Beruflich Dokumente
Kultur Dokumente
Dr Gurpreet Singh
Metabolism : chemical or physical changes undergone by substances in a biological system. Inborn error : an inherited (i.e. genetic) disorder. Genetic mutations can result in alteration of protein structure or amount of protein synthesized. Functional ability of protein whether enzyme, receptor,vehicle, membrane,structural element is compromised leading to biochemical disorders. These hereditary biochemical disorders are collectively termed inborn error of metabolism.
substrate excess
C product deficiency D
toxic metabolite
Organelle disease
Lysosomes Mitochondria Peroxisomes Cytoplasm
in 5000 births collectively Often treatable if diagnosed Most difficult task for clinician is to know when to consider IEM and which tests to order for evaluation Dont be fooled--other diagnoses like sepsis, ICH, pulm. hem. may accompany IEM Clues to presence of IEM may often be found in FH
cycle defects(UCDs).
Organic acidemias-isovaleric acidemia, propoinic acidemia(PPA),
peroxisomal disorders ,lysosomal disorders ,mucopolysaccharidoses. Defects of purines and pyrimidines-Lesh-nyhan syndrome,AMPdeaminase deficiency,orotic aciduria. Miscellaneous wilson disease,alpha-1-anti trypsin deficiency.
Neurological deterioration Metabolic acidosis Hypoglycemia Inappropriate ketosis Hypotonia Cardiomyopathy Hepatocellular dysfunction Failure to thrive
Infant Symptoms indicating possibility of an IEM (one or all) Infant becomes acutely ill after period of normal behavior and feeding; this may occur within hours or weeks Neonate or infant with seizures and/or hypotonia, especially if seizures are intractable Neonate or infant with an unusual odor Symptoms indicating strong possibility of an IEM, particularly when coupled with the above symptoms Persistent or recurrent vomiting Failure to thrive (failure to gain weight or weight loss) Apnea or respiratory distress (tachypnea) Jaundice or hepatomegaly Lethargy Coma (particularly intermittent) Unexplained hemorrhage Family history of neonatal deaths, or of similar illness, especially in siblings Parental consanguinity Sepsis (particularly Escherichia coli)
is not reassuring! CONSANGUINITY, ethnicity, inbreeding unexplained neonatal deaths, fetal losses maternal family history
males - X-linked disorders like ornithine transcaarbamylase(OTC),lesch-nyhan syndrome,fabry disease. Mitochondrial disorders as mitochondrial DNA is acquired from mother.
size), ODOUR H&N - cataracts, retinitis pigmentosa CNS - tone, seizures, tense fontanelle Resp - Kussmauls, tachypnea CVS - myocardial dysfunction Abdo - HEPATOMEGALY Skin - jaundice
Energy Deficiencies
Most common presentation Overwhelming neurologic illness.
Apnea ,seizures,and coma No symptom free period Miochondrial and Peroxisomal disorders Primary lactic acidosis
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Patterns
OF13
Presentation
Neurological abnormalities
Disorders of acid base status Hypoglycemia Liver dysfunction Dysmorphic features Cardiac diseases Abnormal urine and body odour
Acute encephalopathy Neonatal or early infancy Gray matter involvement Seizures, hypotonia,apnea Small molecule Intoxication type Associated with vomiting, lethargy, abnormal respiration , coma
Chronic Progressive encephalopathy Late infancy or childhood White matter involvement Spasticity,ataxia,hypereflexia Large molecule Energy deficiency or intoxication type Associated with liver dysfunction , cardiomyopathy, weakness
NEUROLOGICAL ABNORMALITIES 15
Encephalopathy,seizures seen in organic
pyridoxine dependent seizures, NKH , peroxisomal disorders Few IEM presents with predominant hypotonia such as peroxisomal disorders,respiratory chain disorders.
gap is an importanat feature of many IEMs. Organic acidemias, FAO defects, and defects of glycogenesis, gluconeogensis, pyruvate metabolism, respiratory chain. Respiratory alkalosis is a/w hyperammonemia.
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Hypoglycemia
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persistent without any other etiology suspect IEMs. Hypoglycemia a/w metabolic acidosis suggests an organic acidemia ,defects of gluconeogenesis such as glycogen storage disease,fructose1,6-diphosphatase deficiency
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Liver Dysfunction
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Deficiency, Gilbert and Crigler-Najar syndromes) Conjugated(galactosemia, tyrosinemia, fructose intolerance). Hepatomegaly-asymptomatic in GSD, tyrosinemia. Hypoglycemia wih hepatomegaly in galactosemia,GSD. Hepatocellular dysfunction in alpha-1antitrypsin deficiency, GSD IV and III,
CARDIAC DYSFUNCTION
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defects,GSDII(Pompe disease). Most IEM presents as cardiomyopathy. Few can present with arrthymias(fabry disease),coronary artery disease(familial hypercholesterolemia)
Dysmorphic Features
Peroxisomal disorders
Zellweger syndrome Pyruvate dehydrogenase deficiency
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Large fontalle,prominent forehead, flat nasal bridge, epicanthal folds,hypoplastic supraorbital ridges
Epicanthal folds, flat nasal bridge,small nose with aneverted flared alae nasi,long philtrum. Inverted nipples,lipodystrophy
Glycosylation disorders
associated with hypotonia, intractable seizure and developmental delay PKU: Fair skin and blonde hair Multiple carboxylase deficiency skin rash and partial alopecia
Eye abnormalities
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Cataract:galactosemia,adrenoleukodystrophymuco
polysacharidosis Lens dislocation: homocystinurea, marfan Blue sclera in osteogenesis imperfecta Cherry red spot in lysosomal disorder such as aysachs disease, sandhoff disease, niemann-pick disease,metachromatic leukodystrophy
Odors :-
Glutaric acidemia type 2 sweaty feet Isovaleric acidemia sweaty feet MSUD maple syrup Hypermethioninemia boiled cabbage Multiple carboxylase deficiency tomcat urine PKU mousy or musty Tyrosinemia rancid fishy or cabbage like
Plasma amino acids Plasma carnitine Urine amino acids Urine organic acids
organic acidemias,GSD type Ib. Electrolytes and ABG-Persistent metabolic acidosis w/o asphyxia,shock,compromised perfusion points towards organic acidemias, congenital lactic acidosis. Respiratory alkalosis alkalosis in non ventilated babies suggests hyperammonemia. Plasma Ammonia-should be done in all sick infants with features of unexplained lethargy and neurological intoxication,raised in UCDs.
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LFTs-abnormal in galactosemias,tyrosinemia,alpha-
Maple syrup urine disease with increase leuocine, valine and isoleuocine Hyperglycinemia: increase glycine Urinary organic acid : in patients of metabolic acidosis, seizures, hyperammonemia, ketonuria and used for diagnosing organic acidemias. Carnitine level-elevation seen in FAO defects, organic acidemias. Increased level of long chain fatty acid with perioxisomal disorder.
INFECTION
NORMAL
UREA CYCLE DEFECTS
ACIDOSIS
ORGANIC ACIDEMIAS
NORMAL
AMINOACIDOPATHIES GALACTOSEMIA
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Errors of Metabolism
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Routine childhood illnesses excluded 1st Inborn errors considered only secondarily Unfamiliarity with biochemical interrelationships/ diagnostic tests Inappropriate sample collection Inappropriate sample storage
Galactosemia
Deficiency of galactose-1 phosphate uridyl
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transferase 1/50,000 Start early after feeding Autosomal recessive on chromosome 9p13 with male=female Affect brain, liver, kidney and ovaries
Manifestation
Symptoms begin after lactose feeding or breast
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milk feeding
Lethargy irritability and vomiting Feeding difficulty and poor weight gain Jaundice, hypoglycemia, hepatomegaly
Ascites
Hepatic cirrhosis
Others
Polydipsia, polyurea Rickets Mental retardation Seizure
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Investigation
Positive clinitest and negative clinistix Urine galactose by chromatography Direct hyperbilirubinemia
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Management
Lactose free formula Control seizure Consult ophthalmology Genetic counseling
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PKU
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Autosomal recessive inborn error of metabolism Incidence of 1:10,000 to 1:15,000 Normally: phenylalanine tyrosine by liver
Two Types
Deficiency of PAH
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Symptoms
Severe intellectual impairment
Microcephaly Eczema
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Seizures
Hypopigmentation Hyperactivity
Autistic behavior
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Diagnostic Criteria
Normal: 120 360 mol/L
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PAH Deficient: Mild: 600 1200 mol/L Classical: > 1200 mol/L Non-PAH Deficient: < 600 mol/L
Guthrie Bacterial Inhibition Assay
Treatment
Decrease amount of phenylalanine in diet
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growth and development Food diary Frequent monitoring of phenylalanine levels Once weekly during 1st year Twice monthly from 1 12 years Monthly after 12 years Provide parental and professional support to promote normal growth and development
Tyrosinemia
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Decreased activity of enzyme fumaryl acetoacetate. Tyrosine and methionine levels are high. Presents with hepatosplenomegaly,fanconi like
ALKAPTONURIA
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Deficiency of enzyme homogentistic acidoxidase. Homogenistic acid is excreted in urine . Accumulation in articular tissues leading to
degeneration and osteoarthritis like changes. Pigment stones and nephrosis also seen. Urine shows black reaction with fehlings or benedicts s test.
HOMOCYSTINURIA
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Deficiency of cystathionine synthatase. Elevated levels of homocystine and methionine. Patients presents with subluxation of lens,recurrent
thrombo embolic episodes with marfanoid features. Convulsions and cerebrospinal lesions seen due to thrombo-embolic phenomenon.
Restriction of methionine and pyridoxine
replacement.
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Homocystinuria
dehydrogenase. Poor feeding, vomiting during first week. Lethargy, seizures, coma, muscular rigidity with severe opisthotonus, maple syrup odor in body fluids. High plasma and urine levels of leucine, isoleucine, valine and their respective ketoacids. Ketoacids detected in urine by 2,4-DNPH reagent forming yellow precipitate. Quick removal of branched chain amino acids and their metabolities from tissues ,body fluids Special low branched amino acids diet
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Organic Acidemias
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degradative enzymes involving catabolism of branched amino acids valine,leuine,isoleucine. Most infants presents with severe vomiting, anion gap metabolic acidosis, poor feeding , lethargy, hypotonia, convulsions, coma. Labroratory findings severe ketoacidosis , neutropenia, thrombocytopenias, metabolic acidosis with large anion gap, hypoglycemia, hyperammonemia.
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acidemia (IVA), Propionyl acidemia(PPA), Methyl malonic acidemia(MMA). Management includes hydration and infusion of bicarbonate to correct acidosis. 10% glucose solution with electrolytes correction with intravenous lipids . Restriction of protein intake (1-2 g/kg/24hr) alongwith carnitine ( 50-1oo mg/kg/24hr).
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Symptoms:
: Infants presents with poor feeding, vomiting, lethargy, hypotonia, hyperventilation b/w age of 1 to 5 days. Patients may have seizures, apnea, coma, and increased intracranial pressure. High index of suspicion should be kept for neonates thought to septic without microbiological evidence of infection.
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Deficiency with lab. Features of hyperammonemia, without any specific increase in any amino acid and marked increase in urinary orotic acid . Carbamyl phosphate synthatase and Nacetylglutamate(NAG) synthatase deficiencies presents with hyperammonemia with out any specific amino acid elevation. All other UCDs presents with elevation of specific amino acid elevation prior to their enzymatic deficiency.
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Management of hyperammonemia
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provided i.v. with minimal amount of proteins. Priming doses of sodiun benzoate , sodium phenylacetate, arginine is given. Intiate of hemodialysis or peritoneal dialysis.
Sodium benzoate
SODIUM BENZOATE + GLYCINE HIPPURATE
Cleared by the kidney at 5X the GFR Each mole of benzoate removes one mole of ammonia as glycine
Sodium phenylacetate
PHENYlACETYL GLUTAMINE
Easily excreted in the urine One mole of phenylacetate removes 2 moles of ammonia as glutamine
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ornithine and n-acetylglutamate Abbreviated version of the urea cycle continues not recommended for use in arginase deficiency or organic acidemias
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Contd.
3) Reversal of catabolism/Promotion of anabolism 4)Elimination of toxic metabolite 5)Treatment of precipitating factor 6)Cofactor supplementation
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Monitoring
Mental state changes Overall fluid balance Evidence of bleeding (thrombocytopenia) Evidence of infection (Neutropenia) Biochemical parameters Complete blood count Urine for ketones and specific gravity
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Newborn Screening
PKU - must do on all infants in NICU even if
not advanced to full feeds. GalactosemiaHypothyroidism Sickle cell anemia Biotinidase def, CAH (21-OHase def), MSUD
Autopsy--pref. performed within 4 hours of death Tissue and body fluid samples Blood-clotted and heparinized Urine samples CSF (ventricular tap) skin biopsy-for chromosomal and enzyme assay liver biopsy-frozen in liquid nitrogen Photographs and skeletal radiological screening for dysmorphic features
Case 1
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Patrick: 2 yr 4 mo male
Developmental delay Seizures
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Case 1 (CONTINUED)
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Seizure History
First 11 m Generalized, tonic/clonic Total 4 seizures EEG diffuse slowing, no focal spike/wave MRI decreased grey/white differentiation and cortical atrophy
Case 1 (CONTINUED)
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Seizure History
First 11 m Generalized, tonic/clonic Total 4 seizures EEG diffuse slowing, no focal spike/wave MRI decreased grey/white differentiation and cortical atrophy
Case 1(Cont)
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Physical Exam Growth Blond hair, blue eyes Non-dysmorphic child Neurological exam:
Decreased
DIAGNOSIS- ???
78 A week old baby boy Breast milk only Lethargic, recurrent vomiting, dehydrated, and hypotonic RR 40, intercostal recession, and grunting CXR- no abnormalities Metabolic acidosis, ketotic,NH4 50mmol/l, high plasma. Start convulsing Thrombocytopenia, neutropenia with normal LFT
CASE STUDY-2
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NEONATAL SEPSIS
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Severe
Hurler MPS I H
Severe mental retardation More progressive Severe respiratory disease Obstructive airway disease Death before age 10 years
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Mild
Scheie MPS I S
Normal intelligence Less progressive physical problems Corneal clouding Joint stiffness Valvular heart disease Death in later decades
Multi-systemic Involvement
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Argininosuccinic acidemia
Type II
Hyperammonemia:
Citrullinuria Type I
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Sig incr
Plasma amino acids citrulline
Nl.
THN
ASA
CPS OTC
calories, fluids and electrolytes Minimize protein intake Provide alternate pathways for ammonia removal May require exchange transfusion, peritoneal dialysis or hemodialysis for ammonia removal
Tay-Sachs
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nervous system
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chromosome 15. Hex A normally codes for the alpha sub unit of the hexosaminidase A protein, which is necessary for breaking down GM2 gangliosides in nerve cells. The accumulation of GM2 is toxic and eventually causes death.
4 to 6 months of age when an apparently healthy baby gradually stops smiling, crawling or turning over, loses its ability to grasp or reach out and, eventually, becomes blind, paralyzed and unaware of its surroundings. Death occurs by age 5. There is also adult Tay-Sachs and the symptoms include muscle weakness, cramps, slurred speech, and behavioral changes.
Treatment 93
Sachs disease. However, researchers are pursuing several approaches to finding a cure. Scientists are exploring enzyme replacement therapy to provide the Hex-A that is lacking in babies with Tay-Sachs. Bone marrow transplantation has been attempted also, but to date has not been successful in reversing or slowing damage to the central nervous system in babies with Tay-Sachs. Another avenue of research is gene therapy in which scientists transfer a normal gene into cells to replace an abnormal gene. This approach holds great promise for curing Tay-Sachs.
Gaucher Disease
Lysosomal storage disease (Sphingolipidose) Deficiency of glucocerebrosidase causes buildup of glucocerebroside Gaucher cells, store sphingolipid in spleen, liver, bone marrow, alveolar spaces, brain tissue
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Symptoms
Anemia
Reduced platelet count Bone demineralization
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Jaundice
Hepatosplenomegaly Neurologic effects (ataxia, seizures, )
Diagnosis 96
Three recognized types: Type I (Noncerebral juvenile)
Most
Treatment 97
Splenectomy (rarely cures) Gene therapy Enzyme replacement
Treatment of choice in advanced disease Chemical chaperone treatment Found to aid folding of N370S mutation
IEM Associations
All are AR inherited other than
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Leach Nyhan syndrome XLR. OTC deficiency XLR. Fabrys disease XLR. Hunters syndrome XLR( vs Hurlers syndrome AR)
IEM Associations
Cherry red spot
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.subcutaneous nodules. Metachromatic leukodystrophy ataxia , dementia. Lesch-Nyhans self mutilation , hyperuricemia , hyperuricosuria , gouty arthritis , urate ureterolithiasis)
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Gene Therapy
Gene therapy is an experimental treatment
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that involves introducing genetic material (DNA or RNA) into a persons cells to fight disease. These genes are inserted via viruses or liposomes.
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Gene Therapy
Normal gene inserted into defective cell Compensates for the missing or dysfunctional gene, in somatic cells only Can be inserted into mature cell (ly) Can be inserted into stem cell (bone marrow) Used to treat e.g. ADA deficiency, CF,
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by administration of genes Etiology of metabolic disease : accumulation of metabolic intermediates or loss of products
Inborn errors of metabolism or function treat by replacing the
gene rather than to replace the defective or missing enzymes Logic : to fix what is broken Lesh-Nyhan syndrome, adenosine deaminase deficiency, sickle cell anemia, thallasemias, hemophilia, Gauchers disease, cystic fibrosis, alpha-1 antitrypsin deficiency, inborn errors of metabolism
Case Description
A female baby was delivered normally after an uncomplicated pregnancy. At the time of the infants second immunization, she became fussy and was seen by a pediatrician, where examination revealed an enlarged liver. The baby was referred to a gastroenterologist and later diagnosed to have Glycogen Storage Disease Type IIIB
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family.
abnormalities Hair and skin abnormalities Hematological / Hepatic dysfunction Sepsis Unusual odor
Glycogenolysis
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osmal storage of glycogen in skeletal muscles,cardiac muscles,CNS. Dilated cardiomyopathy with left axis deviation short PR interval, large QRS complexes.