Inborn error of metabolism The lecture is given by Dr Kefah Al qa qa, Consultant metabolic pediatrician, in Queen Rania Al Abdulla children hospital, on Thursday 11/12/2014. Let s tart Metabolism: refers to all biochemical processes and pathways in the body. 1. Catabolism (Breaking down): is the set of metabolic pathways that break down molecules into smaller units and release energy. 2. Anabolism (Building up): is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy *Enzymes play an important role in facilitating the process by serving as catalysts in the conversion of one chemical (metabolite) to another Inborn errors of metabolism are usually caused by a single gene defect that causes a block in metabolic pathways; it may lead to abnormality in a receptor, transport vehicle, membrane pump and structural element. Not necessary the inborn error to be an enzyme deficiency, it can be in anything that the DNA code of that protein. All inborn error of metabolic disease is autosomal recessive except those ones which are x-linked: 1- Lesch Nyhan syndrome: it has an association with uric acid metabolism leads to very high uric acid. The baby born healthy, after a period the mother will notice developmental delay. The thing that distinguish them is that they after awhile is self-mutilating behaviors, characterized by lip and finger biting. 2- OTC deficiency(ornithine transcarbamylase deficiency): it is urea cycle defect.it cause primary hyperammonimia usually leads to death bcz it is very difficult to treat. 3- Fabry s disease has an association with joints 4- Hunter s syndrome: mucopolysscaridosis type 2 storage diseases. 5- Menke s disease: it has defect in cupper metabolism; they come with developmental delay, abnormal hair (kinky). It involves renal system, and usually they die. It affects males mainly. Trial to their treatment is cupper supplement but it is not approved yet The principle of inborn error Metabolism Substrate(A) Other substance(b) Enzyme, cofactor "vitamin or mineral" Intermediate metabolite (C)
In normal conditions substrate(a) will metabolite to substance (B) in the presence of an enzyme and a cofactor.in IBEOM there will be deficiency in the enzyme or/& the cofactor and this will lead to: 1- accumulation of substrate(a) (mechanism of action of group 3 IBOM) 2- Deficiency of the product (B) 3- The body on trying to get rid of the accumulated substrate it will go to other metabolic pathway so there will be new metabolite and accumulation of them; we call them intermediate metabolite (C). These intermediate metabolite are toxic to the body bcz normally they aren't present in the body. 4- Intermediate metabolite will block another metabolic pathways in the body as urea cycle 5- Toxic metabolite has high affinity to other substance in the body called carnitine which leads to secondary carnitine deficiency. So we give them carnitine maintenance dose 50-100 to prevent sec deficiency carnitine is carrier for long chain fatty acid to transport them from cytoplasm to mitochondria to metabolite them there is a benefit to this affinity bcz when the metabolite bind to carnitine they become water soluble and can be excreted in urine and this is imp in the treatment when the patient in acute decompansation we increase the dose from 100 to 300g/kg/day In Organic academia and aminoacidopathies the intermediate metabolite will block another metabolic pathways in the body as urea cycle (which detoxify ammonia, converting it to urea excreted in the urine), by inhibition to one of the enzymes that are catalyzing the urea cycle leading to secondary hyperammonemia Before proceeding note that the doctor was showing some pics and she said notes about them, I wrote the notes that the doctor said about each one Group 1: disorders that gives rise to intoxication This group includes inborn errors of metabolism that lead to an acute or progressive intoxication from the accumulation of toxic compounds proximal to the metabolic block (accumulation of substrate or intermediate metabolite) All the conditions in this group share clinical similarities: They do not interfere with the embryo fetal development (not dysmorphic). They present with a symptom-free interval.(born normal 4-5d then started to have hypoactivity, poor feeding. we think of sepsis,and we do septic workup, given IV antibiotic,but the pt continue to deteriorate. in the fetal life they get rid of toxic metabolites by placenta and they need time to build up these toxic again. What determine the time of presentation and severity of s&s is the level of enzyme deficiency. It includes: 1- Amino acid catabolism disorder 2- organic academia 3- congenital urea cycle defect 4- Sugar intolerance (galactosemia). 5- Metal intoxication (menke's diseases) 6- porphyria phenylketonuria *In phenylketonuria the pt may come first with intractable seizure which leads to neuro damage *in phenylketonuria if the patient strict in low protein diet he will not deteriorate. * U can do antenatal detection for the infant and manage the problem
Tyrosenimea it has 3 types. In the first type there will be triad "jaundice, rickittis, coagulopathy" but there will not be any dysmorphic features We treat them by one drug nitisinone which inhibits an enzyme (succinyl acetone), in the metabolic pathway of tyrosine on step before production of the toxic metabolite. It is very effective but it is lifelong treatment and it is expensive. It come as capsule 2mg, 26 JOD each. The coagulopathy will improve in 24 h, liver back to normal in 48 h maple syrup urine disease also called branched chain ketoaciduria affect brach chained amin acids (leucine, isolucine, valine) ** may cause encephalopathy Most of the organioacacedime cause encephalopathy due to accumulation of ammonia except this one which cause encephalopathy due to Lucien accumulation And it is difficult to treat. Tyrosinemia 2 *We call it oculocutaneous *They came with sensitivity to light and hyperkeratic lesion on the sole, palms. In the past was diagnosed herpetic keratitis but herpetic keratitis is unilateral while tyrosinemia is bilateral We put them in low phynelalanin and tyrosine diet they improve in 2-10 w for the eye manifestation but skin manifestation takes months Clinical signs of intoxication may be: 1- Acute: *vomiting. *Coma. *liver failure. *thromboembolic complications. 2- Chronic: *failure to thrive. * developmental delay. *ectopia lentis. *cardiomyopathy Acute decompansation **It means increase catabolic rate, which leads to increase substrate accumulation >>more toxic metabolites >> more inhibition to urea cycle >>> more deficiency of carnitine. This is important in the treatment; bcz the treatment goal is to stop catabolism. **It is usually provoked by (stress): 1- Fever. 2- intercurrent illness. 3- Food intake. **Most of these disorders are treatable and require the emergency removal of the toxin. **Nutritional therapy is the backbone of the treatment in this group. **Pharmacological doses of vitamins have also shown remarkable efficiency in vitamin-responsive disorders: Ex: Propionic acidemia >>we add (V.B 7) which is the cofactor, Methylmalonic acidemia >> (B12).if I don t know the diagnose I give multi vitamins
Group 2: Disorders involving energy metabolism (most difficult group) These consist of inborn errors of metabolism with symptoms due to a deficiency in energy production or utilization within liver, myocardium, muscle, brain or other tissues. This group can be divided into: 1- Mitochondrial defects: -most severe -diff to diagnose -present at any age -usually untreateble. -involve any system in the body -no specific s&s They include: -Congenital lactic acidemias:(pc,pd,). -Mitochondrial resp chain defects. -Fatty acid oxidation defects. -Ketone body defects 2- Cytoplasmic energy defects: Usually less severe. - Could be: 1- treatable : disorders of glycolysis,gsd (glycogen storage ), gluconeogenesis and hyperinsulinism. 2-partly treatable: creatine metabolism. 3- untreatable: pentose phosphate pathway Common symptoms include: 1-hypoglycemia. 2-Hyperlactatemia. 3- Hepatomegaly. 4- Hypotonia. 5-Myopathy and cardiomyopathy. 6- FTT. 7- Sudden un expected death. 8-Some mitochondrial may interfer with embryo-fetal development leading to dysmorphism.(but not for diagnosis) Biotin deficiency **Symptoms include: Loss of hair, severe eczema, academia, seizure **"Anticonvulsant therapy: Prolonged use of certain drugs, may lead to biotin deficiency; however, valproic acid therapy is less likely to cause this condition. Some anticonvulsant inhibit biotin transport across the intestinal mucosa. Evidence suggests that these anticonvulsants accelerate biotin catabolism. Therefore, supplemental biotin, in addition to the usual minimum daily requirements, has been suggested for patients who are treated with anticonvulsants that have been linked to biotin deficiency".wiki but some are said by the doctor **treated by given Biotine 5mg *2!!
Glycogen storage disease type1 Clinical picture: *Recurrent hypoglycemia, huge hepatomegaly, Elevate liver enzyme but not as in hepatitis, Hyperlipedimia, triglycridemia, hyperlactetimia *Recurrent attack of nasal bledding >>defect in platelet function not number *PT, PTT, INR is normal unless the patient is septic *The bleeding time is prolonged *They are short stature, but we don t give them growth hormone, bcz it is not effective *Liable to hyperthyroidism! Treated by: 1- lactose, glucose, fructose free 2- uncooked corn starch ( bcz they are catabolized to glucose slowly ) 3- Liver transplant not effect (We do transplant to type 4 only) There are 2 forms of type 1: -A -B>> u find neutropenia Group 3: Disorders involving complex molecules This group involves cellular organelles and includes diseases that disturb the synthesis or the catabolism of complex molecules. Symptoms are: 1- progressive. 2- permanent. 3- Independent of intercurrent events (not affected by current infections >> not go to acute decompansation) 4- Unrelated to food intake. This group includes: 1- All lysosomal storage disorders. 2- Peroxisomal disorders. 3- α1-antitrypsin. 4- Carbohydrate deficient glycoprotein (CDG) syndrome. 5- Inborn errors of cholesterol synthesis. Treatment for some of these disorders is available: 1- Enzyme replacement therapy: for several lysosomal disorders such as Gaucher and Fabry diseases and MPS. 2- Organ transplantation.(bone marrow) 3- Gene therapy. Mucoplysacaridosis Type 1(hurler) *They have: Hypertelorism, depressed nasal bridge, Short stature broad flexion deformity *After awhile excess body Hair, The eye's cornea often becomes cloudy from intracellular storage. Type6: Maroteaux-lamy syndrome They die bcz of cardiopulmonary complication Treatment: enzyme replacement. But it is expensive, lifelong (every week given an injection)
Clinical pointers towards an underlying IEM include: Deterioration after a period of apparent normalcy. Parental consanguinity. Family history of neonatal deaths. (cp) Rapidly progressive encephalopathy and seizures of unexplained cause Severe metabolic acidosis Persistent vomiting with metabolic acidosis bcz in other problems they be with alkalosis Special smells to some disorders: Musty or Mousy: PKU Boiled Cabbage Tyrosinemia or hypermethioninemia Maple Syrup maple syrup urine disease(most ccc) Sweaty feet: isovaleric acidemia or glutaric acidemia type II Cat urine multiple carboxylase deficiencies (Biotin deficiency) Times when presentation of inherited metabolic disease is more likely (when there are metabolic stress): 1- Neonatal period 2- Weaning Increased oral intake for example, increased protein load. First exposure to new diet component for example, fructose. 3- End of first year Slowing in growth rate means more protein is catabolised for same Protein intake, thus putting greater load on these pathways. 4- Infection Increased metabolic stress often associated with decreased intake for example, vomiting, diarrhoea. 5- Puberty Alterations in growth rate, hormonal changes. 6- Postnatal Urea cycle defect previously asymptomatic - involution of placenta equates to a signifi cant protein load. Inborn error can be divided into: -treatable (to start medication as early as possible) -untreatable (genetic counseling) First line investigations (metabolic screen): The following tests should be obtained in all babies with suspected IEM. 1- Complete blood count: (neutropenia and thrombocytopenia ).(acidosis>>bone marrow supression>>pancytopnia) 2- Arterial blood gases and electrolytes.(with chloride and electrolyte to calculate anion gap) 3- ammonia, lactate diarrhea normal anion gap: renal tubular acidosis Metabolic acidosis ketoacidosis increased anion gap (usually lactic acidosis organic acidopathy
Other things that those patients will have: Hypoglycemia -definition: Blood glucose < 2.6 mmol/l (45 mg/dl) at all ages To approach hypoglycemia we need critical sample",in this sample we ll take things that would help us in diagnose * for endocrine causes : Growth hormone, cortisone, ACTH, insulin, C-peptide *and we should also look for ketone bodies : I-high ketone bodies ( ketotic hypoglycemia ), found in : 1. GSD 1 ( glycogen storage disease type 1 ) 2. Gluconeogenetic defect 3. Carbohydrate intolerance 4. Organic academia 5. Adrenal / pituitary problems II-not-ketotic hypoglycemia, found in : 1. Hyperinsulism 2. Fat oxidation defect *** if it s negative for ketone bodies, then I should look for the level of insulin: if high hyperinsulinemia. normal fatty acid oxidation defect (FAOD). at first : I prepare glucose 10% and I give it for the patient to prevent convulsions. Hyperammonemia We should know the normal values of Plasma ammonia NH3 1-Neonates: -Healthy<110μmol/l -Sick ( septic) up to 180 μmol/l : but when the pt. recover we should recheck it to make sure that it s back to normal -Suspect metabolic disease >200 umol/l 2-After the neonatal period : 50-80 μmol/l at any time if it s >100 then we should role out IEOM. -Suspect metabolic disease >100 umol/l Hyperlactemia CAUSES OF HYPERAMMONEMIA: 1-primary = Urea cycle defect. 2-secondary : A- wrong sampling : the most important one because ammonia concentration inside the cells is 10x the ammonia conc. in the serum.so if the sample was taken improperly (didn t put it in ice, water) there will be hemolysis of the RBCs > ammonia is out of the cells > gives false high reading. B-liver disease. C- metabolic diseases e.g. organic acidemias and FAOD. D - Sepsis. - Arterial blood lactate Normal values: * Blood <2.1 mmol/l (<19 mg/dl) * CSF <1.8 mmol/l (<16 mg/dl).-> ( sometimes we are highly suspicious that there is mitochondrial disease in which you ll find lactic acidemia, absence of it doesn t rule out mitochondrial diseases but the lactate in the CSF will be high in patients with mitochondrial disease ). Primary lactic acidosis Remember that they are in general metabolic diseases: Amino acid disorders. Organic acidemias. Urea cycle defects. Pyruvate metabolism defects. Krebs cycle defects. Mitochondrial OXPHOS disorders. Fatty acid oxidation disorders. Disorders of liver glycogen metabolism. Disorders of liver gluconeogenesis. Biotinidase deficiency - if a patient has convulsion we don t do investigations if he still uncontrolled,because the convulsion is an exercise so it will raise the lactate level Secondary lactic acidosis Remember-> anything that cause decrease in perfusion or decrease in oxygenation: Poor collection technique. Exercise. *Hypoxia Hypotension Shock Sepsis Cardiac failure/cardiomyopathy Renal failure Short bowel syndrome (D-lactate) Thiamine deficiency.
Other tests: -Liver function tests : like in glycogen disease, liver enzymes will be high + hyperlipidemia. -Urine ketones - Urine reducing substances : for galactosemia. - Serum uric acid (low in molybdenum cofactor deficiency). Second line investigations 1-blood: -Aminoacid -chromatography. -Acylcarnitine profile. -Lactate /pyruvate ratio. -VLCFA( very long chain fatty acid ) 3-Enzyme assay: This is required for definitive diagnosis, but we can t do it for all patients because it needs skin fibroblasts or liver biopsy for enzyme assay. 2-Urine: *Ketones *DNPH (Dinitrophenylhydrazine) : this test is important for patients of maple syrup urine disease -if the mother felt that her son isn t doing well, she uses a dipstick and put it in a urine sample from her son so as to know if he is started to have acute decompansation or not. *reducing substances. *Organic acid chromatography. *Orotic acid : important to distinguish between the types of enzyme deficiency in the urea cycle. 8-CSF : 1-Aminoacid analysis: CSF Glycine levels are elevated in NKH. 2- CSF glucose to plasma glucose ratio for the diagnosis of GLUT defects. 3-CSF lactate. 4- GABA and other neurotransmitters : some metabolic disorders will cause defect in the neurotransmitters 4-Neuroimaging: MRI may provide helpful pointers towards etiology while results of definitive investigations are pending. - for patients with leukodystrophy,because most of the metabolic diseases cause leukodystrophy. Some IEM may be associated with structural malformations such as Agenesis of corpus callosum brainstem and cerebellar edema, basal ganglia signal change, subdural hematoma and frontotemporal atrophys. 5-Magnetic resonance spectroscopy (MRS): -similar to MRI -they use the spectroscope that can detect the concentration of certain metabolites like : 1- lactate peak elevated in mito-chondrial disorders. 2- leucine peak elevated in MSUD (maple syrup urine disease). 6-Electroencephalography (EEG): some EEG abnormalities may be suggestive of particular IEM e.g. : 1-Comb-like rhythm in MSUD. 2- Burst suppression in : NKH (non-ketotic hyperglycemia). Holocarboxylase synthetase deficiency 7-Mutation analysis when available: to know the types of mutations that we have, to do perinatal diagnosis.. so we ll be anticipating that we ll have affected newborn if the family decided to keep the baby (didn t choose abortion ), so I ll do tests immediately, start him on treatment so as to prevent convulsions, encephalopathy and neurological deficit
And now test yourself - Urea cycle defect is the only one of IEOM IE to come with respiratory alkalosis, but if the pt. had brain hypoxia and he came with th sepsis,it might change to metabolic alkalosis because of Hyperlactemia due to hyperperfusion or hypo-oxygenation oxygenation. - Hyperinsulinemia won t come with metabolic acidosis. * Notes : -Limitation Limitation of substrate intake : In aminoacidopathies, organic academia and galactosemia we give the patients formula that doesn t have the substrate that causes the problems. - or we give the enzyme ( as a drug or by organ transplant ). - Supplement product: like in Biotinidase deficiency.. We give biotin in as a treatment. - Gene therapy: it s on the enzyme..but but there are only studies, still there is no prove on it. - If the toxic metabolites causes inhibition of other pathways, we give a treatment to suppress this inhibition. The end شكرا جزيال 9 yaqeen