SlideShare a Scribd company logo
1 of 63
APPROACH
             TO
  INBORN ERRORS OF METABOLISM

    DR.PADMESH.V
  DEPT OF PEDIATRICS,
DR.SMCSI MCH, KARAKONAM.
Dr.Padmesh.V


 METABOLISM
 Metabolism      Catabolism (Breaking down)

                  Anabolism (Building up)

 Enzymes play an important role in facilitating
  the process by serving as catalysts in the
  conversion of one chemical (metabolite) to
  another.
Dr.Padmesh.V

 Catabolism :
 Catabolism is the set of metabolic pathways that
  break down molecules into smaller units and
  release energy.
Dr.Padmesh.V

 Catabolism :
 Catabolism is the set of metabolic pathways that
  break down molecules into smaller units and
  release energy.
Dr.Padmesh.V

 Anabolism :
 Anabolism is the set of metabolic pathways that
  construct molecules from smaller units. These
  reactions require energy.
Dr.Padmesh.V

 Anabolism :
 Anabolism is the set of metabolic pathways that
  construct molecules from smaller units. These
  reactions require energy.
Dr.Padmesh.V

 Anabolism :
 Anabolism is the set of metabolic pathways that
  construct molecules from smaller units. These
  reactions require energy.
 Inborn errors of metabolism (IEM)            Dr.Padmesh.V


 - Inborn errors of metabolism (IEM) are disorders
   in which there is a block at some point in the
   normal metabolic pathway
 - IEMs occur due to mutations in DNA.



      DNA                     Enzyme
  which code for a            Receptor
  Specific protein            Transport vehicle
                              Membrane pump
                              Structural element
Dr.Padmesh.V
 Example of mechanisms in IEM:




Precursor          Substrate      End-Product
   A                   B              C
Dr.Padmesh.V
 Example of mechanisms in IEM:




Precursor          Substrate          End-Product
   A                   B                  C

                        Abnormal metabolic
                             pathway


               Toxic Metabolite D
Dr.Padmesh.V

 The number of diseases due to inherited point
  defects in metabolism now exceeds 500.

 While the diseases individually are rare, they
  collectively account for a significant proportion of
  neonatal and childhood morbidity and mortality.

 Diagnosis is important not only for treatment but
  also for genetic counselling and antenatal
  diagnosis in subsequent pregnancies.
Dr.Padmesh.V


 CLASSIFICATION OF IEM:

1. Amino acid metabolism
2. Carbohydrate metabolism
3. Lipid metabolism
4. Protein metabolism
5. Pigment metabolism
6. Unknown biochemical defects
Dr.Padmesh.V
 CLASSIFICATION OF IEM:

1. Amino acid metabolism
     -Phenylketonuria
     -Tyrosinosis
     -Albinism
     -Alkaptonuria
     -Cystinosis
     -Cystinuria
     -Homocysteinuria
     -Hartnup disease
     -Maple syrup disease
Dr.Padmesh.V
 CLASSIFICATION OF IEM:

2. Carbohydrate synthesis:
    -Congenital lactose intolerance
    -Galatosemia
    -Glycogen storage disease
    -Diabetes mellitus
    -Scurvy
Dr.Padmesh.V
 CLASSIFICATION OF IEM:

3. Lipid metabolism:
   -Abetalipoproteinemia
   -Progressive lipodystrophy
   -Lipid storage disorders
              * Gaucher
              * Neimann-Pick
              * Tay-sachs
              * Hyperlipoproteinemia
Dr.Padmesh.V
 CLASSIFICATION OF IEM:

4. Protein Metabolism:
    -Immunoglobulin deficiencies
    -Absent clotting factors
       (Hemophilia, Christmas dis,
        Hypoprothrombinemia)
   -Metal binding protein deficiency
       (Wilson hepatolenticular degeneration)
   -Alpha-1 anti trypsin deficiency
Dr.Padmesh.V
 CLASSIFICATION OF IEM:

5. Pigment metabolism:
   -Porphyrias
   -Methemoglobinemias
   -Albinism
   -Crigler-Najjar dis
   -Dubin-Johnson dis
   -Gilbert dis
   -Rotor synd
   -Primary hemochromatosis
Dr.Padmesh.V
 CLASSIFICATION OF IEM:

6. Unknown biochemical defect:
   -Osteogenesis imperfecta
   -Marfan synd
   -Achondroplasia
   -Ehler danlos synd
Dr.Padmesh.V




APPROACH TO
    IEM
Dr.Padmesh.V




1. Suspecting
       Inborn Errors:
Dr.Padmesh.V
 Suspecting Inborn Errors:
 Inborn errors should be suspected when
 HISTORY:
(1) Symptoms accompany starting/changes in diet,
(2) Children with seizures,
(3) Developmental delay,
(4) Recurrent vomiting,
(5) Unusual odour of urine,
(6) Parental consanguinity,
(7) Problems suggestive of inborn error such as retardation or
    unexplained deaths in first- and second-degree relatives.
Dr.Padmesh.V
 Suspecting Inborn Errors:
 CLINICALLY:
 IEM must be also considered in the differential diagnosis of
 Critically ill newborns,
 Neurodegeneration,
 Mental retardation ,
 Coarse facies / dysmorphic features,
 Parenchymal liver disease,
 Cardiomyopathy,
 Organomegaly
 Unexplained acidosis,
 Corneal opacity, cataract or dislocation of lens,
 Hyperammonemia, and
 Hypoglycemia
Dr.Padmesh.V


 Clinical pointers towards specific IEMs:
Dr.Padmesh.V


Inborn Errors of Amino Acid Metabolism
Associated with Peculiar Odour:
Dr.Padmesh.V
Patterns of Presentation:
1. Encephalopathy with or without metabolic
   acidosis.
2. Acute liver disease:
       - Jaundice alone
       - Hepatic failure
       - Neonatal cholestasis
       - Hypoglycemia
3. Dysmorphic features.
4. Cardiac disease.
5. Diarrhea
6. Hepatomegaly +/- Splenomegaly
7. Predominant Neurological symptoms
Dr.Padmesh.V
 1) Encephalopathy with or without
     metabolic acidosis:
 Encephalopathy, seizures,and tone abnormalities are
  predominant presenting features of
     -organic acidemias,
     -urea cycle defects,and
     -congenital lactic acidosis.

 Intractable seizures are prominent in
      -pyridoxine dependency,
      -non-ketotic hyperglycinemia,
      -molybdenum co-factor defect,and
      -folinic-acid responsive seizures.
 2) Acute liver disease: could manifest as-                         Dr.Padmesh.V

 Jaundice alone: -Gilbert syndrome,
                       -Criggler-Najjar syndrome
 Hepatic failure (jaundice, ascites, hypoglycemia, coagulopathy):
                  -Tyrosinemia,
                  -galactosemia,
                  -neonatal hemochromatosis,
                  -glycogen storage disease type IV.
 Neonatal cholestasis:
                  -alpha-1 antitrypsin deficiency,
                  -Niemann-Pick disease type C.
 Persistent and severe hypoglycemia:
                   -Galactosemia,
                   -fatty acid oxidation defects,
                   -organic acidemias,
                   -glycogen storage disorders and
                   -disorders of gluconeogenesis.
Dr.Padmesh.V
 3) Dysmorphic features: seen in
       -Peroxisomal disorders,
       -Pyruvate dehydrogenase deficiency,
       -Congenital disorders of glycosylation ,and
       -Lysosomal storage diseases.

Some IEMs may present with
non-immune hydrops fetalis
      -lysosomal storage disorders,and
      -Congenital disorders of glycosylation.
Dr.Padmesh.V
 4) Cardiac disease:
 Cardiomyopathy is a prominent feature in some
 IEM like in:
    -Fatty acid oxidation defects,
    -Glycogen storage disease type II , and
    -Mitochondrial electron transport chain defects.
Dr.Padmesh.V
 6. Diarrhea :
  a. Severe watery diarrhea:
          - Congenital chloride diarrhea
          - Galactosemia
          - Primary lactase,sucrase,isomaltase deficiency.
  b. Chronic diarrhea:
          -Bile acid disorders
          -Infantile Refsum disease
          -Respiratory chain disorders asso with
           steatorrhea
          -Vitamin deficiency osteopenia
          -Hypocholesterolemia
  c. Diarrhea,Failure to thrive,hypotonia,hepatomegaly:
          -Glycogen storage dis 1
          - Wolmans disease
Dr.Padmesh.V
 7. Hepatomegaly :
      -Tyrosinemia
      -Galactosemia
      -Fructosemia
      -Alpha 1 antitrypsin deficiency.
 8. Hepatomegaly + Splenomegaly:
      -Mucolipidosis
      -Gaucher’s dis
      -Niemann-Pick type A
Dr.Padmesh.V
9. Predominant Neurological Symptoms:
 a. Psychomotor delay:
      -Aminoacidopathies
      -Organic acidemias
      -CNS storage diseases
 b. Recurrent Reye :
      -Urea cycle defect
      -Systemic carnitine deficiency
 c. Ataxia:
      -Hartnup dis
      -Urea cycle disorders
      -Pyruvate decarboxylase deficiency
 d. Extrapyramidal signs:
      - Wilsons disease
 e. Hypotonia :
      - Zellweger synd
      -Mitochondrial myopathies
      -Muscle carnitine deficiency
Dr.Padmesh.V




  INVESTIGATIONS:
 Metabolic investigations should be initiated as soon
  as the possibility is considered.
 The outcome of treatment of many IEM especially
  those associated with hyperammonemia is directly
  related to the rapidity with which problems are
  detected and treated.
Dr.Padmesh.V


 First line investigations (metabolic screen):
 The following tests should be obtained in all babies with suspected
    IEM.
   1) Complete blood count: (neutropenia and thrombocytopenia
                         seen in propionic and methylmalonic academia)
   2) Arterial blood gases and electrolytes
   3) Blood glucose
   4) Plasma ammonia (Normal values in newborn: 90-150 mg/dl or
                                                      64-107 mmol/L)
   5) Arterial blood lactate (Normal values: 0.5-1.6 mmol/L)
   6) Liver function tests,
   7) Urine ketones,
   8) Urine reducing substances,
   9) Serum uric acid (low in molybdenum cofactor deficiency).
Dr.Padmesh.V
                  Suspected Metabolic disease
                       Plasma Ammonia
       High                                         Normal


  Blood pH, CO2                                 Blood pH, CO2


 Normal                    Acidosis                 Normal
                                               PKU, Non Ketotic hyper
                                               -glycinemia, Peroxisomal
No Ketosis                                                      disorders



Urea Cycle           No Ketosis       Ketosis with/without lactic acidosis
 defect
                     Fatty acid            Organic acidemias
                  oxidation defect       Mitochondrial disorders
Dr.Padmesh.V

    Normal Plasma Ammonia

         No Acidosis




 PKU, Non Ketotic Hyperglycinemia,
Galacosemia, Peroxisomal disorders
Dr.Padmesh.V

High Plasma Ammonia

    No Acidosis

    No Ketosis



UREA CYCLE DEFECT
Dr.Padmesh.V



    Normal or High Plasma Ammonia

              Acidosis

              Ketosis



Organic acidemias, Mitochondrial disorders
Dr.Padmesh.V



Normal or High Plasma Ammonia

         Acidosis

        No Ketosis



 Fatty acid oxidation defects
Dr.Padmesh.V
Dr.Padmesh.V
Dr.Padmesh.V
Dr.Padmesh.V
Categorization of neonatal IEM using metabolic
screening tests:
Dr.Padmesh.V
Dr.Padmesh.V
Dr.Padmesh.V
 Second line investigations
  (ancillary and confirmatory tests)
 These tests need to be performed in a targeted manner, based
  on presumptive diagnosis after first line investigations:

 1) Gas chromatography mass spectrometry (GCMS) of urine- for
  diagnosis of organic acidemias.

 2) Plasma amino acids and acyl carnitine profile: by Tandem
  mass spectrometry (TMS)- for diagnosis of organic
  acidemias, urea cycle defects, aminoacidopathies and fatty acid
  oxidation defects.

 3) High performance liquid chromatography (HPLC): for
  quantitative analysis of amino acids in blood and urine; required
  for diagnosis of organic acidemias and aminoacidopathies.
Dr.Padmesh.V


 4) Lactate/pyruvate ratio- in cases with elevated lactate.

 5) Urinary orotic acid- in cases with hyperammonemia for
  classification of urea cycle defect.

 6) Enzyme assay: This is required for definitive
  diagnosis, but not available for most IEM’s.
  Available enzyme assays include:
       -Biotinidase assay- in cases with suspected
  biotinidase deficiency (intractable seizures, seborrheic
  rash, alopecia);
       -GALT (galactose 1-phosphate uridyl transferase )
  assay- in cases with suspected galactosemia
  (hypoglycemia, cataracts, reducing sugars in urine).
Dr.Padmesh.V
 7) Neuroimaging: MRI
 Some IEM may be associated with structural
    malformations . Examples:
   Zellweger syndrome has diffuse cortical migration and
    sulcation abnormalities.
   Agenesis of corpus callosum has been reported in
    Menke’s disease, pyruvate decarboxylase deficiency and
    nonketotic hyperglycinemia.
   Maple syrup urine disease (MSUD): brainstem and
    cerebellar edema.
   Propionic & methylmalonic acidemia: basal ganglia signal
    change.
   Glutaric aciduria: frontotemporal atrophy, subdural
    hematomas.
Dr.Padmesh.V


 8) Magnetic resonance spectroscopy (MRS): may be helpful in
  selected disorders
 E.g. lactate peak elevated in mitochondrial disorders, leucine peak
  elevated in MSUD.

 9) Electroencephalography (EEG):
 Comb-like rhythm in MSUD,
 Burst suppression in Non Ketotic Hyperglycemia and
   holocarboxylase synthetase deficiency.

 10) Plasma very long chain fatty acid (VLCFA) levels: elevated in
   peroxisomal disorders.

 11)Mutation analysis when available.

 12) CSF aminoacid analysis: CSF Glycine levels elevated in NKH.
Dr.Padmesh.V




         TREATMENT:
 In most cases, treatment needs to be instituted empirically
  without a specific diagnosis.
 The metabolic screen helps to broadly categorize the patient’s
  IEM (e.g. urea cycle defect, organic academia,
  congenital lactic acidosis etc), on the basis of which, empirical
  treatment can be instituted
Dr.Padmesh.V
 Aims of treatment
 1. To reduce the formation of toxic metabolites by decreasing
   substrate availability (by stopping feeds and preventing endogenous
   catabolism)
 2. To provide adequate calories.
 3. To enhance the excretion of toxic metabolites.
 4. To institute co-factor therapy for specific disease and also
   empirically if diagnosis not established.
 5. Supportive care-
     -Treatment of seizures (avoid sodium valproate –
                         may increase ammonia levels),
     -Maintain euglycemia and normothermia,
     -Fluid, electrolyte & acid-base balance,
     -Treatment of infection,
     -Mechanical ventilation if required.
Dr.Padmesh.V
 Management of hyperammonemia:
   1) Discontinue all feeds. Provide adequate calories by intravenous glucose and
       lipids. Maintain glucose infusion rate 8-10mg/kg/min. Start intravenous lipid
       0.5 g/kg/day (up to 3 g/kg/day). After stabilization gradually add protein 0.25
       g/kg till 1.5 g/kg/day.

   2) Dialysis is the only means for rapid removal of ammonia, and hemodialysis is
       more effective and faster than peritoneal dialysis. Exchange transfusion is
       not useful.

   3) Alternative pathways for nitrogen excretion-:
        -Sodium benzoate (IV/oral)- loading dose 250 mg/kg then 250-400 mg/kg/day
         in 4 divided doses. (Intravenous preparation not available in India.)
        -Sodium phenylbutyrate (not available in India)-loading dose 250 mg/kg
         followed by 250-500 mg/kg/day.
        -L-arginine (oral or IV)- 300 mg/kg/day (IV preparation not available in India)
        -L-carnitine (oral or IV)- 200 mg/kg/day

   4) Supportive care: Treatment of sepsis,seizures,ventilation.
                       Avoid sodium valproate.
Dr.Padmesh.V

 Acute management of newborn with suspected
  organic acidemia:
 1) The patient is kept nil per orally and intravenous glucose is provided.

 2) Supportive care: hydration, treatment of sepsis, seizures, ventilation.

 3) Carnitine: 100 mg/kg/day IV or oral.

 4) Treat acidosis: Sodium bicarbonate 0.35-0.5mEq/kg/hr (max 1-
   2mEq/kg/hr)

 5) Start Biotin 10 mg/day orally.

 6) Start Vitamin B12 1-2 mg/day I/M (useful in B12 responsive forms of
   methylmalonic acidemias)

 7) Start Thiamine 300 mg/day (useful in Thiamine-responsive variants of
   MSUD).
Dr.Padmesh.V

 Management of congenital lactic acidosis:
 1) Supportive care: hydration, treatment of sepsis, seizures, ventilation.
   Avoid sodium valproate.


 2) Treat acidosis: sodium bicarbonate 0.35-0.5mEq/kg/hr
                                         (max 1-2mEq/kg/hr)


 3) Thiamine: up to 300 mg/day in 4 divided doses.


 4) Riboflavin: 100 mg/day in 4 divided doses.


 5) Add co-enzyme Q: 5-15 mg/kg/day


 6) L-carnitine: 50-100 mg/kg orally.
Dr.Padmesh.V

 Treatment of newborn with refractory seizures
  with no obvious etiology (suspected metabolic
  etiology):
 1) If patient persists to have seizures despite 2 or 3
  antiepileptic drugs in adequate doses, consider trial of
  pyridoxine 100 mg intravenously. If intravenous preparation
  not available, oral pyridoxine can be given (15 mg/kg/day).

 2) If seizures persist despite pyridoxine, give trial of biotin 10
  mg/day and folinic acid 15 mg/day (folinic acid responsive
  seizures).

 3) Rule out glucose transporter defect: measure CSF and blood
  glucose. This disorder responds to the ketogenic diet.
Dr.Padmesh.V

 Management of asymptomatic newborn
   with a history of sibling death with
   suspected IEM:
 1) After baseline metabolic screen, start oral dextrose feeds (10%
   dextrose).
 2) After 24 hours, repeat screen. If normal, start breast feeds.
   Monitor sugar, blood gases and urine ketones, blood ammonia Q6
   hourly.
 3) Some recommend starting medium chain triglycerides (MCT oil)
   before starting breast feeds,
 4) After 48 hours, repeat metabolic screen. Obtain samples for urine
   organic acid tests.
 5) The infant will need careful observation and follow-up for the first
   few months, as IEM may present in different age groups in members
   of the same family.
Dr.Padmesh.V


 Long term treatment of IEM
 1) Dietary treatment: This is the mainstay of treatment in
  phenylketonuria, maple syrup urine
  disease, homocystinuria, galactosemia, and glycogen storage
  disease Type I & III.
 Some disorders like urea cycle disorders and organic acidurias
  require dietary modification (protein restriction) in addition to
  other modalities.
 2) Enzyme replacement therapy (ERT): ERT is now
  commercially available for some lysosomal storage disorders.
  However, these disorders do not manifest in the newborn
  period, except Pompe’s disease (Glycogen storage disorder
  Type II) which may present in the newborn period and for
  which ERT is now available.
Dr.Padmesh.V
3) Cofactor replacement therapy:
The catalytic properties of many enzymes depend on the participation
of non protein prosthetic groups, such as vitamins and minerals,as
obligatory cofactors.
Dr.Padmesh.V




PREVENTION
Dr.Padmesh.V


1.Genetic counselling and prenatal diagnosis:
    Most of the IEM are single gene defects, inherited in an autosomal recessive
    manner, with a 25% recurrence risk.
   Therefore when the diagnosis is known and confirmed in the index case, prenatal
    diagnosis can be offered wherever available for the subsequent pregnancies.


   The samples required are Chorionic Villous tissue or Amniotic fluid.


   Modalities available are:
       -Substrate or metabolite detection: useful in phenylketonuria, peroxisomal
                                                                                defects.
       -Enzyme assay: useful in lysosomal storage disorders like Niemann-Pick
                                                        disease, Gaucher disease.
       -DNA based (molecular) diagnosis: Detection of mutation in proband/
                                           carrier parents is a prerequisite.
Dr.Padmesh.V
 2) Neonatal screening:
 Tandem mass spectrometry is used in some countries for
  neonatal screening for IEM.
 Disorders which can be detected by TMS include
     -Aminoacidopathies (
  phenylketonuria, MSUD, Homocystinuria, Citrullinemia,Argini
  nosuccinic aciduria, hepatorenal tyrosinemia),
    -Fatty acid oxidation defects,
    -Organic acidemias (glutaric aciduria, propionic
  acidemia, methylmalonic acidemia, isovaleric acidemia).
 The cost of this procedure is very high.
 Also, though the test is highly sensitive, the specificity is
  relatively low; and there are difficulties in interpretation of
  abnormal test results in apparently healthy infants.
Dr.Padmesh.V
 Reference:
1. Nelson’s textbook of Pediatrics, 18th ed.
2. Essential Pediatrics, 7th ed., O.P.Ghai.
3. Care of the Newborn, 6th ed., Meharban Singh.
4. Current Pediatric Diagnosis & Treatment
   (CPDT), 18th ed.
3. A Clinical Guide to Inherited Metabolic
   Diseases, 2nd ed, Joe T. R. Clarke.
4. AIMS NICU Protocol 2008.
5. Indian Journal of Pediatrics, Vol 72- Apr,2005
Dr.Padmesh.V

More Related Content

What's hot

Approach to a child with failure to thrive
Approach to a child with failure to thriveApproach to a child with failure to thrive
Approach to a child with failure to thrive
Singaram_Paed
 
Gaucher Disease
Gaucher DiseaseGaucher Disease
Gaucher Disease
fitango
 

What's hot (20)

Phenylketonuria (PKU)
Phenylketonuria (PKU)Phenylketonuria (PKU)
Phenylketonuria (PKU)
 
Inborn error of metabolism
Inborn error of metabolismInborn error of metabolism
Inborn error of metabolism
 
Thalassemia.
Thalassemia.Thalassemia.
Thalassemia.
 
Approach to anemia in children
Approach to anemia in childrenApproach to anemia in children
Approach to anemia in children
 
Hypoglycemia in children
Hypoglycemia in childrenHypoglycemia in children
Hypoglycemia in children
 
Mitochondrial diseases
Mitochondrial diseasesMitochondrial diseases
Mitochondrial diseases
 
Overview of Inborn errors of metabolism
Overview of Inborn errors of metabolism Overview of Inborn errors of metabolism
Overview of Inborn errors of metabolism
 
G6PD Deficiency Anaemai
G6PD Deficiency AnaemaiG6PD Deficiency Anaemai
G6PD Deficiency Anaemai
 
Neonatal Cholestasis
Neonatal CholestasisNeonatal Cholestasis
Neonatal Cholestasis
 
Approach to a child with failure to thrive
Approach to a child with failure to thriveApproach to a child with failure to thrive
Approach to a child with failure to thrive
 
Gaucher disease
Gaucher diseaseGaucher disease
Gaucher disease
 
Niemann Pick Disease (Nafisa Nawal Islam)
Niemann Pick Disease (Nafisa Nawal Islam)Niemann Pick Disease (Nafisa Nawal Islam)
Niemann Pick Disease (Nafisa Nawal Islam)
 
Inborn errors of metabolism
Inborn errors of metabolism Inborn errors of metabolism
Inborn errors of metabolism
 
Hemoglobinopathies
Hemoglobinopathies Hemoglobinopathies
Hemoglobinopathies
 
Celiac disease in children 2021
Celiac disease in children 2021Celiac disease in children 2021
Celiac disease in children 2021
 
Galactosemia
GalactosemiaGalactosemia
Galactosemia
 
Alkaptonuria
AlkaptonuriaAlkaptonuria
Alkaptonuria
 
Homocystinuria
HomocystinuriaHomocystinuria
Homocystinuria
 
Gaucher Disease
Gaucher DiseaseGaucher Disease
Gaucher Disease
 
Approach to inborn error of metabolism
Approach  to inborn error of metabolismApproach  to inborn error of metabolism
Approach to inborn error of metabolism
 

Viewers also liked

Photophosphorylation
PhotophosphorylationPhotophosphorylation
Photophosphorylation
carissaf
 
Gluconeogenesis
GluconeogenesisGluconeogenesis
Gluconeogenesis
martin1950
 
Nitrogen cycle
Nitrogen cycleNitrogen cycle
Nitrogen cycle
Carla Palo
 

Viewers also liked (14)

Metabolic Disorders of Phenylalanine and Tyrosine
Metabolic Disorders of Phenylalanine and TyrosineMetabolic Disorders of Phenylalanine and Tyrosine
Metabolic Disorders of Phenylalanine and Tyrosine
 
Inborn errors of metabolism
Inborn errors of metabolismInborn errors of metabolism
Inborn errors of metabolism
 
Photophosphorylation
PhotophosphorylationPhotophosphorylation
Photophosphorylation
 
Ketone bodies
Ketone bodiesKetone bodies
Ketone bodies
 
Thermodynamics ppt
Thermodynamics pptThermodynamics ppt
Thermodynamics ppt
 
Gluconeogenesis
GluconeogenesisGluconeogenesis
Gluconeogenesis
 
Gluconeogenesis
GluconeogenesisGluconeogenesis
Gluconeogenesis
 
BETA-OXIDATION OF FATTY ACIDS
BETA-OXIDATION OF FATTY ACIDSBETA-OXIDATION OF FATTY ACIDS
BETA-OXIDATION OF FATTY ACIDS
 
Photosynthesis Powerpoint
Photosynthesis PowerpointPhotosynthesis Powerpoint
Photosynthesis Powerpoint
 
Nitrogen cycle
Nitrogen cycleNitrogen cycle
Nitrogen cycle
 
Cholesterol synthesis steps and regulation
Cholesterol synthesis   steps and regulationCholesterol synthesis   steps and regulation
Cholesterol synthesis steps and regulation
 
Photosynthesis
PhotosynthesisPhotosynthesis
Photosynthesis
 
Nitrogen cycle
Nitrogen cycleNitrogen cycle
Nitrogen cycle
 
Fatty acid synthesis
Fatty acid synthesisFatty acid synthesis
Fatty acid synthesis
 

Similar to Approach to Inborn Errors of Metabolism .. Dr.Padmesh

Lesson 7.1 inborn errors of metabolism
Lesson 7.1 inborn errors of metabolism Lesson 7.1 inborn errors of metabolism
Lesson 7.1 inborn errors of metabolism
princesa2000
 
DISORDER OF LIPIDS METABOLISM PART 1.pptx
DISORDER OF LIPIDS METABOLISM PART 1.pptxDISORDER OF LIPIDS METABOLISM PART 1.pptx
DISORDER OF LIPIDS METABOLISM PART 1.pptx
Mkindi Mkindi
 
inbornerrorsofcarbohydratemetabolismseminaron18-2-2011-151129054802-lva1-app6...
inbornerrorsofcarbohydratemetabolismseminaron18-2-2011-151129054802-lva1-app6...inbornerrorsofcarbohydratemetabolismseminaron18-2-2011-151129054802-lva1-app6...
inbornerrorsofcarbohydratemetabolismseminaron18-2-2011-151129054802-lva1-app6...
tejasvivats
 

Similar to Approach to Inborn Errors of Metabolism .. Dr.Padmesh (20)

Iems
IemsIems
Iems
 
IEM2.pptx
IEM2.pptxIEM2.pptx
IEM2.pptx
 
Inborn errors of lipid metabolism
Inborn errors of lipid metabolismInborn errors of lipid metabolism
Inborn errors of lipid metabolism
 
approachtoiem-dr-padmesh-111129123245-phpapp01.pptx
approachtoiem-dr-padmesh-111129123245-phpapp01.pptxapproachtoiem-dr-padmesh-111129123245-phpapp01.pptx
approachtoiem-dr-padmesh-111129123245-phpapp01.pptx
 
Inborn Errors of Metabolism.pptx
Inborn Errors of Metabolism.pptxInborn Errors of Metabolism.pptx
Inborn Errors of Metabolism.pptx
 
Lesson 7.1 inborn errors of metabolism
Lesson 7.1 inborn errors of metabolism Lesson 7.1 inborn errors of metabolism
Lesson 7.1 inborn errors of metabolism
 
Neonate iem may 2021
Neonate iem  may 2021Neonate iem  may 2021
Neonate iem may 2021
 
Pediatrics 5th year, 15th lecture/part one (Dr. Jamal)
Pediatrics 5th year, 15th lecture/part one (Dr. Jamal)Pediatrics 5th year, 15th lecture/part one (Dr. Jamal)
Pediatrics 5th year, 15th lecture/part one (Dr. Jamal)
 
DISORDER OF LIPIDS METABOLISM PART 1.pptx
DISORDER OF LIPIDS METABOLISM PART 1.pptxDISORDER OF LIPIDS METABOLISM PART 1.pptx
DISORDER OF LIPIDS METABOLISM PART 1.pptx
 
Inborn error approach.pptx
Inborn error approach.pptxInborn error approach.pptx
Inborn error approach.pptx
 
Genetics, IEM.ppt
Genetics, IEM.pptGenetics, IEM.ppt
Genetics, IEM.ppt
 
Metabolic Disorders-September 2012.ppt a
Metabolic Disorders-September 2012.ppt aMetabolic Disorders-September 2012.ppt a
Metabolic Disorders-September 2012.ppt a
 
inbornerrorsofcarbohydratemetabolismseminaron18-2-2011-151129054802-lva1-app6...
inbornerrorsofcarbohydratemetabolismseminaron18-2-2011-151129054802-lva1-app6...inbornerrorsofcarbohydratemetabolismseminaron18-2-2011-151129054802-lva1-app6...
inbornerrorsofcarbohydratemetabolismseminaron18-2-2011-151129054802-lva1-app6...
 
Inborn errors of carbohydrate metabolism
Inborn errors of carbohydrate metabolismInborn errors of carbohydrate metabolism
Inborn errors of carbohydrate metabolism
 
Iem heart disease 26july 2015
Iem    heart disease  26july 2015Iem    heart disease  26july 2015
Iem heart disease 26july 2015
 
Inborn_Errors_of_Metabolism.ppt for msc biochemistry
Inborn_Errors_of_Metabolism.ppt for msc biochemistryInborn_Errors_of_Metabolism.ppt for msc biochemistry
Inborn_Errors_of_Metabolism.ppt for msc biochemistry
 
INBORN ERRORS OF METABOLISM(IEMs).pptx
INBORN ERRORS OF METABOLISM(IEMs).pptxINBORN ERRORS OF METABOLISM(IEMs).pptx
INBORN ERRORS OF METABOLISM(IEMs).pptx
 
Inborn errors of metabolism
Inborn errors of metabolism Inborn errors of metabolism
Inborn errors of metabolism
 
APPROACH TO A CHILD WITH IEM DR GRK.pptx
APPROACH TO A CHILD WITH IEM DR GRK.pptxAPPROACH TO A CHILD WITH IEM DR GRK.pptx
APPROACH TO A CHILD WITH IEM DR GRK.pptx
 
ENZYMES INHERITED ENZYMOPATHIES. APPLICATION OF ENZYME IN THE TREATMENT OF DI...
ENZYMES INHERITED ENZYMOPATHIES. APPLICATION OF ENZYME IN THE TREATMENT OF DI...ENZYMES INHERITED ENZYMOPATHIES. APPLICATION OF ENZYME IN THE TREATMENT OF DI...
ENZYMES INHERITED ENZYMOPATHIES. APPLICATION OF ENZYME IN THE TREATMENT OF DI...
 

More from Dr Padmesh Vadakepat

More from Dr Padmesh Vadakepat (20)

Neonatal Nursing of Extremely Premature Neonates - Dr Padmesh
Neonatal Nursing of Extremely Premature Neonates - Dr PadmeshNeonatal Nursing of Extremely Premature Neonates - Dr Padmesh
Neonatal Nursing of Extremely Premature Neonates - Dr Padmesh
 
Update on Antenatal Steroids 2021 - Dr Padmesh
Update on Antenatal Steroids 2021  - Dr PadmeshUpdate on Antenatal Steroids 2021  - Dr Padmesh
Update on Antenatal Steroids 2021 - Dr Padmesh
 
Inhaled Nitric Oxide (iNO) in Newborns - Dr Padmesh - Neonatology
Inhaled Nitric Oxide (iNO) in Newborns - Dr Padmesh - NeonatologyInhaled Nitric Oxide (iNO) in Newborns - Dr Padmesh - Neonatology
Inhaled Nitric Oxide (iNO) in Newborns - Dr Padmesh - Neonatology
 
Approach to Ano Rectal Malformations - Dr Padmesh - Neonatology
Approach to Ano Rectal Malformations - Dr Padmesh - NeonatologyApproach to Ano Rectal Malformations - Dr Padmesh - Neonatology
Approach to Ano Rectal Malformations - Dr Padmesh - Neonatology
 
ROP - Dr Padmesh - Neonatology
ROP  - Dr Padmesh - NeonatologyROP  - Dr Padmesh - Neonatology
ROP - Dr Padmesh - Neonatology
 
Blood Group Selection in Newborn Transfusion - Dr Padmesh - Neonatology
Blood Group Selection in Newborn Transfusion  - Dr Padmesh - NeonatologyBlood Group Selection in Newborn Transfusion  - Dr Padmesh - Neonatology
Blood Group Selection in Newborn Transfusion - Dr Padmesh - Neonatology
 
Vaccination in Preterms by - Dr Padmesh - Neonatology
Vaccination in Preterms by  - Dr Padmesh - NeonatologyVaccination in Preterms by  - Dr Padmesh - Neonatology
Vaccination in Preterms by - Dr Padmesh - Neonatology
 
European Consensus Statement on RDS 2019
European Consensus Statement on RDS 2019European Consensus Statement on RDS 2019
European Consensus Statement on RDS 2019
 
Blood Brain Barrier by Dr Padmesh V
Blood Brain Barrier by Dr Padmesh VBlood Brain Barrier by Dr Padmesh V
Blood Brain Barrier by Dr Padmesh V
 
Humidication in NICU - Dr Padmesh - Neonatology
Humidication in NICU - Dr Padmesh - NeonatologyHumidication in NICU - Dr Padmesh - Neonatology
Humidication in NICU - Dr Padmesh - Neonatology
 
Subgaleal Hemorrhage - Dr Padmesh - Neonatology
Subgaleal Hemorrhage - Dr Padmesh - NeonatologySubgaleal Hemorrhage - Dr Padmesh - Neonatology
Subgaleal Hemorrhage - Dr Padmesh - Neonatology
 
Touch and Massage Therapy in Newborn - Dr Padmesh V
Touch and Massage Therapy in Newborn - Dr Padmesh VTouch and Massage Therapy in Newborn - Dr Padmesh V
Touch and Massage Therapy in Newborn - Dr Padmesh V
 
Perinatal infections- Diagnosis & Management - Dr Padmesh - Neonatology
Perinatal infections- Diagnosis & Management  - Dr Padmesh - NeonatologyPerinatal infections- Diagnosis & Management  - Dr Padmesh - Neonatology
Perinatal infections- Diagnosis & Management - Dr Padmesh - Neonatology
 
Shock & Inotropes in Neonates - Dr Padmesh - Neonatology
Shock & Inotropes in Neonates  - Dr Padmesh - NeonatologyShock & Inotropes in Neonates  - Dr Padmesh - Neonatology
Shock & Inotropes in Neonates - Dr Padmesh - Neonatology
 
ABC of ABG - Dr Padmesh
ABC of ABG - Dr PadmeshABC of ABG - Dr Padmesh
ABC of ABG - Dr Padmesh
 
Assessment of Fetal Well being - Dr Padmesh - Neonatology
Assessment of Fetal Well being - Dr Padmesh - NeonatologyAssessment of Fetal Well being - Dr Padmesh - Neonatology
Assessment of Fetal Well being - Dr Padmesh - Neonatology
 
Ballard score.. - Dr Padmesh - Neonatology
Ballard score..  - Dr Padmesh - NeonatologyBallard score..  - Dr Padmesh - Neonatology
Ballard score.. - Dr Padmesh - Neonatology
 
European Consensus Guidelines- RDS in Preterm Newborns
European Consensus Guidelines- RDS in Preterm NewbornsEuropean Consensus Guidelines- RDS in Preterm Newborns
European Consensus Guidelines- RDS in Preterm Newborns
 
Say NO to drugs .. Dr.Padmesh
Say NO to drugs .. Dr.PadmeshSay NO to drugs .. Dr.Padmesh
Say NO to drugs .. Dr.Padmesh
 
Pulmonary Abscess in Children .. Dr Padmesh
Pulmonary Abscess in Children .. Dr PadmeshPulmonary Abscess in Children .. Dr Padmesh
Pulmonary Abscess in Children .. Dr Padmesh
 

Recently uploaded

Best medicine 100% Effective&Safe Mifepristion ௵+918133066128௹Abortion pills ...
Best medicine 100% Effective&Safe Mifepristion ௵+918133066128௹Abortion pills ...Best medicine 100% Effective&Safe Mifepristion ௵+918133066128௹Abortion pills ...
Best medicine 100% Effective&Safe Mifepristion ௵+918133066128௹Abortion pills ...
Abortion pills in Kuwait Cytotec pills in Kuwait
 

Recently uploaded (20)

Overview on the Automatic pill identifier
Overview on the Automatic pill identifierOverview on the Automatic pill identifier
Overview on the Automatic pill identifier
 
Cervical screening – taking care of your health flipchart (Vietnamese)
Cervical screening – taking care of your health flipchart (Vietnamese)Cervical screening – taking care of your health flipchart (Vietnamese)
Cervical screening – taking care of your health flipchart (Vietnamese)
 
VVIP Yelahanka ℂall Girls 6350482085 Heat-immolating { Bangalore } Coveted Gi...
VVIP Yelahanka ℂall Girls 6350482085 Heat-immolating { Bangalore } Coveted Gi...VVIP Yelahanka ℂall Girls 6350482085 Heat-immolating { Bangalore } Coveted Gi...
VVIP Yelahanka ℂall Girls 6350482085 Heat-immolating { Bangalore } Coveted Gi...
 
Let's Talk About It: Ovarian Cancer (The Emotional Toll of Treatment Decision...
Let's Talk About It: Ovarian Cancer (The Emotional Toll of Treatment Decision...Let's Talk About It: Ovarian Cancer (The Emotional Toll of Treatment Decision...
Let's Talk About It: Ovarian Cancer (The Emotional Toll of Treatment Decision...
 
The Orbit & its contents by Dr. Rabia I. Gandapore.pptx
The Orbit & its contents by Dr. Rabia I. Gandapore.pptxThe Orbit & its contents by Dr. Rabia I. Gandapore.pptx
The Orbit & its contents by Dr. Rabia I. Gandapore.pptx
 
ANAPHYLAXIS BY DR.SOHAN BISWAS,MBBS,DNB(INTERNAL MEDICINE) RESIDENT.pptx
ANAPHYLAXIS BY DR.SOHAN BISWAS,MBBS,DNB(INTERNAL MEDICINE) RESIDENT.pptxANAPHYLAXIS BY DR.SOHAN BISWAS,MBBS,DNB(INTERNAL MEDICINE) RESIDENT.pptx
ANAPHYLAXIS BY DR.SOHAN BISWAS,MBBS,DNB(INTERNAL MEDICINE) RESIDENT.pptx
 
DR. Neha Mehta Best Psychologist.in India
DR. Neha Mehta Best Psychologist.in IndiaDR. Neha Mehta Best Psychologist.in India
DR. Neha Mehta Best Psychologist.in India
 
Tips and tricks to pass the cardiovascular station for PACES exam
Tips and tricks to pass the cardiovascular station for PACES examTips and tricks to pass the cardiovascular station for PACES exam
Tips and tricks to pass the cardiovascular station for PACES exam
 
Unlocking Holistic Wellness: Addressing Depression, Mental Well-Being, and St...
Unlocking Holistic Wellness: Addressing Depression, Mental Well-Being, and St...Unlocking Holistic Wellness: Addressing Depression, Mental Well-Being, and St...
Unlocking Holistic Wellness: Addressing Depression, Mental Well-Being, and St...
 
Integrated Neuromuscular Inhibition Technique (INIT)
Integrated Neuromuscular Inhibition Technique (INIT)Integrated Neuromuscular Inhibition Technique (INIT)
Integrated Neuromuscular Inhibition Technique (INIT)
 
Premium ℂall Girls In Mumbai👉 Dail ℂALL ME: 📞9833325238 📲 ℂall Richa VIP ℂall...
Premium ℂall Girls In Mumbai👉 Dail ℂALL ME: 📞9833325238 📲 ℂall Richa VIP ℂall...Premium ℂall Girls In Mumbai👉 Dail ℂALL ME: 📞9833325238 📲 ℂall Richa VIP ℂall...
Premium ℂall Girls In Mumbai👉 Dail ℂALL ME: 📞9833325238 📲 ℂall Richa VIP ℂall...
 
Best medicine 100% Effective&Safe Mifepristion ௵+918133066128௹Abortion pills ...
Best medicine 100% Effective&Safe Mifepristion ௵+918133066128௹Abortion pills ...Best medicine 100% Effective&Safe Mifepristion ௵+918133066128௹Abortion pills ...
Best medicine 100% Effective&Safe Mifepristion ௵+918133066128௹Abortion pills ...
 
Cardiovascular Physiology - Regulation of Cardiac Pumping
Cardiovascular Physiology - Regulation of Cardiac PumpingCardiovascular Physiology - Regulation of Cardiac Pumping
Cardiovascular Physiology - Regulation of Cardiac Pumping
 
Evidence-based practiceEBP) in physiotherapy
Evidence-based practiceEBP) in physiotherapyEvidence-based practiceEBP) in physiotherapy
Evidence-based practiceEBP) in physiotherapy
 
A thorough review of supernormal conduction.pptx
A thorough review of supernormal conduction.pptxA thorough review of supernormal conduction.pptx
A thorough review of supernormal conduction.pptx
 
5Cladba ADBB 5cladba buy 6cl adbb powder 5cl ADBB precursor materials
5Cladba ADBB 5cladba buy 6cl adbb powder 5cl ADBB precursor materials5Cladba ADBB 5cladba buy 6cl adbb powder 5cl ADBB precursor materials
5Cladba ADBB 5cladba buy 6cl adbb powder 5cl ADBB precursor materials
 
Tips to Choose the Best Psychiatrists in Indore
Tips to Choose the Best Psychiatrists in IndoreTips to Choose the Best Psychiatrists in Indore
Tips to Choose the Best Psychiatrists in Indore
 
Creating Accessible Public Health Communications
Creating Accessible Public Health CommunicationsCreating Accessible Public Health Communications
Creating Accessible Public Health Communications
 
Is Rheumatoid Arthritis a Metabolic Disorder.pptx
Is Rheumatoid Arthritis a Metabolic Disorder.pptxIs Rheumatoid Arthritis a Metabolic Disorder.pptx
Is Rheumatoid Arthritis a Metabolic Disorder.pptx
 
Denture base resins materials and its mechanism of action
Denture base resins materials and its mechanism of actionDenture base resins materials and its mechanism of action
Denture base resins materials and its mechanism of action
 

Approach to Inborn Errors of Metabolism .. Dr.Padmesh

  • 1. APPROACH TO INBORN ERRORS OF METABOLISM DR.PADMESH.V DEPT OF PEDIATRICS, DR.SMCSI MCH, KARAKONAM.
  • 2. Dr.Padmesh.V METABOLISM  Metabolism Catabolism (Breaking down) Anabolism (Building up)  Enzymes play an important role in facilitating the process by serving as catalysts in the conversion of one chemical (metabolite) to another.
  • 3. Dr.Padmesh.V  Catabolism :  Catabolism is the set of metabolic pathways that break down molecules into smaller units and release energy.
  • 4. Dr.Padmesh.V  Catabolism :  Catabolism is the set of metabolic pathways that break down molecules into smaller units and release energy.
  • 5. Dr.Padmesh.V  Anabolism :  Anabolism is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy.
  • 6. Dr.Padmesh.V  Anabolism :  Anabolism is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy.
  • 7. Dr.Padmesh.V  Anabolism :  Anabolism is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy.
  • 8.  Inborn errors of metabolism (IEM) Dr.Padmesh.V - Inborn errors of metabolism (IEM) are disorders in which there is a block at some point in the normal metabolic pathway - IEMs occur due to mutations in DNA. DNA Enzyme which code for a Receptor Specific protein Transport vehicle Membrane pump Structural element
  • 9. Dr.Padmesh.V  Example of mechanisms in IEM: Precursor Substrate End-Product A B C
  • 10. Dr.Padmesh.V  Example of mechanisms in IEM: Precursor Substrate End-Product A B C Abnormal metabolic pathway Toxic Metabolite D
  • 11. Dr.Padmesh.V  The number of diseases due to inherited point defects in metabolism now exceeds 500.  While the diseases individually are rare, they collectively account for a significant proportion of neonatal and childhood morbidity and mortality.  Diagnosis is important not only for treatment but also for genetic counselling and antenatal diagnosis in subsequent pregnancies.
  • 12. Dr.Padmesh.V  CLASSIFICATION OF IEM: 1. Amino acid metabolism 2. Carbohydrate metabolism 3. Lipid metabolism 4. Protein metabolism 5. Pigment metabolism 6. Unknown biochemical defects
  • 13. Dr.Padmesh.V  CLASSIFICATION OF IEM: 1. Amino acid metabolism -Phenylketonuria -Tyrosinosis -Albinism -Alkaptonuria -Cystinosis -Cystinuria -Homocysteinuria -Hartnup disease -Maple syrup disease
  • 14. Dr.Padmesh.V  CLASSIFICATION OF IEM: 2. Carbohydrate synthesis: -Congenital lactose intolerance -Galatosemia -Glycogen storage disease -Diabetes mellitus -Scurvy
  • 15. Dr.Padmesh.V  CLASSIFICATION OF IEM: 3. Lipid metabolism: -Abetalipoproteinemia -Progressive lipodystrophy -Lipid storage disorders * Gaucher * Neimann-Pick * Tay-sachs * Hyperlipoproteinemia
  • 16. Dr.Padmesh.V  CLASSIFICATION OF IEM: 4. Protein Metabolism: -Immunoglobulin deficiencies -Absent clotting factors (Hemophilia, Christmas dis, Hypoprothrombinemia) -Metal binding protein deficiency (Wilson hepatolenticular degeneration) -Alpha-1 anti trypsin deficiency
  • 17. Dr.Padmesh.V  CLASSIFICATION OF IEM: 5. Pigment metabolism: -Porphyrias -Methemoglobinemias -Albinism -Crigler-Najjar dis -Dubin-Johnson dis -Gilbert dis -Rotor synd -Primary hemochromatosis
  • 18. Dr.Padmesh.V  CLASSIFICATION OF IEM: 6. Unknown biochemical defect: -Osteogenesis imperfecta -Marfan synd -Achondroplasia -Ehler danlos synd
  • 20. Dr.Padmesh.V 1. Suspecting Inborn Errors:
  • 21. Dr.Padmesh.V  Suspecting Inborn Errors:  Inborn errors should be suspected when  HISTORY: (1) Symptoms accompany starting/changes in diet, (2) Children with seizures, (3) Developmental delay, (4) Recurrent vomiting, (5) Unusual odour of urine, (6) Parental consanguinity, (7) Problems suggestive of inborn error such as retardation or unexplained deaths in first- and second-degree relatives.
  • 22. Dr.Padmesh.V Suspecting Inborn Errors: CLINICALLY: IEM must be also considered in the differential diagnosis of  Critically ill newborns,  Neurodegeneration,  Mental retardation ,  Coarse facies / dysmorphic features,  Parenchymal liver disease,  Cardiomyopathy,  Organomegaly  Unexplained acidosis,  Corneal opacity, cataract or dislocation of lens,  Hyperammonemia, and  Hypoglycemia
  • 23. Dr.Padmesh.V  Clinical pointers towards specific IEMs:
  • 24. Dr.Padmesh.V Inborn Errors of Amino Acid Metabolism Associated with Peculiar Odour:
  • 25. Dr.Padmesh.V Patterns of Presentation: 1. Encephalopathy with or without metabolic acidosis. 2. Acute liver disease: - Jaundice alone - Hepatic failure - Neonatal cholestasis - Hypoglycemia 3. Dysmorphic features. 4. Cardiac disease. 5. Diarrhea 6. Hepatomegaly +/- Splenomegaly 7. Predominant Neurological symptoms
  • 26. Dr.Padmesh.V  1) Encephalopathy with or without metabolic acidosis:  Encephalopathy, seizures,and tone abnormalities are predominant presenting features of -organic acidemias, -urea cycle defects,and -congenital lactic acidosis.  Intractable seizures are prominent in -pyridoxine dependency, -non-ketotic hyperglycinemia, -molybdenum co-factor defect,and -folinic-acid responsive seizures.
  • 27.  2) Acute liver disease: could manifest as- Dr.Padmesh.V  Jaundice alone: -Gilbert syndrome, -Criggler-Najjar syndrome  Hepatic failure (jaundice, ascites, hypoglycemia, coagulopathy): -Tyrosinemia, -galactosemia, -neonatal hemochromatosis, -glycogen storage disease type IV.  Neonatal cholestasis: -alpha-1 antitrypsin deficiency, -Niemann-Pick disease type C.  Persistent and severe hypoglycemia: -Galactosemia, -fatty acid oxidation defects, -organic acidemias, -glycogen storage disorders and -disorders of gluconeogenesis.
  • 28. Dr.Padmesh.V  3) Dysmorphic features: seen in -Peroxisomal disorders, -Pyruvate dehydrogenase deficiency, -Congenital disorders of glycosylation ,and -Lysosomal storage diseases. Some IEMs may present with non-immune hydrops fetalis -lysosomal storage disorders,and -Congenital disorders of glycosylation.
  • 29. Dr.Padmesh.V  4) Cardiac disease: Cardiomyopathy is a prominent feature in some IEM like in: -Fatty acid oxidation defects, -Glycogen storage disease type II , and -Mitochondrial electron transport chain defects.
  • 30. Dr.Padmesh.V  6. Diarrhea : a. Severe watery diarrhea: - Congenital chloride diarrhea - Galactosemia - Primary lactase,sucrase,isomaltase deficiency. b. Chronic diarrhea: -Bile acid disorders -Infantile Refsum disease -Respiratory chain disorders asso with steatorrhea -Vitamin deficiency osteopenia -Hypocholesterolemia c. Diarrhea,Failure to thrive,hypotonia,hepatomegaly: -Glycogen storage dis 1 - Wolmans disease
  • 31. Dr.Padmesh.V  7. Hepatomegaly : -Tyrosinemia -Galactosemia -Fructosemia -Alpha 1 antitrypsin deficiency.  8. Hepatomegaly + Splenomegaly: -Mucolipidosis -Gaucher’s dis -Niemann-Pick type A
  • 32. Dr.Padmesh.V 9. Predominant Neurological Symptoms: a. Psychomotor delay: -Aminoacidopathies -Organic acidemias -CNS storage diseases b. Recurrent Reye : -Urea cycle defect -Systemic carnitine deficiency c. Ataxia: -Hartnup dis -Urea cycle disorders -Pyruvate decarboxylase deficiency d. Extrapyramidal signs: - Wilsons disease e. Hypotonia : - Zellweger synd -Mitochondrial myopathies -Muscle carnitine deficiency
  • 33. Dr.Padmesh.V INVESTIGATIONS:  Metabolic investigations should be initiated as soon as the possibility is considered.  The outcome of treatment of many IEM especially those associated with hyperammonemia is directly related to the rapidity with which problems are detected and treated.
  • 34. Dr.Padmesh.V  First line investigations (metabolic screen):  The following tests should be obtained in all babies with suspected IEM.  1) Complete blood count: (neutropenia and thrombocytopenia seen in propionic and methylmalonic academia)  2) Arterial blood gases and electrolytes  3) Blood glucose  4) Plasma ammonia (Normal values in newborn: 90-150 mg/dl or 64-107 mmol/L)  5) Arterial blood lactate (Normal values: 0.5-1.6 mmol/L)  6) Liver function tests,  7) Urine ketones,  8) Urine reducing substances,  9) Serum uric acid (low in molybdenum cofactor deficiency).
  • 35. Dr.Padmesh.V Suspected Metabolic disease Plasma Ammonia High Normal Blood pH, CO2 Blood pH, CO2 Normal Acidosis Normal PKU, Non Ketotic hyper -glycinemia, Peroxisomal No Ketosis disorders Urea Cycle No Ketosis Ketosis with/without lactic acidosis defect Fatty acid Organic acidemias oxidation defect Mitochondrial disorders
  • 36. Dr.Padmesh.V Normal Plasma Ammonia No Acidosis PKU, Non Ketotic Hyperglycinemia, Galacosemia, Peroxisomal disorders
  • 37. Dr.Padmesh.V High Plasma Ammonia No Acidosis No Ketosis UREA CYCLE DEFECT
  • 38. Dr.Padmesh.V Normal or High Plasma Ammonia Acidosis Ketosis Organic acidemias, Mitochondrial disorders
  • 39. Dr.Padmesh.V Normal or High Plasma Ammonia Acidosis No Ketosis Fatty acid oxidation defects
  • 43. Dr.Padmesh.V Categorization of neonatal IEM using metabolic screening tests:
  • 46. Dr.Padmesh.V  Second line investigations (ancillary and confirmatory tests)  These tests need to be performed in a targeted manner, based on presumptive diagnosis after first line investigations:  1) Gas chromatography mass spectrometry (GCMS) of urine- for diagnosis of organic acidemias.  2) Plasma amino acids and acyl carnitine profile: by Tandem mass spectrometry (TMS)- for diagnosis of organic acidemias, urea cycle defects, aminoacidopathies and fatty acid oxidation defects.  3) High performance liquid chromatography (HPLC): for quantitative analysis of amino acids in blood and urine; required for diagnosis of organic acidemias and aminoacidopathies.
  • 47. Dr.Padmesh.V  4) Lactate/pyruvate ratio- in cases with elevated lactate.  5) Urinary orotic acid- in cases with hyperammonemia for classification of urea cycle defect.  6) Enzyme assay: This is required for definitive diagnosis, but not available for most IEM’s. Available enzyme assays include: -Biotinidase assay- in cases with suspected biotinidase deficiency (intractable seizures, seborrheic rash, alopecia); -GALT (galactose 1-phosphate uridyl transferase ) assay- in cases with suspected galactosemia (hypoglycemia, cataracts, reducing sugars in urine).
  • 48. Dr.Padmesh.V  7) Neuroimaging: MRI  Some IEM may be associated with structural malformations . Examples:  Zellweger syndrome has diffuse cortical migration and sulcation abnormalities.  Agenesis of corpus callosum has been reported in Menke’s disease, pyruvate decarboxylase deficiency and nonketotic hyperglycinemia.  Maple syrup urine disease (MSUD): brainstem and cerebellar edema.  Propionic & methylmalonic acidemia: basal ganglia signal change.  Glutaric aciduria: frontotemporal atrophy, subdural hematomas.
  • 49. Dr.Padmesh.V  8) Magnetic resonance spectroscopy (MRS): may be helpful in selected disorders  E.g. lactate peak elevated in mitochondrial disorders, leucine peak elevated in MSUD.  9) Electroencephalography (EEG):  Comb-like rhythm in MSUD,  Burst suppression in Non Ketotic Hyperglycemia and holocarboxylase synthetase deficiency.  10) Plasma very long chain fatty acid (VLCFA) levels: elevated in peroxisomal disorders.  11)Mutation analysis when available.  12) CSF aminoacid analysis: CSF Glycine levels elevated in NKH.
  • 50. Dr.Padmesh.V TREATMENT:  In most cases, treatment needs to be instituted empirically without a specific diagnosis.  The metabolic screen helps to broadly categorize the patient’s IEM (e.g. urea cycle defect, organic academia, congenital lactic acidosis etc), on the basis of which, empirical treatment can be instituted
  • 51. Dr.Padmesh.V  Aims of treatment  1. To reduce the formation of toxic metabolites by decreasing substrate availability (by stopping feeds and preventing endogenous catabolism)  2. To provide adequate calories.  3. To enhance the excretion of toxic metabolites.  4. To institute co-factor therapy for specific disease and also empirically if diagnosis not established.  5. Supportive care- -Treatment of seizures (avoid sodium valproate – may increase ammonia levels), -Maintain euglycemia and normothermia, -Fluid, electrolyte & acid-base balance, -Treatment of infection, -Mechanical ventilation if required.
  • 52. Dr.Padmesh.V  Management of hyperammonemia:  1) Discontinue all feeds. Provide adequate calories by intravenous glucose and lipids. Maintain glucose infusion rate 8-10mg/kg/min. Start intravenous lipid 0.5 g/kg/day (up to 3 g/kg/day). After stabilization gradually add protein 0.25 g/kg till 1.5 g/kg/day.  2) Dialysis is the only means for rapid removal of ammonia, and hemodialysis is more effective and faster than peritoneal dialysis. Exchange transfusion is not useful.  3) Alternative pathways for nitrogen excretion-: -Sodium benzoate (IV/oral)- loading dose 250 mg/kg then 250-400 mg/kg/day in 4 divided doses. (Intravenous preparation not available in India.) -Sodium phenylbutyrate (not available in India)-loading dose 250 mg/kg followed by 250-500 mg/kg/day. -L-arginine (oral or IV)- 300 mg/kg/day (IV preparation not available in India) -L-carnitine (oral or IV)- 200 mg/kg/day  4) Supportive care: Treatment of sepsis,seizures,ventilation. Avoid sodium valproate.
  • 53. Dr.Padmesh.V  Acute management of newborn with suspected organic acidemia:  1) The patient is kept nil per orally and intravenous glucose is provided.  2) Supportive care: hydration, treatment of sepsis, seizures, ventilation.  3) Carnitine: 100 mg/kg/day IV or oral.  4) Treat acidosis: Sodium bicarbonate 0.35-0.5mEq/kg/hr (max 1- 2mEq/kg/hr)  5) Start Biotin 10 mg/day orally.  6) Start Vitamin B12 1-2 mg/day I/M (useful in B12 responsive forms of methylmalonic acidemias)  7) Start Thiamine 300 mg/day (useful in Thiamine-responsive variants of MSUD).
  • 54. Dr.Padmesh.V  Management of congenital lactic acidosis:  1) Supportive care: hydration, treatment of sepsis, seizures, ventilation. Avoid sodium valproate.  2) Treat acidosis: sodium bicarbonate 0.35-0.5mEq/kg/hr (max 1-2mEq/kg/hr)  3) Thiamine: up to 300 mg/day in 4 divided doses.  4) Riboflavin: 100 mg/day in 4 divided doses.  5) Add co-enzyme Q: 5-15 mg/kg/day  6) L-carnitine: 50-100 mg/kg orally.
  • 55. Dr.Padmesh.V  Treatment of newborn with refractory seizures with no obvious etiology (suspected metabolic etiology):  1) If patient persists to have seizures despite 2 or 3 antiepileptic drugs in adequate doses, consider trial of pyridoxine 100 mg intravenously. If intravenous preparation not available, oral pyridoxine can be given (15 mg/kg/day).  2) If seizures persist despite pyridoxine, give trial of biotin 10 mg/day and folinic acid 15 mg/day (folinic acid responsive seizures).  3) Rule out glucose transporter defect: measure CSF and blood glucose. This disorder responds to the ketogenic diet.
  • 56. Dr.Padmesh.V  Management of asymptomatic newborn with a history of sibling death with suspected IEM:  1) After baseline metabolic screen, start oral dextrose feeds (10% dextrose).  2) After 24 hours, repeat screen. If normal, start breast feeds. Monitor sugar, blood gases and urine ketones, blood ammonia Q6 hourly.  3) Some recommend starting medium chain triglycerides (MCT oil) before starting breast feeds,  4) After 48 hours, repeat metabolic screen. Obtain samples for urine organic acid tests.  5) The infant will need careful observation and follow-up for the first few months, as IEM may present in different age groups in members of the same family.
  • 57. Dr.Padmesh.V  Long term treatment of IEM  1) Dietary treatment: This is the mainstay of treatment in phenylketonuria, maple syrup urine disease, homocystinuria, galactosemia, and glycogen storage disease Type I & III.  Some disorders like urea cycle disorders and organic acidurias require dietary modification (protein restriction) in addition to other modalities.  2) Enzyme replacement therapy (ERT): ERT is now commercially available for some lysosomal storage disorders. However, these disorders do not manifest in the newborn period, except Pompe’s disease (Glycogen storage disorder Type II) which may present in the newborn period and for which ERT is now available.
  • 58. Dr.Padmesh.V 3) Cofactor replacement therapy: The catalytic properties of many enzymes depend on the participation of non protein prosthetic groups, such as vitamins and minerals,as obligatory cofactors.
  • 60. Dr.Padmesh.V 1.Genetic counselling and prenatal diagnosis: Most of the IEM are single gene defects, inherited in an autosomal recessive manner, with a 25% recurrence risk.  Therefore when the diagnosis is known and confirmed in the index case, prenatal diagnosis can be offered wherever available for the subsequent pregnancies.  The samples required are Chorionic Villous tissue or Amniotic fluid.  Modalities available are: -Substrate or metabolite detection: useful in phenylketonuria, peroxisomal defects. -Enzyme assay: useful in lysosomal storage disorders like Niemann-Pick disease, Gaucher disease. -DNA based (molecular) diagnosis: Detection of mutation in proband/ carrier parents is a prerequisite.
  • 61. Dr.Padmesh.V  2) Neonatal screening:  Tandem mass spectrometry is used in some countries for neonatal screening for IEM.  Disorders which can be detected by TMS include -Aminoacidopathies ( phenylketonuria, MSUD, Homocystinuria, Citrullinemia,Argini nosuccinic aciduria, hepatorenal tyrosinemia), -Fatty acid oxidation defects, -Organic acidemias (glutaric aciduria, propionic acidemia, methylmalonic acidemia, isovaleric acidemia).  The cost of this procedure is very high.  Also, though the test is highly sensitive, the specificity is relatively low; and there are difficulties in interpretation of abnormal test results in apparently healthy infants.
  • 62. Dr.Padmesh.V  Reference: 1. Nelson’s textbook of Pediatrics, 18th ed. 2. Essential Pediatrics, 7th ed., O.P.Ghai. 3. Care of the Newborn, 6th ed., Meharban Singh. 4. Current Pediatric Diagnosis & Treatment (CPDT), 18th ed. 3. A Clinical Guide to Inherited Metabolic Diseases, 2nd ed, Joe T. R. Clarke. 4. AIMS NICU Protocol 2008. 5. Indian Journal of Pediatrics, Vol 72- Apr,2005

Editor's Notes

  1. Zellweger- peroxisomal import disorder.Menkes disease (kinky hair disease) is a progressive neurodegenerative condition inherited as a sex-linked recessive trait. The Menkes gene codes for a copper transporting P-type ATPase, and mutations in the protein are associated with low serum copper and ceruloplasmin levels as well as a defect in copper absorption and transport across the intestines.
  2. Wolman- lipd storage disorder
  3. THAN Transient hyperammonemia of newborn