Race Course Road } Book Call Girls in Bangalore | Whatsapp No 6378878445 VIP ...
Iem pro
1. Approach &
Management of
Inborn Errors of Metabolism
DR R PETER M.D.(PAED)., D.M.(NEO).,
NEONATOLOGIST
GOVT.MEDICAL COLLEGE
PUDUKKOTTAI
2. Introduction
Congenital Metabolic Disorders/ Inherited Metabolic Diseases
• Absence or Abnormality of an enzyme or its cofactor,
• Accumulation or deficiency of a specific metabolite
• Most of these disorders are transmitted as autosomal recessive traits.
• Germ line Mutation/ Sporadic Mutation
‘Metabolic
distress’
3. Staged evaluation
Treatment and prognostication of Index Case
Genetic Counselling and Antenatal diagnosis in subsequent pregnancies
4. Incidence
Disorder Type Incidence
Galactosaemia Carbohydrate Disorder 1 in 23 000 to 1 in 44 000
Ornithine transcarbamylase
deficiency
Urea Cycle Disorder 1 in 14 000
Methylmalonic acidaemia Organic Acidemia 1 in 50 000
Glycogen storage disorder
type 1
Carbohydrate Metabolism 1 in 100 000
Familial
hypercholesterolaemia
Lipid disorder 1 in 500
IEM 1in 800 to 2500 births
10. IEM Vs Non IEM
Poor feeding,
Drowsiness,
Lethargy,
Hypotonia and failure to thrive
o Sepsis,
o Hypoxic-ischemic encephalopathy,
o Duct-dependant cardiac lesions,
o Congenital adrenal hyperplasia and
congenital infections
12. Case Scenario 1
• G6A3P2L0
• USG Cranium & Abdomen / ECHO - Normal
• Baby had Jaundice treated with Phototherapy
• Presented with clinical sepsis / shock/Pustules
• Severe Metabolic acidosis with Hyponatremia
• IEM screening- TMS
• Sepsis screen -
13. Case Scenario 2
• G4P3L1
• Admitted on D15 of life
• Failure to thrive / Dehydration / Excessive Cry/Hyperpigmentation
• Severe Hyponatremia / Hyperkalemia
• Elevated 17 OHP
• Treated with Hydrocortisone, Fludrocortisone and Salt supplementation
• Genetic Study – Autosomal Recessive / Homozygos CAH
14. Case Scenario 3
• Primi
• Admitted for Perinatal Asphyxia /MAS/Pulmonary
Hemorrhage
• Ventilator dependent – 15 days
• Neurosonogram normal and ECHO showed –ASD/PPHN
• Carnitine Uptake defect
• L-Carnitine supplementation 100 mg
15. Deterioration after a period of apparent normalcy
Parental consanguinity
Family history of neonatal deaths
Rapidly progressive encephalopathy and seizures of
unexplained cause
Severe metabolic acidosis
Persistent vomiting
Peculiar odor
Acute fatty liver or HELLP
20. Encephalopathy with or without metabolic acidosis
• Encephalopathy, seizures, and tone abnormalities
• Organic acidemias
• Urea cycle defects
• Congenital lactic acidosis
• Intractable seizures
• Pyridoxine dependency
• Non-ketotic hyperglycinemia
• Molybdenum co-factor defect
• Folinic-acid responsive seizures
21. • 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.
• Hypoglycemia: galactosemia, fatty acid oxidation defects, organic acidemias,
glycogen storage disorders and disorders of gluconeogenesis.
Acute liver disease
22. Dysmorphic facies
• Peroxisomal disorders, pyruvate dehydrogenase deficiency, congenital
disorders of glycosylation (CDG), and lysosomal storage diseases.
• Non-immune hydrops fetalis: lysosomal storage disorders and CDG
23. Cardiac disease
• Cardiomyopathy:
• Fatty acid oxidation defects,
• Glycogen storage disease type II and mitochondrial electron transport
chain defects
27. Hyperammonemia
Premature Full term
THAM PC Deficiency Organic
acidemia
UCD
Citrulline
Absent
citrulline
Moderate Markedly
Urine orotic
acid
CPS
deficiency
OTC
deficiency ASA citrullinemia
Acidosis
28. Metabolic Acidosis with Increased Anion Gap
Normal Lactate Elevated Lactate
Abnormal Organic acids
ORGANIC ACIDEMIA
Abnormal Organic acids
Dicarboxylase aciduria
FAOD MMA,PA,MCD
Normal Organic acids
Elevated Pyruvate
Normal L-P ratio
Hypoglycemia No Hypoglycemia
Normal or Low
Pyruvate
Elevated L-P ratio
GSD Type 1, Fructose 1,6
DP Deficiency
PEP Carboxy kinase
deficiency
Pyruvate Dehydrogenase
deficicincy
Pyruvate carboxylase
deficiency
Respiratory chain defects
29. Neonate in Coma
Blood for NH3, pH
Electrolytes
Urine Ketones
NH3
Metabolic
Acidosis
Classic organic
aciduria
Glutaric aciduria
Urea Cycle Defects
Transient Neonatal
Hyperammonemia
Maple Syrup urine
disease
Ketolysis Defects
NKH
Sulfite oxidase or
Molybdenum
cofactor efieciency
Ketonuria
30. Hypoglycaemia
Urine for non glucose
reducing substance
GALT
FAOD
Ketogenic Defects
GSD
Organic Acidemia
Galactosemia Ketones
31. Normal NH3
No Metabolic Acidosis
Refractory myoclonic
seizure
Opisthotonus
Vomiting
Hypoglycemia
HSM
Jaundice
Sepsis
Dysmorphic features
Hypotonia
Blindness
Galactosemia
Non Ketotic
Hyperglycinemia
Peroxisomal Disorder
32. General Aspects
• Knowledge of the natural history of the diseases and a comprehensive
understanding of the molecular basis and the pathophysiological
consequences of gene defects.
• Continuous sympathetic company and guidance of patients and their
families are essential for optimal outcome.
• Inherited metabolic diseases are chronic conditions that involve various
different organ systems and often show progressive pathology.
33. • Affected individual to achieve optimal development during childhood
• Maximal independence, social integration, and self-esteem as an adolescent and
adult.
• Multidisciplinary approach
34. Management
Airway , Breathing & Circulation
Ventilate the baby If needed
Omit all protein, fat and galactose and lactose including TPN
Glucose infusion 6-8mg/kg/mt
Start insulin if Hyperglycemic
Correct hydration, acid base disorder and electrolyte disturbance
Antibiotics
Control seizure (avoid sodium valproate )
36. Disorder Management
Methyl malonic acidemia Vit B12 1mg IM/day
Biotinidase deficiency Biotin 10 to 60 mg/day oral
Multiple carboxylase deficiency Biotin 10 to 60 mg /day oral
Glutaric aciduria type II Riboflavin 100 to 300 mg/ day oral
Thiamine 10 to 200 mg/day
Homocystinuria Pyridoxine IM/IV 200 to 1000mg/24hrs
Carnitine deficiency Carnitine 100 to 400 mg of L-carnitine/kg/day oral
MSUD Thiamine 10mg to 200mg/24hrs
Riboflavin 200 to 300 mg/oral TID
Mevalonic acidemia Prednisone 2mg / kg / 24 hrs
Hartnup disease Nicotinamide 50 to 300mg/day High protein
37. • Substrate reduction / removal
• Provision of ‘ conditionally ’ essential or essential nutrients
• Provision of alternative energy substrates
• Avoidance of fasting / prolonged fasting to avoid accumulation
of toxic metabolites or defi -ciency of substrate
Dietary Modification
39. Counselling
1. Food and food components
2. Chromosomes, genes and mutations
3. Inheritance
4. Productions and function of enzymes
5. Normal metabolism
6. Disease-specific disorders of metabolism
7. Diagnostic investigations for screening and confirmation of diagnosis
8. Principles of treatment
9. Measures for monitoring treatment and outcome
10. Principles of prognosis as a statistical and individual concept
40. Preventive aspects
• Genetic Counselling and Prenatal Diagnosis
• Chorionic Villus Sampling/Amniocentesis
• The possibility of carrier detection, and prenatal
or preimplantation diagnosis
• Severe psychosocial burden for individuals and
families as a whole.
• Screening TMS
41. Metabolic Autopsy
• Blood: 5-10 ml; frozen at -200c; both heparinized (for
chromosomal studies) and EDTA (for DNA studies) samples to be
taken
• Urine: frozen at -200c
• CSF: store at -200c
• Skin biopsy: including dermis in culture medium or saline with
glucose. Store at 4-80c. Do not freeze.
• Liver, muscle, kidney and heart biopsy: as indicated.
• Clinical photograph (in cases with dysmorphism)
• Infantogram (in cases with skeletal abnormalities)
43. Conclusion
• IEM are not uncommon
• Do suspect IEMs in all babies with unexplained deterioration of clinical condition and
suspected sepsis when sepsis screen is negative.
• Start with a simple approach to hold on to a ‘thread of logic’ which will lead on to the
diagnosis.
• Stabilization is the key to management.
• Sample for metabolic Autopsy if the child is very sick.
• An attempt to make a diagnosis gives the choice to the parents in subsequent pregnancies.
• Genetic counseling to the parents
Good morning to all
Before starting my talk I would like to thank organizer for giving me the opportunity
After two sessions about Investigating the error in metabolism I think everyone knows that IEM is TOO complicated
I will try to explain the approach in simple way and proper management to reverse it to normal and to prevent the recurrence
IEM is also called as congenital metabolic disorder/ Inherited metabolic disease even we can say it as metabolic distress as like respiratory distress
IEM is due to Absence or Abnormality of an enzyme or its cofactor, leading to either accumulation or deficiency of a specific metabolite(s).
Most of these disorders are transmitted as autosomal recessive traits or started as newer onset due to sporadic mutation. With few exceptions like ornithine transcarbamylase defieciency transmitted as X linked inheritance
Step by step evaluation is important to diagnose IEM
Diagnosis is important not only for treatment and prognostication but also for genetic counselling and antenatal diagnosis in subsequent pregnancies
The number of diseases in humans known to be 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
When a precursor “A” in the body is to be converted to product “C” through product “B”
with one helping enzyme in the pathway, the inadequacy or absence of that particular enzyme (E) results in one of three things
Absence of product “C”
Excess of substance “A” and “B”
A new pathway taken by product “B” to produce new products “D” and “D1”
Manifestations will be of these three types intoxication type like PKU, Energy defiecient like Mitochondrial Disorder and Storage type like LYSOSOMAL Storage disorder
Some of maternal IEM Like PKU can affect fetus and cause dysmorphology in the fetus which results in congenital malformations (Fig.2). Vice versa, some disorders of the fetus can affect the mother too, eg. Very long chain hydroxy acyl CoA deficiency (VLCHAD) of fetus can manifest as acute fatty necrosis of maternal liver and hemolysis, elevated liver enymes, low platelets (HELLP) syndrome in the mother when she is
The signs and symptoms can manifest at any age from neonatal period through infancy and childhood to adulthood. Age of onset has a significance since many IEM can have a typical age of onset. This is because the age of onset depends upon the developmental stage of a particular organ system,2 eg.cholesterol, peroxisomal biogenic disorders and lysosomal disorders can present at birth.4 The presentation may be insidious, eg.lysosomal storage disorders
or acute, E.g. peroxisomal disorders.
Intoxication type of disorders usually present one week….
There are three types of onset
Acute stormy onset with rapid life threatening deterioration over hours, eg. some of the mitochondrial disorders with lactic acidosis.
Episodic with intermittent decompensation and asymptomatic intervals, eg. some of the organic acidurias.
Insidious onset with slow degeneration over decades, eg.neurodegenerative disorders - Canavan’s disease.
Severe illness in the newborn, regardless of the underlying cause, tends to manifest with nonspecific findings, such as poor feeding, drowsiness, lethargy, hypotonia and failure to thrive. IEM should be considered in the differential diagnosis of any sick neonate along with common acquired causes such as sepsis, hypoxic-ischemic encephalopathy, duct- dependant cardiac lesions, congenital adrenal hyperplasia and congenital infections
We use to think of IEM in sick term neonate rather in preterm neonate because premeturity itself will cause lethargy, poor feeding and hypoglycaemia and some of the lab use to ask whether baby is term or preterm
Whenever we come across sick infant or neonate we use to think about these four groups of diseases with IEM
when to suspect IEM
Deterioration after a period of apparent normalcy
Parental consanguinity
Family history of neonatal deaths
Rapidly progressive encephalopathy and seizures of unexplained cause
Severe metabolic acidosis
Persistent vomiting
Peculiar odor
Acute fatty liver or HELLP (hemolysis, elevated liver enzymes & low platelet counts) during pregnancy: seen in women carrying fetuses with long-chain-3-hydroxyacyl-coenzyme dehydrogenase deficiency (LCHADD)
Here some of the clinical clues for specific disorders to look for
List of IEM with unusual odours
If metabolic disease is not considered within the differential
diagnosis, it is unlikely to be identified through
standard blood, urine, or cerebral spinal fluid investigations
Early discussion with a specialist centre is vital.
If a diagnosis is clear, then specific diagnostic investigations
can be performed, including genetic testing.
Investigations are often
staged
Complete blood count: (neutropenia and thrombocytopenia - propionic and methylmalonic academia)
Arterial blood gases and electrolytes
Blood glucose
Plasma ammonia (Normal values in newborn: 90-150 g/dl or 64-107 mol/L)
Arterial blood lactate (Normal values: 0.5-1.6 mmol/L)
Liver function tests
Urine ketones
Urine reducing substances.
Serum uric acid (low in molybdenum cofactor deficiency)
Some time will get basic investigations normal but clinically baby will be sick
In that situation we have to keep these conditions in mind
Care and treatment of patients with an inherited
metabolic disease require both a detailed knowledge
of the natural history of the diseases and a
comprehensive understanding of the molecular
basis and the pathophysiological consequences
of gene defects. Continuous sympathetic company
and guidance of patients and their families
are essential for optimal outcome. Inherited
metabolic diseases are chronic conditions that
involve various different organ systems and
often show progressive pathology.
The aim is to
help the affected individual to achieve optimal
development during childhood and maximal
independence, social integration, and self-esteem
as an adolescent and adult. This goal can only be
achieved by a multidisciplinary approach
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.
These are cofactor supplementations needed in treating IEM
Substrate reduction / removal reducing the intake of nutrients/substrates that produce toxic metabolites, e.g. phenylalanine in phenylketonuria (PKU), branched-chain amino acids in maple syrup urine disease (MSUD), galactose in galactosaemia and long-chain fat in long chain hydroxyacyl-CoA dehydrogenase defi -ciency (LCHADD).
Provision of ‘ conditionally ’ essential or essential nutrients : This is necessary as a consequence of the enzyme block, e.g. tyrosine in PKU, arginine/citrulline in urea cycle disorders and phenylalanine in tyrosinaemias Provision of alternative energy substrates , e.g. use of medium-chain triglycerides (MCT) in long-chain fatty acid oxidation disorders (LCFAODs), or provision of glucose and uncooked
cornstarch (UCCS) in glycogen storage disease (GSD).
Avoidance of fasting / prolonged fasting to avoid
accumulation of toxic metabolites or defi -
ciency of substrate , e.g. increased acylcarnitines/ free fatty acids in LC-FAOD, increased odd-chain fatty acids in propionic acidaemia (PA) and lack of glucose in GSD.
There are four key strategies:
– sup a defi product, e.g. supply of glucose in hepatic gsd Type I by regular daytime feeds and
continuous overnight feed
– preventing accumulation of a toxic substrate e.g.
phenylalanine restriction in phenylketonuria to
reduce harmful metabolites. To prevent
malnutrition, protein substitutes and vitamin
and mineral supplementation is required,
guided by a specialist dietician
– prevention of catabolism. Metabolic demands
are increased when ill;, e.g.
hyperammonaemia in urea cycle disorders.
Oral glucose in the form of a glucose polymer, e.g. Polycal, is
preferred during minor illnesses as it can be
given at home.
– ketogenic diet. Ketones can be used by the
brain as an alternative fuel. Patients with GLUT1
(glucose transporter 1) deficiency are unable to
transport glucose in to the central nervous
system and thus rely on ketones as an
alternative energy source for the brain and so
require a ketogenic diet.
Thiamine: mitochondrial disorders, thiamine responsive variants of MSUD, PDH deficiency & complex I deficiency)
Riboflavin: Glutaric aciduria Type I, Type II, mild variants of ETF, ETF-DH, complex I deficiency
Pyridoxine: 50% of cases of homocystinuria due to cystathionine β-synthetase deficiency, pyridoxine dependency with seizures, xanthurenic aciduria, primary hyperoxaluria type I, Hyperornithemia with gyrate atrophy
Cobalamin: Methylmalonic academia (cblA, cblB), Homocystinuria and methylmalonic academia (cblC, cblD, cblF)
Folinic acid: Hereditary orotic aciduria, Methionine synthase deficiency, Cerebral folate transporter deficiency, hereditary folate malabsorption, Kearns-Sayre syndrome
Biotin: Biotinidase deficiency, holocarboxylase synthetase deficiency
Its very difficult for doctors to make care givers to understand about IEM
We have to keep these ten steps in mind while counselling parents
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 villus tissue or amniotic fluid. Modalities available are
1Substrate or metabolite detection: useful in phenylketonuria, peroxisomal defects.
2Enzyme assay: useful in lysosomal storage disorders like Niemann-Pick disease, Gaucher disease.
3 DNA based (molecular) diagnosis: Detection of mutation in proband/ carrier parents is a prerequisite.
These are the Samples to be obtained in infant with suspected IEM when diagnosis is uncertain and death seems inevitable.
Collectively Called as metabolic autopsy
Generally IEM disorders will have guarded prognosis but few conditions have good prognosis too
• IEM are not uncommon • Do suspect IEMs in all babies with unexplained deterioration of clinical condition and suspected sepsis when sepsis screen is negative. • Start with a simple approach to hold on to a ‘thread of logic’ which will lead on to the diagnosis. • Stabilization is the key to management. • If a diagnosis is not made when the child is alive, do collect blood samples and freeze to send for subsequent analysis. • An attempt to make a diagnosis gives the choice to the parents in subsequent pregnancies. • We have a long way to go in effective treatment and in the current scenario genetic counseling to the parents is the crux
