indicated that GA markedly reduced the diarrhea rate in puppies throughout the trial period and caused a moderate decline of serum cortisol and HSP-70 levels after transportation. Also, GA alleviated the oxidative stress and inflammatory response caused by multiple environmental stressors. Meanwhile, puppies fed GA had a higher abundance of fecal Firmicutes and Lactobacillus and lower Proteobacteria, Escherichia–Shigella, and Clostridium_sensu_stricto_1 after transportation. As a result, the TS+GA group had the highest total short-chain fatty acids and acetic acid. Also, the fecal and serum metabolomics analyses revealed that GA markedly reversed the abnormalities of amino acid metabolism, lipid metabolism, carbohydrate metabolism, and nucleotide metabolism caused by stresses. Finally, Spearman’s correlation analysis was carried out to explore the comprehensive microbiota and metabolite relationships. Overall, dietary supplementation of GA alleviates oxidative stress and inflammatory response in stressed puppies by causing beneficial shifts on gut microbiota and metabolites that may support gut and host health.

Serum Metabolomic Analysis of Feline Mammary Carcinomas based on LC-MS and MRM Techniques.

IntroductionTo date, there have been no panoramic studies of the serum metabolome in feline mammary carcinoma. As the first such study, metabolomics techniques were used to analyse the serum of cats with these tumours. Three important metabolic pathways of screened differential metabolites closely related to feline mammary carcinomas were analysed to lay a theoretical basis for further study of the pathogenesis of these carcinomas.Material and MethodsBlood in a 5–8 mL volume was sampled from twelve cats of the same breed and similar age (close to nine years on average). Six were feline mammary carcinoma patients and six were healthy. L glutamate, L alanine, succinate, adenine, hypoxanthine, and inosine were screened as were alanine, aspartate, and glutamate metabolism, the tricarboxylid acid (TCA) cycle, and purine metabolism. Data were acquired with LC-MS non-target metabolomics, multiple reaction monitoring target metabolomics, and multivariate statistical and bioinformatic analysis.ResultsExpression of five of the metabolites was upregulated and only inosine expression was downregulated. Up- and downregulation of metabolites related to glycometabolism, potentiation of the TCA cycle, greater content of lipid mobilisation metabolites, and abnormality of amino acid metabolism were closely related to the occurrence of the carcinomas.ConclusionThese findings provide a new direction for further study of the mechanisms associated with cat mammary neoplasms.

Some Amino Acids Levels: Glutamine, Glutamate, and Homocysteine, in Plasma of Children with Chronic Kidney Disease

Background: The high prevalence of protein-energy malnutrition is a critical issue for patients with chronic kidney disease (CKD). Serum albumin is the most commonly used nutritional marker. Another index is plasma amino acid (AA) profile. Of these, the plasma levels of glutamine, glutamate and homocysteine, correlate well with nutritional status. We measured some plasma AAs in children with different stages CKD to provide information in monitoring the therapeutic strategy, particularly in AA supplementary therapy or protein restriction. Methods: Three amino acids were evaluated along with albumin and high sensitivity C-reactive protein (hs-CRP) in 30 patients with advanced CKD stages 4 and 5. They were divided into two groups undergoing conservative treatment (CT) (n=15) or hemodialysis (HD) (n=15). An additional group of patients with nephrotic syndrome [CKD stage 2] was also studied to assess the alterations of plasma free amino acids with the early stage of CKD. Another 30 age- and sex-matched healthy children served as controls. Results: A significant increase in plasma concentration of amino acid glutamine was observed in children with advanced CKD stages 4 and 5 when compared with controls (P=0.02).Plasma glutamine level was significantly higher in ESRD children on HD than in children with nephrotic syndrome (P=0.02). We did not find a significant difference between HD children and CT children as regard to glutamine level. Notable differences were in the plasma homocysteine level detected in the CKD groups patients, which was greater than that in controls (P=0.0001). Plasma homocysteine level was significantly higher in children on HD than in children with nephrotic syndrome (P=0.01).A significant differences was observed in hs-CRP levels between the CKD groups and the controls (P=0.04).Albumin levels were lower in CKD groups than in controls (p=0.01). Glutamine showed significant positive correlations with blood urea level (r=0.84, P=0.002) and blood ammonia level (r=0.72, P=0.0001). On multiple linear regression, urea was the only variable independently associated with an elevated plasma glutamine level (Beta=0.77, P=0.02). Conclusion: This study indicates that the advanced stages of CKD are associated with increased plasma concentrations of glutamine and homocysteine. Glutamine retained in the plasma of children with CRF, possibly producing higher levels of the waste products (urea and NH3). Dialysis alone is insufficient to redress completely the abnormalities in AA metabolism in ESRD children. Careful consideration of dialysis and dietary measures are necessary.

Metabonomic analysis of hepatitis E patients shows deregulated metabolic cycles and abnormalities in amino acid metabolism

Hepatitis E, which is endemic to resource-poor regions of the world, is largely an acute and self-limiting disease, but some patients have an increased susceptibility to develop fulminant hepatitis. The pathogenesis of hepatitis E in humans is poorly characterized. To understand the metabolic pathways involved in the pathophysiology of hepatitis E, we have used (1) H nuclear magnetic resonance spectroscopy to quantify various metabolites in the plasma and urine of the patients with hepatitis E. These were compared with specimens from patients with acute hepatitis B as disease controls and healthy volunteers. Data were analysed using chemometric statistical methods and metabolite databases. The main metabonomic changes found in patients with hepatitis E, but not in those with hepatitis B, included increased plasma levels of L-isoleucine, acetone, and glycerol, reduced plasma levels of glycine, and reduced urinary levels of imidazole, 3-aminoisobutanoic acid, 1-methylnicotinamide, biopterin, adenosine, 1-methylhistidine, and salicyluric acid. Patients with hepatitis E or B both showed increased levels of plasma and urinary L-proline and decreased levels of various other metabolites. Pathway analysis tools suggest the involvement of glycolysis, tricarboxylic acid cycle, urea cycle, and amino acid metabolism in patients with acute hepatitis E. These findings may help better understand the clinical and biochemical manifestations in this disease and the underlying pathophysiologic processes. Based on our findings, it would be worthwhile determining whether patients with hepatitis E are more prone to develop lactic acidosis and ketosis compared with other forms of viral hepatitis.

Abnormality of amino acid metabolism in the mutant-skunk of the silkworm, Bombyx mori

Abnormality of amino acid metabolism in the mutant-skunk of the silkworm, Bombyx mori

Comparative Metabolism and Structure of BCKD-E2 in Primary Biliary Cirrhosis

The identification and cloning of the mitochondrial autoantigens in primary biliary cirrhosis (PBC) have provided new clues in disease pathogenesis. The two major autoantigens are the E2 subunits of pyruvate dehydrogenase and branched-chain ketoacid dehydrogenase (BCKD). Interestingly, one of these complexes, BCKD-E2, is already well known to clinical medicine based on its association with genetic mutations in maple syrup urine disease (MSUD). Patients with this disease have an inability to metabolize branched-chain amino acids. In the present study, we have taken advantage of the known sequence of BCKD-E2 from normal humans, and addressed the issue of whether there is an altered autoantigen sequence in hepatocytes of individuals with primary biliary cirrhosis. In particular, we examined both the leader sequence and the B-cell immunodominant epitope, the lipoic acid domain. In addition, because patients with PBC have autoantibodies to the BCKD-E2 complex, we have quantitated plasma levels of alpha-ketoacids potentially affected in maple syrup urine disease. These include pyruvic acid (PY), phenylpyruvic acid (PP), alpha-ketoisocaproic acid (KIC) alpha-ketoisovalerate (KIV) and alpha-keto-beta-methylvaleric acid (KMV). The levels of these alpha-ketoacids were compared in patients with primary sclerosing cholangitis and normal volunteers. The sequence of BCKD-E2 obtained from PBC hepatocytes showed homology with normal BCKD. Further studies of autoantigen structure and sequence are clearly indicated, including those involved in mitochondrial transport and localization. Finally, we noted a statistically significant increase in all plasma alpha-ketoacids except alpha-keto-beta-methylvaleric acid in PBC patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Unusual biochemical development of genetically seizure-susceptible El mice

Looking for the ‘epilepsy gene’, we used ddY derived, genetically seizure-susceptible El mice. To find biochemical abnormalities, we examined the amino acid metabolism and gene activity, including poly(A) + RNA and sodium channel mRNA expressions, in the developmental growth of El mice. At the early postnatal stage, abnormalities in amino acid metabolism were aberrant free amino acid fluctuations. Almost all free amino acids in the liver of newborn El mice showed considerably lower levels than did ddY mice. Among those amino acids, Asp, Glu and Tyr were extremely low, but rapidly recovered to the ddY level within a week. During the successive growth period, we observed no significant difference in hepatic amino acid levels between El and ddY mice. No such drastic changes were noted in the amino acid levels in the brains of ddY and El mice; only the Gly level was greater in El mice than in ddY mice on the day of birth. Rotatory stimulation which evokes convulsions in El mice but not in ddY mice was applied to adult mice and changes in the amino acid level were assessed. The level of Glu and Tyr in seizure-induced El mice was approximately twice that noted in the liver and brain of El mice, which did not experience seizures. It was also somewhat increased in ddY mice subjected to rotational stress which did not induce seizures in that strain. Gene activity that expresses poly(A) + RNAs, including sodium channel mRNA, was determined by Northern blot analysis, which reveals unscheduled mRNA synthesis by the appearance of an extra band approximately 3 kb in size. This activity was demonstrated in the liver of El mice one day after birth, using a ‘Cot 100 DNA’ probe which represents a single-copy sequence DNA fraction. Northern blot analysis of the brain did not provide clear results because of hazy smear hybridization on several blot bands. Concerning the activity of the sodium channel gene, channel mRNA was always overexpressed in the brains of El mice: it was approximately 1.3–2 times higher in El mice of fetal stage through the 10th week of age than in ddY mice. Our studies showed that the abnormalities were present during the early growth stages, i.e. in neonate El mice, particularly in the liver and to a lesser extent in the brain. Metabolic imbalance during development would primarily affect neurotransmitter modulation and result in distortion of the biochemical architecture, including hypersusceptibility to excitation of the central nervous system by excess production of sodium channels. In other words, genetic predisposition to epilepsy may involve a gene-dependent alteration in the biochemical development of El mice.

Abnormalities in Amino Acid Metabolism in Clinical Medicine.

Abnormalities in Amino Acid Metabolism in Clinical Medicine.

Lifespan and protein synthesis in several Bombyx mori mutants with genetic abnormalities in amino acid and protein metabolism

Three kinds of “white eggs” and red-blooded Bombyx mutants (w 1, w 2, w 3 and rb) which lack enzymes in tryptophan metabolism showed almost no difference in their lifespans from that of normal stock. However, other Bombyx mutants, such as Nd, Nd-s and DES-Nd, unable to synthesize fibroin, had shorter lifespans than normal. Among these fibroin-deficient mutants, only the lifespan of DES-Nd was similar to the normal. However, further analysis of the amino acid composition in the cocoon of the mutant showed that its lifespan was also dependent on its ability to synthesize fibroin-like protein. It is very likely that, different from abnormalities in amino acid metabolism, a genetic abnormality in protein metabolism affects the maintenance of adult life in silkmoths and this results in the short lifespan. Generally speaking, an abnormality in amino acid metabolism seems to have no influence on silkmoth lifespan. However, an abnormality in protein metabolism results in shortening lifespan. The greater the abnormality in protein metabolism possessed by a silkmoth, the shorter the lifespan.

Fructose-1,6-diphosphatase deficiency: Another enzyme defect which can present itself with the clinical features of “tyrosinosis”

An infant with a picture of hereditary liver disease corresponding in many respects with so-called “tyrosinosis” is described. The primary defect appeared to be fructose-l,6-diphosphatase deficiency, which was not recognized during the patient's life. Many abnormalities of amino acid metabolism and transport occurred when the patient was on a diet containing saccharose. At that time tyrosyluria was excessive and serum tyrosine strongly elevated. Serum methionine was moderately increased, but a striking cystathioninuria was present and once even homocystine was traced in the urine. In the serum alanine was excessive, but also phenylalanine, lysine, proline, valine, threonine, leucine, serine and other amino acids were increased. There was a generalized amino aciduria and a massive lactic aciduria. Once even phenyllactic acid was found in the urine. When the diagnosis “tyrosinosis” is proposed, fructose-1,6-diphosphatase deficiency as a primary cause should also be kept in mind.

The effect of monosodium glutamate on the early biochemical and behavioral development of the rat.

AbstractSprague Dawley rats were given monosodium glutamate (MSG) (4 mg/g) on each of the first 10 days of life and subsequently tested in a swimming maze at 50 days. They appeared less able to learn the maze than littermate controls that had received only saline. Amino acid analyses performed on animals prepared identically but sacrificed on Day 10 showed increased levels of aspartic and glutamic acids, taurine, urea, and glutathione in the brain, liver, and blood of the MSG animals as compared to their controls. Tyrosine and histidine levels were consistently lower. These abnormalities of amino acid metabolism appear to be of sufficient magnitude to alter the structural development of the CNS. The behavioral changes observed suggest an enduring impairment of function.

Studies on Congenital Metabolic Abnormalities in Children with Mental Deficiency and Physically Handicapped Children, Especially Abnormalities of Amino Acid Metabolism

Pediatrics InternationalVolume 14, Issue 2 p. 37-38 Studies on Congenital Metabolic Abnormalities in Children with Mental Deficiency and Physically Handicapped Children, Especially Abnormalities of Amino Acid Metabolism Moyuru Suzuki, Moyuru Suzuki Department of Pediatrics, Tokyo Medical College (Director: Term Honda)Search for more papers by this author Moyuru Suzuki, Moyuru Suzuki Department of Pediatrics, Tokyo Medical College (Director: Term Honda)Search for more papers by this author First published: December 1972 https://doi.org/10.1111/j.1442-200X.1972.tb02902.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume14, Issue2December 1972Pages 37-38 RelatedInformation

PHENYLKETONURIA AND THE PHENYLALANINEMIAS OF INFANCY

In 1965 this Committee issued a statement outlining the responsibilities of the physician to the child with phenylketonuria, an inherited abnormality of amino acid metabolism. A lack of knowledge about the disorder and about the results of treatment placed constraints on the 1965 statement. The Committee therefore feels that, with recent advances in knowledge about the disorder, a new statement is needed. An increased level of phenylalanine in the blood can occur under sporadic and transient conditions in the absence of disease, with or without a concomitant elevation of serum tyrosine; it is always present in the disorder now called phenylketonuria. Because of incomplete information, simple classification of a specific case of phenylalaninemia is often not possible. Screening programs allow for the detection of infants with elevated blood levels of phenylalanine. Screening programs should be encouraged and supported because they are the best available means for identifying all infants with abnormalities of protein metabolism resulting in serum phenylalanine elevations. Two important, unresolved issues need clarification: (1) the effect of a persistently elevated blood level of phenylalanine on the intellectual growth of the child when there are no other indications of disease, and (2) the possibility of harmful effects of a diet low in phenylalanine. The basic treatment of phenylketonuria is to reduce circulating phenylalanine by dietary restriction; and, because a spectrum of disorders causes an elevation of that amino acid, differing approaches in management seem indicated. The relative rarity of phenylketonuria precludes the opportunity for individual physicians to gain widespread experience and expertise in management outside of a hospital specialty clinic setting.

Applications médicales et perspectives thérapeutiques déduites des connaissances en pathologie moléculaire

The rapid development of knowledge in the field of genetic metabolic blocks, of abnormalities of transport systems, of cellular receptors and of diseases of lysosomes has completely modified, in medical practice , the approach to many old problems. One must thus progressively set up a new organization in four main areas: o 1) The biochemical and enzymatic diagnosis of these diseases, and the study of new data. 2) The screening for these abnormalities during the neonatal period i.e. phenylketonuria, galactosemia and leucinosis. 3) Prenatal diagnosis, through early amniocentesis and examination of amniotic fluid. 4) Recognition of heterozygotes. All these measures converge to help genetic counseling, prevention and treatment of these diseases. One can hope that in the future, significant advances will be made in therapeutics, when the molecular basis of abnormalities of the genetic message are better understood and when corrections or substitution of this message become possible in the human species. A few examples will be developed concerning present therapeutical possibilities, which are not negligible. Replacement of an absent or abnormal macromolecule . This system has been applied with success to the treatment of hemophilia, afibrinogenemia and genetic abnormalities of the immunoglobulins; limited results have been obtained in the event of abnormal hemoglobins. Genetic metabolic blocks . They induce toxic effects above the block, and carential effects beneath it. Three types of direct treatment of these blocks are used. Replacement of the deficient enzymatic activity . This is seldom possible. Maltase can be given orally in genetic intolerance to saccharose or isomaltose. Stimulation of vitamin dependency . The dependence on vitamins of certain genetic blocks have been established for thiamine, pyridoxine, cholecalciferol and vitamin B 12. The problem of vitamin B 12 dependency and its therapeutical consequences will be discussed with respect to methylmalonic acidemia. Administration of the final product of a blocked metabolic chain . In two cases, brilliant results are obtained: administration of cortisol and or mineralocorticoids in genetic blocks of adrenal hormono-synthesis and of T3 or T4 or iodide in genetic abnormalities of synthesis of thyroid hormones. Suppression of a nutrient used at the top of a metabolic chain to prevent toxic effects, and eventually administration of a substitutive product below the block to prevent carential effects . Three examples will be discussed, with their results : genetic abnormalities of disaccharide hydrolysis, galactosemia and fructose intolerance, and some disorders of amino-acids metabolism (phenylketonuria, leucinosis and tyrosinosis). Aid to the urinary elimination of excess metabolites . This will be discussed with respect to genetic uricemia of Lesch-Nyhan and to Wilson's disease. Abnormalities of hydrolysis by lysosomes . No direct treatment of these abnormalities exist at the present time. Some trials have been made in cystinosis, which probably belongs to this type of disease. Long term results of sulfur-poor diets and of penicillamine have been been nil in our experience. Abnormalities of transport systems . The molecular bases of the abnormalities are still obscure. However, some have benefited from effective treatment, for instance: exclusion diets in abnormalities of intestinal transfert of hexoses subject to an active transportmechanism (glucose and galactose); partial exclusion diet and penicillamine in disorders of intestinal and renal transfer of dibasic aminoacids (cystinuria); administration of sodium and potassium bicarbonate in abnormalities of H + ion elimination by the distal renal tubule. Abnormalities of cellular receptor systems . Here also, the molecular basis of these abnormalities are not sufficiently clear. However, a few therapeutical measures are effective: sodium supplements when the renal tubule is insensitive to the action of aldosterone, administration of calcium and 25-OH cholecalciferol in the syndrome of tubular insensitivity to parathormone, and finally chlorothiazide derivatives, which lower free water clearance and partially simulate the action of vasopressin, in the syndrome of tubular insensitivity to this hormone. Indirect and complementary therapeutical measures . Finally, a certain number of indirect therapeutical measures have been developed, which have no logical relationship to the metabolic disorder but act on their long-term consequences. Thus, though much is known at present concerning many types of neonatal acidosis linked to genetic abnormalities of aminoacid metabolism, good therapeutical results are obtained by simply giving the children glucose and sodium bicarbonate. Peritoneal dialysis is an effective and rapid means of ridding the organism of toxic metabolites, for instance in leucinosis. Finally, renal transplantations have sometimes met with success when the metabolic disorder principally affects the kidney as in cystinosis, oxalosis and distal tubular acidosis.