Metabolic diseases. Metabolism

Transcription

1 Metabolic diseases dr hab. n. med. Sylwia Kołtan Metabolism all biochemical processes and pathways in the body enzymes play a key role in many of these processes; changes in their function, as a result, of genetic mutation can lead to problems in metabolism important role coenzymes and cofactors 1

2 Coenzymes coenzymes are organic molecules that are required by certain enzymes to carry out catalysis they bind to the active site of the enzyme and participate in catalysis but are not considered substrates of the reaction coenzymes often function as intermediate carriers of electrons, specific atoms or functional groups that are transfered in the overall reaction Cofactors inorganic substances that are required for, or increase the rate of, catalysis 2

3 Metabolic diseases - definition any of the diseases or disorders that disrupt normal metabolism etiology: can be inherited, in which case they are also known as inborn errors of metabolism, or they may be acquired during lifetime affect many systems of the body, some of them will only dietary restrictions, other - significantly reduce psychomotor performance, and even lead to death Inborn metabolic diseases individual inborn or congenital errors are very rare but: more than 1400 inherited metabolic diseases have been described many of these disorders are potentially treatable via diet and/or drug therapy it is essentiale a rapid accurate diagnosis and adequate treatment 3

4 Inborn metabolic diseases pathophysiological diagnostics group Disorders that disrupt the synthseis or catabolism of complex molecules with symptomes that are permanent, progressive, independent of intercurrent events and not related to food intake; these include lysosomal disorders, peroxisomal disorders and disorders of intracellular transprt and processing Disorders that lead to an acute or progressive accumulation of toxic compounds as a result of metabolic block; these include disorders of amino acid metabolism (phenylketonuria, homocystynuria, maple syrup urine disease), organic acidurias, congenital urea cycle defects and sugar intolerances (galactosemia) Disorders with symptomes due to a deficiency of energy production or utilisation within the liver, myocardium, muscle or brain; these include congenital lactic acidemias, fatty acid oxydation defects, gluconeogenesis defects and mitochondrial respiratory chain disorders Inborn metabolic diseases (IMD) incidence and prevalance the majority of IMD are inherited by autosomal recessive genetics the individual incidence of metabolic disorders can vary depending on the ethnic origin of the local population especially high risk of incidence in closed population overall incidence of individual IMD can range as follows:: very rare (e.g. maple syrup urine disease 1: , homocystinuria 1: ) extremely rare (1: ) relatively more common but still rare (e.g. phenlketonuria 1 : , galaktozemia 1 : ) however, if there are more than 1000 IMD overall, each occurring at the rate of one in a milion, this means that one in 1000 people will be affected and one in 500 will be a carrier! 4

5 IMD the importance of family history diagnosis of metabolic disease in the family - the risk of repetition, especially in siblings! unexplained deaths of children in the family - an alarm for many congenital diseases, including metabolic! IMD signs and symptomes acute neonatal symptomes non-specific symptoms in apparently healthy baby: respiratory distress without signs of respiratory disease hypotonia poor sucking reflex vomiting diarrhoea dehydration lethargy seizures These can easily be attributed to other causes, such as infection 5

6 IMD signs and symptoms failure to thrive CNS symptoms: developmental delay, movement or psychiatric disorder cerebral palsy sudden infant death syndrome (SIDS) SUID - Sudden Unexpected Infant Death IMD signs and symptoms episodic illness - anorexia, vomiting, lethargy, coma cardiomyopathy muscular hypotonic, weakness, cramps gastrointestinal: anorexia vomiting diarrhoea malabsorption 6

7 IMD signs and symptoms liver disease, cholestasis ophtalmic abnormalities Reye s syndrome like illness dysmorphic features metabolic: acidosis hypoglycaemia IMD signs and symptoms a Reye-like syndrome is attributed to inborn errors of metabolism in Reye-like syndrome hypoglycemia, hypoketonemia, elevated ammonia, and organic aciduria are often evident it is well-known that fatty-acid oxidation defects can present as Reye-like syndrome the most commonly diagnosed metabolic disorder in association with Reye syndrome has been medium-chain acyl coenzyme A dehydrogenase deficiency the present consensus seems to be that Reye syndrome is very rare, and that any child suspected of manifesting this disorder should undergo investigations for inborn errors of metabolism 7

8 IMD clinical cathegories acute symptoms in neonatal period (as above) babies with metabolic disorders of accumulation show deterioration after a normal initial period of hours to weeks late-onset acute and recurrent symptomes occurs in one third of patients with IMD of toxic accumulation or energy production fhe symptom free period is often over one year and may extend into late childhood, adolescence or even adulthood symptoms may be precipitated by minor viral infection, fever or severe diarrhea witch result in the body reverting to the breakdown of stored protein within the cells and tissue this is known as decompensation children may improve spontaneously without intervention or require intensive care; they may appear normal between attacks IMD clinical cathegories chronic and progressive general symptoms; many apparently delayed onset presentations of metabolic disorders may be preceded by insidious symptoms such as gastrointestinal, neurological and muscular complaints specific and permanent symptoms may reveal or accompany metabolic disorders some symptoms are distinctive but rare (lens discolouration and thromboembolic events in homocystynuria), other are nonspecific and common (hepatomegaly, seizures, mental retardation) 8

9 IMD diagnosis easy, if the disease is detected through screening tests (eg. phenylketonuria) or actively diagnosed disease in families with a positive family history screening tests for suspected metabolic disease, suspected based on the clinical picture (GCMS, tandem mass spectrometry - TANDEM) specialized blood tests, tissue (eg. liver biopsy), fibroblasts in the detection of various metabolic errors genetic studies, confirming the diagnosis of congenital metabolic error at some IMD diagnosis TANDEM is used in some countries for neonatal screening for IMD. 9

10 IMD diagnosis IMD the main aim of managing induce activity, as in the vitamin-responsive disorders 10

11 IMD the main aim of managing counteract the biochemical disturbance and prevent acute intercurrent decompensation prevent chronic and progressive deterioration by diet and/or drug therapy approximately 12% of inborn errors of metabolism can be significantly controlled by therapy in a further 55%, treatment is beneficial but in the remaining 33%, treatment has little efect IMD emergency treatment suspicion of metabolic disease in an infant with acute symptoms - fast diagnosis, symptomatic treatment, and in case of suspicion of the disease, in which it is possible to eliminate the intolerant substance - diet, f.e. in galactosemia 11

12 IMD suppoprtive care in acute decompensation ventilatory and circulatory support correction of electrolyte imbalance rehydration and maintenance hydration to counter poor feeding, increased renal fluid loss and to ensure efficient diuresis of toxic metabolites correction of acidosis, although mild acidosis can be protective against hyperammonemia in urea cycle defects adequate nutricion exogenus toxin removal peritoneal dialysis, haemofiltration or hemodialysis can be effective in removing toxic metabolites, such as ammonemia in urea cycle defects vitamins mega-doses of specific vitamins can act as cofactors to induce metabolism in various metabolic disorders Question to the students Which of the following situations may suggest a inborn metabolic disease in a child? 1. newborn to 3 weeks of age, in the opinion of the parents - previously healthy; admitted to the ward because of a lack of appetite from the day before, vomiting, muscle flaccidity, pathological sleepiness - the child did not respond even to very strong pain stimuli; in additional studies - hypoglycemia, metabolic acidosis 2. newborn to 3 weeks of age, previously healthy; from two days more anxious, rhinitis, sporadic cough. On admission to the ward poor apetite, quickly gets tired during breastfeeding; tachypnea, tachycardia; in additional studies, decreased oxygen saturation (89%), compensated respiratory acidosis 12

13 Selected IMD Congenital hypothyroidism definition: thyroid deficiency present at birth the most common congenital human endocrinopathy from 1: 2000 to 1: 4000 births the most common preventable causes of mental retardation clinical manifestations are often subtle or not present at birth due to: trans-placental passage of some maternal thyroid hormone and/or many infants have some thyroid production of their own 13

14 Permanent CH in iodine sufficient countries 85% of CH is due to thyroid dysgenesis (thyroid ectopy, athyreosis and thyroid hypoplasia) 10-15% of cases can be attributed to the inborn errors of thyroid hormone synthesis dyshormonogenesis permanent CH requires life-long treatment Transient CH a temporary deficiency of thyroid hormones at birth, but then recovering to normal thyroid hormone production recovery to euthyroidism typically occurs in the first few months or years of life most commonly occurs in preterm infants born in areas of endemic iodine deficiency 14

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16 Clinical manifestations of CH depend on the degree of thyroid hormones deficiency and its duration in the neonatal period can be very discreet the only way of the early diagnosis can be newborn thyroid screening test CH 16

17 CH common symptoms at birth: decreased activity feeding difficulty constipation prolonged jaundice common signs in newborns and infants: myxedematous facies large fontanelles macroglossia a distandet abdomen with umbilical hernia hypotonia 17

18 Signs and symptoms of CH in untreated older children and adults mild to severe impairment of both physical and mental growth and development poor length growth is apparent as early as the first year of life; adult stature without treatment ranges from 1 to 1.6 metres, depending on severity, sex and other genetic factors bone maturation and puberty are severely delayed; ovulation is impeded and infertility is common neurological impairment may be mild, with reduced muscle tone and coordination, or so severe that the person cannot stand or walk cognitive impairment may also range from mild to so severe that the person is nonverbal and dependent on others for basic care thought and reflexes are slower other signs may include thickened skin, enlarged tongue, or a protruding abdomen Signs and symptoms of CH in untreated older children and adults 18

19 Signs and symptoms of CH in untreated older children and adults October 08, 2009By Sandra E. Kurtin, RN, MS CH lack of diagnosis and treatment from neonatal period - irreversible developmental disorders, especially the central nervous system Early treatment excellent recovery!!! 19

20 CH newborn thyroid screening tests very important to early diagnosis but of the worlwide birth population of 127 million, it is estimated that 25% undergo screening for congenital hypothyroidism various algorithms using measurement of T4, TSH, or both CH diagnostic algorithm 20

21 CH diagnostic algorithm CH other evaluation X-ray of the long bones retarded bone age ECG - ST-segment changes EEG - low voltage, excess slow activities, delay of bioelectric maturation CBC - normocytic anemia 21

22 Treatment and prognosis Levothyroxine the treatment of choice the recommended starting dose is mcg/kg/day the immediate goal of treatment are to rapidly raise the serum T4 above 10 ug/dl and normalize serum TSH levels frequent laboratory monitoring in infancy is essential to ensure optimal neurocognitive outcome; serum TSH and T4 should be measured every 1-2 month in the first 6 months of life and every 3-4 months thereafter in general, the prognosis of infants detected by screening and started on treatment easly is excellent, with IQs similar to sibling or classmate controls a lower neurognitive outcome may occur in those infants started at a later age (>30 days of age), on lower l-thyroxine doses than currently recommended, and in those infants with more sever hypothyroidism Introduction to galactosemi 22

23 Introduction to galactosemia galactose is a monosaccharide sugar galactose + glucose = lactose (disacharide) in nature, lactose is found primarily in milk and milk products galactose metabolism, which converts galactose into glucose, is carried out by the three principal enzymes in a mechanism known as the Leloir pathway; the enzymes are listed in the order of the metabolic pathway: galactokinase (GALK), galactose-1-phosphate uridyltransferase (GALT), and UDP-galactose-4 -epimerase (GALE) galactose forms part of glycolipids and glycoproteins, which is found in many tissues galactose is a component of the antigens present on blood cells that determine blood type within the ABO blood group system; in O and A antigens, there are two monomers of galactose on the antigens, whereas in the B antigens there are three monomers of glucose Introduction to galactosemia 23

24 Galactosemia there are three forms of the disease: galactose-1 phosphate uridyl transferase deficiency (classic galactosemia, the most common and most severe form) deficiency of galactose kinase deficiency of galactose-6-phosphate epimerase Galactosemia an inherited disorder autosomal recessive disease occurs in approximately 1 of every births among Caucasians; the rate is different for other groups: from 1 : to in Europe to 1 : in Japan 24

25 Biochemical abnormalities a high level of: galactose-1-phosphate galctose galactilol additionally: hypoglicemia hyperbilirubinemia Clinical description a child with galactosemia is born apparently healthy, although there have been cases intrauterine fetal damage symptoms appear several hours or days after the first milk feeding 25

26 Signs and symptoms in neonates Finding Percent Additional details Hepatocellular damage 89% Food intolerance 76% Failure to thrive 29% Lethargy 16% Seizures 1% Sepsis 10% Jaundice (74%) Hepatomegaly (43%) Abnormal liver function tests (10%) Coagulation disorders (9%) Ascites (4%) Vomiting (47%) Diarrhea (12%) Poor feeding (23%) E.Coli (26 cases) Klebsiella (3) Enterobacter (2) Staphylococcus (1) Beta-Streptococcus (1) Streptococcus faecalis (1) From a survey reporting in 270 symptomatic neonates (Waggoner et al. 1990) Signs and symptoms if a lactose-restricted diet is provided during the first 10 days of life, the neonatal signs usually quickly resolve and the complications of liver failure, sepsis and neonatal death are prevented despite adequate treatment from an early age, children with classic galactosemia remain at increased risk for: developmental delays speech problems (childhood apraxia of speech and dysarthria) abnormalities of motor function (tremors, cerebellar ataxia, dystonia) cataract diminished bone density almost all females premature ovarian insufficiency (POI) 26

27 Signs and symptoms Organs damage high levels of galactose 1-phosphate cause of brain damage excessive hydration and environmental hypertonia due to high concentration of galactilol - cataracts Galactosemia GALT mutations three variants of disease: classic galactosemia: severe GALT enzyme deficiency with absent or barely detectable activty in erythrocytes and liver clinical variant galactosemia: 1-10% residual GALT enzyme activity in erythrocytes and liver biochemical variant galactosemia: 15-33% residual GALT enzyme activity in erythrocytes; is associated with specific mutations in GALT (Duarte variant D2) 27

28 Galactosemia: diagnosis classic galactosemia and clinical variant galactosemia may be suspected and confirmed in three clinical scenarios: a newborn who is positive on newborn screening (NBS) a newborn with a previously affected sib and/or high-risk ethnicity an infant, child, or adult with signs and/or symptoms suggestive of classic galactosemia or clinical variant galactosemia 28

29 Galactosemia: newborn screening newborn screening utilizes a small amount of blood obtained from a heel prick to quantify: total content of erythrocyte galactose-1-phosphate and blood galactose concentration AND/OR erythrocyte GALT enzyme activity Clinical Chemistry 56: (2010) WRI, within reference interval Galactosemia: other laboratory tests concentration of glucose liver function tests (ALT, AST, GGTP, bilirubin) coagulogram albumin level electrolytes serum levels CBC urine analysis 29

30 Differential diagnosis infectious diseases but very important: establishing the diagnosis of sepsis does not exclude the possibility of galactosemia, as sepsis, particularly E. coli sepsis occurs commonly in infants with classic galactosemia hereditary spherocytosis biliary atresia other metabolic diseases Differential diagnosis 30

31 Treatment prevention of primary manifestations: standard of care in any newborn who is screen-positive for galactosemia or suspected of galactosemia is immediate dietary intervention while diagnostic testing is underway if erythrocyte galactose-1-phosphate concentration is >10 mg/dl and erythrocyte GALT enzyme activity is 10% of control activity (i.e., the child has classic galactosemia or clinical variant galactosemia), restriction of galactose intake is continued and all milk products are replaced with lactose-free formulas (e.g., Isomil or Prosobee ) containing non-galactose carbohydrates management of the diet becomes less important after infancy and early childhood Treatment treatment of manifestations: in rare instances cataract surgery may be needed in the first year of life childhood apraxia of speech and dysarthria require expert speech therapy developmental assessment at age one year by a psychologist is recommended in order to formulate a treatment plan with the speech therapist and treating physician for school age children, an individual education plan and/or professional help with learning skills and special classrooms as needed hormone replacement therapy as needed for delayed pubertal development and/or primary or secondary amenorrhea. 31

32 Treatment and surveillance prevention of secondary complications: recommended calcium and vitamin intake to help prevent decreased bone mineralization routine monitoring for: the accumulation of toxic analytes (e.g., erythrocyte galactose-1-phosphate and urinary galactitol) cataracts speech and development premature ovarian insufficiency (POI) osteoporosis Avoindance agents/circumstances to avoid: breast milk, proprietary infant formulas containing lactose, cow s milk, dairy products, and casein or whey-containing foods; medications with lactose and galactose 32

33 Hereditary fructose intolerance - introduction Hereditary fructose intolerance - introduction fructose, or fruit sugar, is a simple ketonic monosaccharide found in many plants, where it is often bonded to glucose to form the disaccharide sucrose 33

34 Hereditary fructose intolerance - introduction other fructose metabolism in liver, muscle and adipose tissue muscle and adipose tissue: fructose phosphorylation by hexokinase fructose-6-phosphate entrance to glycolysis liver: fructokinase converts fructose to fructose-1-phosphate cleavage by fructose-1-phosphate aldolase to glyceraldehyde and dihydroxyacetone phosphate entrance to glycolysis Abnormalities in fructose metabolism inborn errors in fructose metabolism: essential fructosuria: the absence of fructokinase asymptomatic condition hereditary fructose intolerance: the absence of fructose-1- phosphate aldolase (aldolase B) very serious consequences 34

35 Hereditary fructose intolerance (HFI) autosomal recessive disorder the incidence of HFI in Europe is about 1: the accumulated fructose-1-phosphate inhibits glycogen breakdown and glucose synthesis severe hypoglicaemia following ingestion of fructose accumulation of fructose-1-phosphate hepatic and/or kidney failure and death Hereditary fructose intolerance signs and symptoms the condition is manifested usually during infancy at weaning, when the child is introduced to fruits and vegetables, or when feeding is transferred from breast milk to artificial nutrients usually very serious, occur after the intake of fructose: hypoglycemia severe metabolic acidosis seizures jaundice hepatomegaly coagulation disorders emaciation coma renal Fanconi syndrome vomiting affected children soon develop an aversion to all foods and protect themselves by self-imposed fructose and sucrose restriction 35

36 Hereditary fructose intolerance diagnosis current diagnostic methods include the measurement of clinical symptoms upon intravenous fructose challenge or the direct assay of aldolase activity in liver biopsy samples both of these diagnostic methods are relatively invasive and the clinical analyses of fructose loading tests or aldolase assays are not routinely available in addition, diagnosis by a fructose tolerance test leads to the same acute symptoms that can be life threatening Hereditary fructose intolerance tretment the treatment for HFI is the exclusion of fructose, sucrose, and sorbitol (less than 40 mg/kg per day) from the diet and results in complete alleviation of most symptoms and a normal life span older HFI subjects who adhere to a self-imposed fructose-restricted diet may continue to live undiagnosed and lead relatively normal lives complete exclusion of fructose is often difficult, however, and many HFI patients develop a syndrome of chronic fructose intoxication characterized by retarded growth, chronic liver disease, and hepatomegaly; furthermore, if not treated properly, these patients suffer episodes of hypoglycemia, general ill health, and strained relationships with family members due to their peculiar eating habits constant daily risk remains for HFI individuals due to the increasingly widespread use of these sugars as nutrients and sweeteners 36

37 Phenylalanine an essential amino acid (the human body cannot make it so it is essential to the diet) phenylalanine that is ingested is largely transformed (hydroxylated) to form the amino acid tyrosine, which is used in protein synthesis Metabolic pathways the conversion of Phe to Tyr occurs by a hydroxylating system consisting of: phenylalanine hydroxylase (PAH) the unconjugated pterin cofactor, tetrahydrobiopterin (BH4) enzymes which serve to regenerate BH4, namely dihydropteridine reductase and 4α-carbinolamine dehydratase 37

38 Hyperphenyloalaninemia may be classified into: classical phenylketonuria (PKU) mild PKU non-pku HPA, depending on the level of serum phenylalanine at the time of diagnosis; this level provides an estimate of the residual enzyme activity that partly depends on the mutation in the PAH gene and makes it possible to define the biochemical phenotype atypical PKU (variant PKU), results from the deficient biosynthesis or regeneration of the PAH cofactor, tetrahydrobiopterin (BH4) Phenylketonuria 38

39 Phenylketonuria autosomal recessive disorder prevalence: varies by country ranging from between one in 10,000 and one in 20,000 births in U.S.A. and Europe 39

40 PKU natural history infants appear until normal thay are a few months old the natural history of the phenylketonuria consists in a progressive irreversible neurological impairment during infancy and childhood the most common outcome is severe mental retardation a mousy odor, eczema and reduced hair skin and iris pigmentation reduced growth, microcephaly and neurological signs as tremor, epilepsy all untreated patients have behavioral problems as hyperactivity, stereotypy and anxiety the severity of the clinical phenotype directly correlates with blood phenylalanine levels that reflect the degree of enzymatic deficiency PKU - diagnosis in advanced clinical presentation is easy, confirmed by the high levels of phenylalanine in serum - but there is no possibility of effective treatment in most european countries newborn screening is routinely carried out within 72 hours of birth, by taking a small pin prick of blood from the baby s heel for laboratory analysis 40

41 PKU - treatment the foundation of PKU treatment is a low Phe diet which, by reducing or normalising Phe concentrations, prevents the development of the neurological and psychological changes since neurological changes have been demonstrated within one month of birth, it is recommended that dietary restriction should be started early and be continued through childhood when neural development is maximal clinical neurological abnormalities, affected neuropsychological performance and brain imaging in adults with PKU has led to a consensus opinion that the PKU diet should be followed for life an even more stringent regime of Phe restriction is required for women with PKU contemplating starting a family, particularly during pregnancy, as elevated blood Phe concentrations are teratogenic towards the developing foetus PKU - treatment but early treated PKU patients have normal intellectual quotients (I.Q.), but can have an I.Q. gap when compared to their non-pku siblings patients with PKU frequently have lower scores for certain neuropsychological functions, with executive function being the most affected area the Phe-restricted diet with semi-synthetic supplementation is not without risk PKU patients under dietary treatment can have low concentrations of trace elements and cholesterol, and some disturbance to folate metabolism as well as distortion of their fatty acid profile 41

42 Phe in food New Strategies for the Treatment of Phenylketonuria (PKU) 42

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