Inborn errors of metabolism are a growing group of monogenic hereditary diseases whose pathogenesis may be accounted
for by biochemical disorders. The great majority of these diseases may occur as a metabolic crisis at any period of life. For
their adequate treatment, fast recognition of the cause of the metabolic disorder is necessary, as well as good collaboration
of all health professionals involved in immediate patient healthcare. On the path to final diagnosis, it is advisable to consult
specialised centres in order to select appropriate diagnostic tests and procedures

KARMEN BILIĆ

KSENIJA FUMIĆ

HRČAK - Portal of Croatian Scientific and Professional Journals

70 www.signavitae.comLaboratory diagnostics of emergency conditions associated with inborn errors of metabolismABSTRACTInborn errors of metabolism are a growing group of monogenic hereditary diseases whose pathogenesis may be accounted for by biochemical disorders. The great majority of these diseases may occur as a metabolic crisis at any period of life. For their adequate treatment, fast recognition of the cause of the metabolic disorder is necessary, as well as good collaboration of all health professionals involved in immediate patient healthcare. On the path to final diagnosis, it is advisable to consult specialised centres in order to select appropriate diagnostic tests and procedures.  KSENIJA FUMIĆ(  )Department of Laboratory Diagnostics University Hospital Centre ZagrebKišpatićeva 12, 10000 Zagreb, CroatiaPhone: +385914629921Fax: +3852367395Email: kfumic@kbc-zagreb.hrKARMEN BILIĆDepartment of Medical Biochemistry and Haematology, Faculty of Pharmacy and Biochemistry, University of Zagreb Zagreb, CroatiaKSENIJA FUMIĆ • KARMEN BILIĆ    SIGNA VITAE 2014; 9 (Suppl 1): 70 - 72Key words: inborn errors of meta-bolism, metabolic crises, laboratory testsIntroductionInborn errors of metabolism (IEMs) are a consequence of biochemical altera-tions originating in genes that result in the alteration of a protein. As the possi-bility of mutations is extremely high, a variety of changes at the biochemical level is understandable, as well as a high variability of clinical data.  Taken individually, IEMs are highly infrequent but, taken as a whole, IEMs (of which over 550 have been described to date) can affect 1/500 newborn babies. The field of inborn errors of metabolism has been developing very fast over the past few years. New diseases have been detected, new diagnostic tests developed and novel treatment opportunities have been found. (1) Although IEMs have usually been con-sidered as paediatric diseases, the fact that they can be present at any age represents a special challenge in general and paediatric practice. They are frequently characterised by acute, life-threatening crises that require an immediate and specific intervention. The development and prognosis of affected patients may depend on rapid and effective treatment, but the large number of genetic defects in various metabolic pathways makes it difficult to be familiar with all diagnostic strate-gies and specific therapies. (2)The diagnostic approach The fact that treatment is becoming available for an ever-increasing number of disorders from this group of diseases imposes the need for their early clinical recognition and for adequate labora-tory diagnostics. Given their individual infrequency, most physicians and labo-ratory professionals have limited expe-rience in dealing with these diseases, so that their collaboration is of utmost importance. IEMs that occur with increased frequen-cy in certain populations and are curable (but cannot be clinically recognised at an early stage), are included in newborn screening programmes (e.g. phenyl-ketonuria, congenital hypothyroidism, leucinosis, homocystinuria, fatty acid beta-oxidation disorders, etc.). The tech-nology of tandem mass spectrometry currently enables the diagnosis of more than 50 inherited metabolic diseases as early as in the newborn period (dried blood spot). Regrettably, most of these diseases are not treatable at present; and since diseases in the pre-sympto-matic phase are also being detected, such an approach to diagnostics opens a number of ethical doubts that each community must solve. (3) Another approach to the diagnostics of these rare diseases implies the labora-tory management of symptomatic pati-ents (so-called selective screening). The majority of diseases are detected in this process in the manner that the possibi-lity of an inherited metabolic disorder is suspected on the basis of typical data from the patient’s medical history, sta-tus and basic laboratory test results. Subsequently, certain specific metabolic analyses are performed in suspected patients in order to confirm/reject the suspicion as soon as possible. Metabolic crisesThe clinical symptoms of the most  71www.signavitae.comimportant metabolic diseases can be classified according to their pathop-hysiological background as being of “intoxication type, energy deficiency type, diseases due to limited intole-rance of starvation, neurotransmission disorders, and other acute metabolic disorders”. A large number of these diseases manifest themselves with suddenly occurring life-threatening conditions, or so-called metabolic cri-ses. Metabolic crises frequently occur as early as in the first days of life and may also be explained as newborn sepsis. Circumstances that can pro-voke acute metabolic attacks include prolonged starvation, stressful situa-tions, fever, intercurrent illness, and these may even manifest for the first time at an adult age. (4) In order to provide urgent and adequate treatment of patients with a metabolic crisis, inborn errors of metabolism sho-uld be suspected and assessed (based on metabolic test results) in order to be classified among one of the above-mentioned groups of disorders.  Disorders that give rise to intoxication lead to an acute or progressive intoxi-cation from the accumulation of toxic compounds proximal to the metabolic block. This group consists of IEMs of amino acid catabolism (leucino-sys, tyrosinemia, etc.), most organic acidurias (methylmalonic, propionic, isovaleric, etc.), congenital urea cycle defects, glucose intolerances (galac-tosemia, hereditary fructose intole-rance), metal intoxication and porp-hyrias. All the conditions in this group are characterised by a symptom-free interval and clinical signs of “intoxica-tion”, which may be acute (vomiting, coma, liver failure, thromboembolic complications, etc.) or chronic (fai-lure to thrive, developmental delay, ectopia lentis, cardiomyopathy, etc.). Most of these disorders are treatable and require the emergency removal of the toxin by special diets, extra-corporeal procedures or “cleansing” drugs (carnitine, sodium benzoate, penicillamine, etc.).Disorders involving energy metabolism comprise IEMs with symptoms due at least partly to a deficiency in energy production or utilisation within the liver, myocardium, muscle, brain or other tissues. They encompass congenital lactic acidemias (defects of the pyru-vate transporter, pyruvate carboxylase, pyruvate dehydrogenase and the Krebs cycle), mitochondrial respiratory chain disorders, fatty acid oxidation and keto-ne body defects, disorders of glycolysis and glycogen metabolism. Common symptoms in this group include hypo-glycemia, hyperlactatemia, hepatome-galy, severe generalised hypotonia, myopathy, cardiomyopathy, failure to thrive, cardiac failure, circulatory collap-se, sudden unexpected death in infan-cy and brain involvement. Diseases caused by starvation into-lerance (hepatic glycogenoses, glu-coneogenesis disorders, some fatty acid beta-oxidation disorders, disor-ders of carnitine cycle, ketogenesis and ketolysis) are characterised by hypogl-ycemia after relatively brief starvation. The period of starvation necessary for symptoms to manifest varies depen-ding on disease and a number of other factors.   Although pathophysiology is somew-hat different from the inborn errors of neurotransmitter synthesis and catabo-lism (monoamines, GABA and glycine), the inborn errors of amino acid synt-hesis (serine, glutamine) can also be included in this group. These disorders manifest themselves as acute encep-halopathy with epilepsy, with treatable convulsions. (5)Emergency laboratory tests in an acute metabolic crisis After clinically suspecting an IEM, samples for laboratory tests should be urgently collected, if possible during the metabolic crisis. Efforts should be made to perform sampling prior to infusion (of glucose, carnitine, etc.) because such samples provide the most information since they are often the only source of diagnostically significant metabolites.   In addition to basic laboratory tests (blood count, C-reactive protein, elec-trolytes, aminotransferases, creatine kinase, urea, creatinine, urates, basic coagulation tests), basic metabolic tests should also be carried out  (acid-base status, glucose, ammonium, lac-tate and methyketones). The results of these tests may indicate the presence of a metabolic disorder to a physician, yet they do not reveal the cause of the disorder. For a clinician, it is of utmost importance to receive the results of these tests as urgently as possible (wit-hin 60 minutes) in order to manage the patient before the basic cause of meta-bolic crisis is detected. (6,7) The above-mentioned tests are part of the laboratory test panel of all general hospitals. A further step in the search for the cause of the metabolic crisis is the interpretati-on of results of specific metabolic tests, i.e. amino acid concentration in pla-sma and/or cerebrospinal fluid, organic acids in urine, total and free carnitine in plasma and acyl-carnitine profile from a dried blood spot on filter paper and/or plasma.These specific metabolic tests are ava-ilable only in laboratories dealing with diagnostics of inborn errors of meta-bolism because specific equipment is needed for their implementation, as well as adequately educated medical biochemistry specialists. In a large number of cases, it is also necessary to perform a whole series of other spe-cific tests on the pathway to a final diagnosis (e. g. biotinidase, galactose, homocysteine, creatine, neurotransmi-tters, free fatty acids, glutation, porp-hyrins, pyrimidines, etc.). Methods to perform these tests are often available only in specialist diagnostic centres. These tests should therefore be uti-lised economically after performing basic metabolic analyses, considering clinical data and providing specialist patient management. Due to a num-ber of specificities that accompany the carrying out of most confirmation tests, it is advisable to consult spe-cialist centres in order to additionally ensure correct sampling, storage and transport of adequate samples. It is important to mention that in cases when a patient cannot be cured, every 72 www.signavitae.comeffort should be made to collect and adequately store samples of plasma, urine and EDTA whole blood for DNA isolation, as well as to perform biopsy of the skin and, when necessary, other tissues. Only such an approach may enable the establishment of a post-mortem diagnosis and provide other members of the family of a patient diagnosed with IEM with this informa-tion. (8)ConclusionHowever, although they are being incre-asingly recognised, IEM remain rare. They should be considered in parallel with other more common conditions and it should be remembered that an IEM can be present at any age. Satis-factory care for acutely compromised IEM patients is only possible through teamwork that involves personnel in emergency admission wards, laborato-ries and centres specialised for IEM. In this regard, algorithms for procedures in certain situations that are prepared in advance may be of substantial aid.  REFERENCES1. Scriver CR, Beaudet AL, Sly WS, Valle D. The metabolic and molecular basis of inherited diseases. 8th ed.New York:McGraw-Hill, 2001.2. Blau N, Duran M, Blaskovics M, Gibson M. Physician´s guide to the laboratory diagnosis of metabolic diseases. Springer-Verlag, Berlin, 2003.3. Wilcken B. The consequences of extended newborn screening programmes: Do we know who needs treatment? J Inherit Metab Dis 2008;31:173-177.4. Fernandes J, Saudubray JM, van den Berghe G. Inborn metabolic diseases. Diagnosis and treatment. 2 ed. Springer Verlag, Berlin, 2003.5. Prietsch V, Lindner M, Zschocke J, Nyhan WL, Hoffmann GF. Emergency management of inherited metabolic diseases. J Inherit Metab Dis 2002;25:531-46.6. Barić I, Maradin M, Fumić K. Rational diagnostics of inherited metabolic diseases. Paediatr Croat 2004;48(suppl 1):155-159.7. Barić I, Ćuk M, Maradin M, Fumić K. Basic metabolic tests:indication and evaluation. Paediatr Croat 2004;48(suppl 1):89-93.8. Fumić K, Maradin M, Granić P. Selective laboratory screening for hereditary metabolic errors. Paediatr Croat 1997;41(suppl 1):113-117.

English

Laboratory diagnostics of emergency conditions associated with inborn errors of metabolism

Hrčak - Portal of scientific journals of Croatia

70 www.signavitae.comLaboratory diagnostics of emergency conditions associated with inborn errors of metabolismABSTRACTInborn errors of metabolism are a growing group of monogenic hereditary diseases whose pathogenesis may be accounted for by biochemical disorders. The great majority of these diseases may occur as a metabolic crisis at any period of life. For their adequate treatment, fast recognition of the cause of the metabolic disorder is necessary, as well as good collaboration of all health professionals involved in immediate patient healthcare. On the path to final diagnosis, it is advisable to consult specialised centres in order to select appropriate diagnostic tests and procedures.  KSENIJA FUMIĆ( ? )Department of Laboratory Diagnostics University Hospital Centre ZagrebKišpatićeva 12, 10000 Zagreb, CroatiaPhone: +385914629921Fax: +3852367395Email: kfumic@kbc-zagreb.hrKARMEN BILIĆDepartment of Medical Biochemistry and Haematology, Faculty of Pharmacy and Biochemistry, University of Zagreb Zagreb, CroatiaKSENIJA FUMIĆ • KARMEN BILIĆ    SIGNA VITAE 2014; 9 (Suppl 1): 70 - 72Key words: inborn errors of meta-bolism, metabolic crises, laboratory testsIntroductionInborn errors of metabolism (IEMs) are a consequence of biochemical altera-tions originating in genes that result in the alteration of a protein. As the possi-bility of mutations is extremely high, a variety of changes at the biochemical level is understandable, as well as a high variability of clinical data.  Taken individually, IEMs are highly infrequent but, taken as a whole, IEMs (of which over 550 have been described to date) can affect 1/500 newborn babies. The field of inborn errors of metabolism has been developing very fast over the past few years. New diseases have been detected, new diagnostic tests developed and novel treatment opportunities have been found. (1) Although IEMs have usually been con-sidered as paediatric diseases, the fact that they can be present at any age represents a special challenge in general and paediatric practice. They are frequently characterised by acute, life-threatening crises that require an immediate and specific intervention. The development and prognosis of affected patients may depend on rapid and effective treatment, but the large number of genetic defects in various metabolic pathways makes it difficult to be familiar with all diagnostic strate-gies and specific therapies. (2)The diagnostic approach The fact that treatment is becoming available for an ever-increasing number of disorders from this group of diseases imposes the need for their early clinical recognition and for adequate labora-tory diagnostics. Given their individual infrequency, most physicians and labo-ratory professionals have limited expe-rience in dealing with these diseases, so that their collaboration is of utmost importance. IEMs that occur with increased frequen-cy in certain populations and are curable (but cannot be clinically recognised at an early stage), are included in newborn screening programmes (e.g. phenyl-ketonuria, congenital hypothyroidism, leucinosis, homocystinuria, fatty acid beta-oxidation disorders, etc.). The tech-nology of tandem mass spectrometry currently enables the diagnosis of more than 50 inherited metabolic diseases as early as in the newborn period (dried blood spot). Regrettably, most of these diseases are not treatable at present; and since diseases in the pre-sympto-matic phase are also being detected, such an approach to diagnostics opens a number of ethical doubts that each community must solve. (3) Another approach to the diagnostics of these rare diseases implies the labora-tory management of symptomatic pati-ents (so-called selective screening). The majority of diseases are detected in this process in the manner that the possibi-lity of an inherited metabolic disorder is suspected on the basis of typical data from the patient’s medical history, sta-tus and basic laboratory test results. Subsequently, certain specific metabolic analyses are performed in suspected patients in order to confirm/reject the suspicion as soon as possible. Metabolic crisesThe clinical symptoms of the most  71www.signavitae.comimportant metabolic diseases can be classified according to their pathop-hysiological background as being of “intoxication type, energy deficiency type, diseases due to limited intole-rance of starvation, neurotransmission disorders, and other acute metabolic disorders”. A large number of these diseases manifest themselves with suddenly occurring life-threatening conditions, or so-called metabolic cri-ses. Metabolic crises frequently occur as early as in the first days of life and may also be explained as newborn sepsis. Circumstances that can pro-voke acute metabolic attacks include prolonged starvation, stressful situa-tions, fever, intercurrent illness, and these may even manifest for the first time at an adult age. (4) In order to provide urgent and adequate treatment of patients with a metabolic crisis, inborn errors of metabolism sho-uld be suspected and assessed (based on metabolic test results) in order to be classified among one of the above-mentioned groups of disorders.  Disorders that give rise to intoxication lead to an acute or progressive intoxi-cation from the accumulation of toxic compounds proximal to the metabolic block. This group consists of IEMs of amino acid catabolism (leucino-sys, tyrosinemia, etc.), most organic acidurias (methylmalonic, propionic, isovaleric, etc.), congenital urea cycle defects, glucose intolerances (galac-tosemia, hereditary fructose intole-rance), metal intoxication and porp-hyrias. All the conditions in this group are characterised by a symptom-free interval and clinical signs of “intoxica-tion”, which may be acute (vomiting, coma, liver failure, thromboembolic complications, etc.) or chronic (fai-lure to thrive, developmental delay, ectopia lentis, cardiomyopathy, etc.). Most of these disorders are treatable and require the emergency removal of the toxin by special diets, extra-corporeal procedures or “cleansing” drugs (carnitine, sodium benzoate, penicillamine, etc.).Disorders involving energy metabolism comprise IEMs with symptoms due at least partly to a deficiency in energy production or utilisation within the liver, myocardium, muscle, brain or other tissues. They encompass congenital lactic acidemias (defects of the pyru-vate transporter, pyruvate carboxylase, pyruvate dehydrogenase and the Krebs cycle), mitochondrial respiratory chain disorders, fatty acid oxidation and keto-ne body defects, disorders of glycolysis and glycogen metabolism. Common symptoms in this group include hypo-glycemia, hyperlactatemia, hepatome-galy, severe generalised hypotonia, myopathy, cardiomyopathy, failure to thrive, cardiac failure, circulatory collap-se, sudden unexpected death in infan-cy and brain involvement. Diseases caused by starvation into-lerance (hepatic glycogenoses, glu-coneogenesis disorders, some fatty acid beta-oxidation disorders, disor-ders of carnitine cycle, ketogenesis and ketolysis) are characterised by hypogl-ycemia after relatively brief starvation. The period of starvation necessary for symptoms to manifest varies depen-ding on disease and a number of other factors.   Although pathophysiology is somew-hat different from the inborn errors of neurotransmitter synthesis and catabo-lism (monoamines, GABA and glycine), the inborn errors of amino acid synt-hesis (serine, glutamine) can also be included in this group. These disorders manifest themselves as acute encep-halopathy with epilepsy, with treatable convulsions. (5)Emergency laboratory tests in an acute metabolic crisis After clinically suspecting an IEM, samples for laboratory tests should be urgently collected, if possible during the metabolic crisis. Efforts should be made to perform sampling prior to infusion (of glucose, carnitine, etc.) because such samples provide the most information since they are often the only source of diagnostically significant metabolites.   In addition to basic laboratory tests (blood count, C-reactive protein, elec-trolytes, aminotransferases, creatine kinase, urea, creatinine, urates, basic coagulation tests), basic metabolic tests should also be carried out  (acid-base status, glucose, ammonium, lac-tate and methyketones). The results of these tests may indicate the presence of a metabolic disorder to a physician, yet they do not reveal the cause of the disorder. For a clinician, it is of utmost importance to receive the results of these tests as urgently as possible (wit-hin 60 minutes) in order to manage the patient before the basic cause of meta-bolic crisis is detected. (6,7) The above-mentioned tests are part of the laboratory test panel of all general hospitals. A further step in the search for the cause of the metabolic crisis is the interpretati-on of results of specific metabolic tests, i.e. amino acid concentration in pla-sma and/or cerebrospinal fluid, organic acids in urine, total and free carnitine in plasma and acyl-carnitine profile from a dried blood spot on filter paper and/or plasma.These specific metabolic tests are ava-ilable only in laboratories dealing with diagnostics of inborn errors of meta-bolism because specific equipment is needed for their implementation, as well as adequately educated medical biochemistry specialists. In a large number of cases, it is also necessary to perform a whole series of other spe-cific tests on the pathway to a final diagnosis (e. g. biotinidase, galactose, homocysteine, creatine, neurotransmi-tters, free fatty acids, glutation, porp-hyrins, pyrimidines, etc.). Methods to perform these tests are often available only in specialist diagnostic centres. These tests should therefore be uti-lised economically after performing basic metabolic analyses, considering clinical data and providing specialist patient management. Due to a num-ber of specificities that accompany the carrying out of most confirmation tests, it is advisable to consult spe-cialist centres in order to additionally ensure correct sampling, storage and transport of adequate samples. It is important to mention that in cases when a patient cannot be cured, every 72 www.signavitae.comeffort should be made to collect and adequately store samples of plasma, urine and EDTA whole blood for DNA isolation, as well as to perform biopsy of the skin and, when necessary, other tissues. Only such an approach may enable the establishment of a post-mortem diagnosis and provide other members of the family of a patient diagnosed with IEM with this informa-tion. (8)ConclusionHowever, although they are being incre-asingly recognised, IEM remain rare. They should be considered in parallel with other more common conditions and it should be remembered that an IEM can be present at any age. Satis-factory care for acutely compromised IEM patients is only possible through teamwork that involves personnel in emergency admission wards, laborato-ries and centres specialised for IEM. In this regard, algorithms for procedures in certain situations that are prepared in advance may be of substantial aid.  REFERENCES1. Scriver CR, Beaudet AL, Sly WS, Valle D. The metabolic and molecular basis of inherited diseases. 8th ed.New York:McGraw-Hill, 2001.2. Blau N, Duran M, Blaskovics M, Gibson M. Physician´s guide to the laboratory diagnosis of metabolic diseases. Springer-Verlag, Berlin, 2003.3. Wilcken B. The consequences of extended newborn screening programmes: Do we know who needs treatment? J Inherit Metab Dis 2008;31:173-177.4. Fernandes J, Saudubray JM, van den Berghe G. Inborn metabolic diseases. Diagnosis and treatment. 2 ed. Springer Verlag, Berlin, 2003.5. Prietsch V, Lindner M, Zschocke J, Nyhan WL, Hoffmann GF. Emergency management of inherited metabolic diseases. J Inherit Metab Dis 2002;25:531-46.6. Barić I, Maradin M, Fumić K. Rational diagnostics of inherited metabolic diseases. Paediatr Croat 2004;48(suppl 1):155-159.7. Barić I, Ćuk M, Maradin M, Fumić K. Basic metabolic tests:indication and evaluation. Paediatr Croat 2004;48(suppl 1):89-93.8. Fumić K, Maradin M, Granić P. Selective laboratory screening for hereditary metabolic errors. Paediatr Croat 1997;41(suppl 1):113-117.

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