Module : Clinical correlates of disorders of metabolism Block 3, Week 2

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1 Module : Clinical correlates of disorders of metabolism Block 3, Week 2 Department of Paediatrics and Child Health University of Pretoria Tutor : Prof DF Wittenberg : dwittenb@medic.up.ac.za Aim of this module: At the end of this module, the student will be able to: Understand and discuss the relevance of protein biochemistry to clinical disease Describe the clinical circumstances which require investigation of possible metabolic disorder Differentiate between acquired and congenital metabolic disorders List and group the main symptoms and signs of inherited metabolic disease in children Key Case This 3 year old girl is brought to the hospital in a critically ill state which has developed over the course of one day. The day before, she had eaten a lot of nuts at a party, but had otherwise been well. Her mother states that this sickness is very similar to a previous episode 9 months ago, when she had to be admitted to hospital for several days on an intravenous drip. On both occasions, the sickness started suddenly with very severe vomiting but no diarrhoea. This got progressively worse until she was dehydrated, had deep abnormal breathing with an acetone-like smell and was barely conscious. As a baby, she had also had very frequent vomiting and she has never grown normally. Her physical development is much slower than that of her older brother at equivalent ages. A previous sibling had died in infancy of an unknown cause. On examination, she weighs only 8.5 Kg (average weight for 1 year of age = 10 kg). She is severely ill with deep sighing respirations. She has a decreased level of consciousness but is very irritable. Her deep tendon reflexes are very brisk. She is not jaundiced, and liver and spleen are not enlarged. Biochemical tests show the following results: ph 7.07, pco mm Hg, HCO mmol/l Blood glucose 1.1 mmol/l Blood lactate 13.9 mmol/l (N <0.5) Serum ammonia 263 mol/l (N < 50) Urea/electrolytes : normal Urine ketones 4+ Task: Work out the answers to the following questions What evidence is there on the history that this is not an usual kind of illness? Is there any information which could help explain why this disease has developed now? What should we make of the fact that the child is not growing and developing well? Do the blood tests help us to know which organs or metabolic processes are abnormal in this child? Can the biochemistry knowledge gained in this week help solve the problem? Diseases resulting from inborn errors of metabolism Normal biochemical and metabolic processes are regulated and mediated by enzymes. Each enzyme is under control of a gene. Therefore there are very many possible genetic defects in normal biochemical processes. Each biochemical error can lead to abnormal metabolic reaction; not all disturb homeostasis

2 Abnormal biochemistry can result in and explain clinical symptoms and signs Integrated metabolic pathways result in shared clinical features of different disorders Clustering and patterns of symptoms and signs permit recognition of specific groups of conditions, but the final diagnosis of inborn metabolic disease is made by the laboratory rather than on clinical grounds. The clinician needs to recognize the pointers to possible inherited metabolic disease and then involve the laboratory. The differentiation between an acquired and an inherited disorder of metabolism or biochemical homeostasis requires clinical diagnosis. Tests of biochemical homeostasis The body s homeostasis may be disturbed by a large number of conditions and circumstances including acute systemic illness, organ system dysfunction and also inherited metabolic disease. The following tests are routinely obtained: Blood glucose control Liver metabolic function Synthesis of proteins Conjugation and detoxification Excretion of bile Kidney metabolic function Excretion of waste products Acid Base Balance Electrolyte balance Lung metabolic function Blood gases Acid base balance Anion gap Presence of additional/exogenous acids Keto-acids Lactic acid Organic acid Exogenous eg salicylic acid Other (eg uraemia) The presence of a metabolic disturbance does not yet indicate that this must be an inherited metabolic disease. Almost all severe acute systemic disease is associated with disturbance of metabolic homeostasis. Indeed, the treatment of metaolic disturbances may be a very important component of the management of systemic illnesses. Examples of systemic illnesses and their metabolic derangement are given below: Gastrointestinal tract: In gastroenteritis, large fluid end electrolyte losses result in dehydration, metabolic acidosis, hyper- or hyponatraemia or hypokalaemia. If fluid losses are bad enough, circulatory failure leads to tissue hypoxaemia, anaerobic metabolism and lactic acidosis. Failure to maintain food intake can lead to

3 depletion of glycogen stores, ketosis and hypoglycaemia; alternatively the severe stress response of dehydration may be accompanied by short-term hyperglycaemia. Renal disease: Failure to maintain glomerular filtration and urine output results in retention of urea, creatinine, hydrogen ion and phosphate. Damage to the renal tubule is associated with disturbances of potassium, hydrogen ion, calcium/phosphate, sodium and osmotic balance. Glomerular leakage of albumen leads to hypoalbuminaemia and osmotic consequences. Liver disease: In severe liver disease, the important processes of intermediary metabolism are disturbed. The maintenance of blood glucose during fasting is a liver function under control of a number of endocrine influences. The detoxification and conjugation function manifests itself strongly in the liver s ability to remove ammonia and other neurotoxic metabolites; hyperammonaemia is one consequence of disease. Other metabolic consequences of liver failure include derangement of electrolyte balance, an abnormal anion gap, retention of bilirubin and failure to synthesize important plasma proteins and clotting factors. Lung disease : In severe lung disease, there is failure to maintain oxygenation and removal of carbon dioxide. This alters the blood gas and acid base balance. Severe metabolic disorders can thus be the consequence of acquired systemic diseases, but it is also possible that an inherited error of metabolism initiates the disturbance and results in the disease. Accordingly, clinicians need pointers to the possibility that a metabolic disturbance is caused by an inherited defect rather than an acquired illness such as an infection, which must be treated in its own right in addition to giving attention to the metabolic disturbance. Inborn errors are characterised by the following: Recurrent/persistent symptoms. A careful history shows that the patient is not completely well even between the apparent episodes. Family history. This may obviously not always be present especially in the case of first affected children within a family, but when present, it must be taken seriously. Progressive deterioration. This applies particularly to brain function and developmental progress. Suspicious association of symptoms and biochemical features. Modes of presentation of inborn errors of metabolism 1. Abnormal phenotype (outward appearance eg dysmorphic appearance, malformations, deformities, abnormal skin colour or abnormal smell) together with biochemical disturbance 2. Acute metabolic crisis : neonatal or later onset, progressive or recurrent

4 3. Storage disorders : Enlargement of organs (eg liver, kidneys, heart etc) together with biochemical disorder and with or without evidence of specific organ dysfunction It is useful to categorise these according to the age at presentation. Newborn age period Acute metabolic crisis mimics sepsis and includes unexplained hypoglycaemia, acidosis, electrolyte disturbance, jaundice. If this occurs suddenly in a previously normal infant, must consider inherited metabolic disease especially if infection or other aetiological cause cannot be found. Later onset Predominantly liver symptoms: Recurrent vomiting, hepatomegaly, jaundice, failure to thrive Predominantly neurological symptoms: Developmental delay, floppiness, progressive retardation, seizures Abnormal odour and pigmentation Specific organ abnormalities : enlargement, dysfunction A useful explanation of the clinical features of metabolic disease is provided by the following scheme: Substrate 1 Metabolic Block Usual metabolic pathway Product 2 Alternative Pathway Minor/ alternative Product 3 Explanation: The usual reaction cannot take place because of a missing or abnormal enzyme. Clinical disease may develop because of the following consequences to a metabolic block: 1 Substrate and precursor accumulation: This can occur inside cells (storage disorders) or in the blood (eg galactosaemia). The abnormally accumulated precursor can appear in the urine (eg phenylketonuria)

5 2 Product deficit : In the case of galactosaemia, the product of the reaction galactose conversion to glucose is glucose: the deficit manifests by hypoglycaemia. 3 Utilization of minor or alternative pathways with abnormal product accumulation. A good example of this is found in the adrenogenital syndrome due to 21-Hydroxylase deficiency. Here, a block in the cortisol biosynthetic pathway leads to accumulation and diversion into the production of androgenic precursors which cause virilization of a female fetus in utero. Case analysis: Acute onset of symptoms after apparent normality, but she has had this before = recurrent. Vomiting without diarrhoea leading to dehydration, ketosis and near-coma. Possibility that symptoms precipitated by the nuts? (Absence of other explanation) Failure to thrive and not developing normally = chronic underlying condition. Previous sibling death = possibility of genetic inherited condition Metabolic derangement: hypoglycaemia, metabolic acidosis, lactic acidosis, ketosis, hyperammonaemia = disorder affecting liver metabolic function Investigation In view of severe acidosis and large anion gap, an organic acid was suspected. The branched chain amino acids valine, leucine, isoleucine are converted to organic acids; defects in their metabolism is commonly associated with hyperammonaemia. Defects of the urea cycle do not usually lead to acidosis. Investigation resulted in the diagnosis of Propionic acidaemia being made. Conclusion There are many hundreds of inherited metabolic disorders. The diagnosis must be made by a laboratory receiving the correct samples for analysis with an appropriate description of the circumstances pertaining at the time of sample collection. It is the clinician s duty to recognize the circumstances which call for the performance of laboratory tests to investigate inherited metabolic disease.