approach to inborn error of metabolism dr.mounika

APPROACH TO INBORN ERRORS OF METABOLISM
DR.MOUNIKA
MODERATOR :
DR.AKSHAY REDDY

Inborn errors of metabolism
 IEM are individually rare
 Over all incidence upto 1 in 1000 to 1 in 2000
 High index of suspicion needed for diagnosis
 Most common presentation of IEM is sepsis ( 30 %)
 Mostly transmitted as Autosomal recessive

Classification
• Metabolic disorders can be classified using variety of schemes
based on
 Clinical symptoms
 Age of onset
 Organ systems involved
 Defective metabolic pathways involved

Classification of IEM
 Defects of Amino acid metabolism : Phenylketonuria- Homocystinuria -
tyrosinemia
 Carbohydrate metabolism defects : Galactosemia , fructose intolerance , GSD
 Organic acidemias: Methylmalonic aciduria- propionic aciduria- Isovaleric aciduria
 Peroxisomal disorders: Adrenoleukodystrophy – zellweger syndrome
 Lipidoses : Tay sach’s disease – Gaucher’s disease – metachromatic leukodystrophy

Classification of IEM
 Lysosomal storage disorders : Mucopolysaccaridosis
 Urea cycle disorders: Ornithine transcarbamylase deficiency-
arginosuccinase deficiency- carbamoyl phosphate synthetase deficiency
 Metal metabolic disorders : Wilson’s disease , Menkes disease

Clinical pointers
 Deterioration after a period of apparent normalcy
 Parental consanguinity
 Family history of neonatal deaths
 Rapidly progressive encephalopathy and seizures
Of unexplained cause
 Persistent vomitings

Clinical pointers
 Hypoglycemia
 Severe metabolic acidosis
 Abnormal urine odour
 Dysmorphic features
 Hydrops fetalis
 HELLP syndrome and Acute fatty liver of pregnancy (LCHADD)

IEM with Hypoglycemia
 Organic aciduria
 Fatty acid oxidation defects
 Defects of gluconeogenesis
( Hepatomegaly with hypoglycaemia)

IEM With Metabolic Acidosis
 Maple syrup urine disease
 Organic acidurias
 Primary lactic acidemias : Defects of gluconeogenesis, Pyruvate
metabolism, Mitochondrial respiratory chain defects

IEM With Hyper Ammonemia
 Urine cycle disorders
 Propionic acidemia
 Methyl malonic acidemia

IEM With Seizures
 Pyridoxine responsive seizures : 1st day
Folinic acid responsive seizures : 1st day
 Non ketotic hyperglycinemia ( In utero)
 Sulfite oxidase / Molybdenum cofactor deficiency
 Peroxisomal disorders

IEM with Hypotonia
• Peroxisomal disorders
• Mitochondrial respiratory chain disorders
• Sulfite oxidase deficiency
• Molybdenum cofactor deficiency
• Non ketotic Hyperglycinemia

IEM With Abnormal Odor
 Glutaric aciduria
 Isovaleric aciduria
Sweaty Foot Odor

IEM With Abnormal Odor
Maple syrup urine disease : Maple syrup
Hypermethioninemia: Boiled cabbage
Multiple carboxylase deficiency: Tomcat urine

IEM With Dysmorphism
Zellweger syndrome
• Large Fontanelle
• Prominent Forehead
• Flat nasal bridge
• Epicanthal folds
• Hypoplastic supraorbital ridges

 Cholesterol biosynthetic defects
 Epicanthal folds
 Flat nasal bridge
 Toe syndactyly
 Cataracts
 Genital abnormalities

 Pyruvate dehydrogenase deficiency
 Glutaric aciduria
 Congenital glycolysation disorders
 Lysosomal storage disorders

IEM with apnea
 Long Chain Fatty acid oxidation defects
 Non ketotic hyperglycinemia

IEM with Cholestatic jaundice
• Alpha-1-antitrypsin deficiency
• Niemann-Pick disease type C
• Inborn error of bile acid metabolism
• Peroxisomal disorders
• Citrin deficiency

IEM with skin changes
 Biotidinase deficiency ( Seizures with rash)
 Holocarboxylase deficiency

Hydrops fetalis
Glycosylation disorders
Lysosomal disorders
Gaucher disease
Sialidosis

Evaluation of a neonate
with suspected IEM

1. Complete blood picture
 Neutropenia and Thrombocytopenia : Organic aciduria
 Neutropenia: Glycogen storage type 1b, Mitochondrial disease
like Barth’s and pearson syndrome

2. Blood gas
 Check if there is acidosis or alkalosis
 Categorise to respiratory or metabolic and if there is increased anion gap
 Metabolic acidosis with increased anion gap: Organic acidemia and
primary lactic acidosis
 Mild Respiratory alkalosis: Organic acidemia
 Significant Respiratory alkalosis: Urea cycle disorders
 Also you can see the serial trend of lactates in blood gases

Metabolic acidosis
• Presence of ketosis will narrow down the diagnosis
• Gluconeogenesis defects
• Respiratory chain disorders
• Organic aciduria
• Maple syrup urine disease
• Fatty acid oxidation defects
• Pyruvate dehydrogenase
defects
• Renal tubular defects
Present Absent

3. Blood Glucose
• Hypoglycemia :
 Organic acidemias
 Defects of gluconeogenesis
 Hyperinsulinism

4. Plasma Ammonia levels
 Urea cycle disorder ( Respiratory alkalosis)
 Organic Acidemia ( Metabolic acidosis)
 Transient Hyper ammonemia of neonate ( +/- mild respiratory alkalosis)

5. Plasma lactate
 High lactate: Hypoxia, cardiac disease, shock, Infection, Seizures,
Primary lactic acidemias, FAO defects, Gluconeogenesis defects
 Persistent increase of lactate above 3mmol/L in a neonate who did not
suffer from asphyxia, who is hemodynamically stable should lead to
investigation of IEM.

6. Liver Function Tests
• Abnormal LFT:
 Galactosemia
 Tyrosinemia
 Neonatal Hemochromatosis
 Nieman picks

7. Urine for reducing Substances
 Urine for Reducing substances, Ph and Ketones
 Clinitest: Excess excretion of galactose and glucose are detected but not
fructose
 Clinistix ( Glucose oxidase based) : Specific for Glucose not for
galactose

7. Urine for reducing Substances
 Reducing substances in urine can be used as screening for galactosemia
( Should not be used as a diagnostic test)
 Presence of ketones in urine is always abnormal and an important sign
of metabolic disease.

• 8. Plasma amino acids : Aminoacidopathies
• 9. Urine organic acid analysis : Organic aciduria
• 10. Plasma carnitine and acylcarnitine profile

IEM with Neonatal seizures
• 1. Pyridoxine ( B6 ) responsive seizures:
Autosomal recessive disorder of lysine metabolism pathway
C/F : encephalopathy and seizures , usually with in first day of life
Diagnosis: Established by cessation of seizure on pyridoxine
supplementation ( 50 – 100 mg 0ral)

 Documentation of cessation of seizure with Continuous EEG monitoring
will be helpful.
 Increased pipecolic acid in CSF and plasma , increase in AASA ( Alpha
amino adipic semialdehyde ) in CSF, plasma and urine.
 Treatment with pyridoxine should be continued life long.

2. Pyridoxine phosphate responsive seizures
• Autosomal recessive disorder due to deficiency of pyridoxine 5 phosphate oxidase
• C/F: Neonatal seizures not respoinsive to pyridoxine, microcephaly and hypotonia
• Diagnosis: Demonstration of cessation of seizure on pyridoxal phosphate ( 30 mg per
day oral )

3. Non ketotic hyperglycinemia ( NKH)
 Autosomal recessive disorder due to deficiency of glycine cleavage complex
 Results in Glycine accumulation
 C/F: Lethargy, hypotonia, poor feeding, seizures, hiccups and apnea
episodes are common.
 EEG: Burst suppression pattern is diagnostic
 Many infants die in few weeks of life.
 Profound psychomotor retardation in survivors

• Diagnosis: Elevated glycine levels in plasma and CSF.
• Treatment: No effective treatment.
• Sodium benzoate to reduce glycine levels
• Dextromethorphan or memantine can be used to block neuroexcitatory
effects of glycine upon NMDA receptors and possibly improve seizure control.

Management of Infant at risk for IEM
• Before pregnancy and Antenatal: If sibling has a metabolic
disorder following steps should be followed.
1) All clinical reports should be reviewed
2) Prenatal genetic counselling
3) Parents should be screened
4) If diagnosis is known , intrauterine diagnosis by Amniotic fluid analysis or
chorionic villus Sampling
5) Plan delivery in an equipped set up.

Initial Evaluation
 Careful examination
 Non metabolic causes of symptoms like asphyxia and sepsis should be ruled out.
 Newborn screening should be planned
 Blood and Urine for TMS and GCMS

Treatment
• Limit the Intake of the Offending Substance:
• the basis of treatment in Galactosemia, fructose intolerance and PKU.
• Increase Excretion of Toxic Metabolites:
• by exchange transfusion, peritoneal dialysis (PD), hemodialysis, forced diuresis, using
alternative pathways for the excretion of toxic metabolites. For example, carnitine is
useful in the elimination of organic acids in the form of carnitine esters. Sodium
benzoate and phenylacetate are useful in treating hyperammonemia.

Management of acute metabolic decompensation
 Prevention of catabolism and Anabolism promotion:
 NPO for 1 to 2 days
 Provide adequate hydration
 IV Dextrose ( GIR: 6 TO 8 mg/ kg/min)
 Insulin is a potent anabolic hormone,
 can be administered at a dose of 0.05 to 0.1 unit/ kg/ hour
 Avoid RL, as Ringer lactate worsens lactic acidosis

Management of acute metabolic
decompensation
LIPIDS : Can be added to supply extra calories in the form of Medium
chain triglycerides or parenteral lipids.
Lipids should be added only when Fatty acid oxidation disorders are ruled
out. If not very severe metabolic acidosis sets in.
PROTEIN: Avoid adding Amino acids for 2 to 3 days when baby is acutely
ill. Afterward amino acid supplementation will be helpful in enhancing
anabolism.

Correction of metabolic acidosis:
 If ph less than 7.2 and bicarbonate less than 14 meq/l, soda
bicarbonate infusion can be used.
 If hypernatremia is a problem, potassium acetate can be used.

• Limit the Intake of the Offending Substance:
• Basis of treatment in Galactosemia, fructose intolerance and
PKU.
• Elimination of toxic substances:
• Hydration promotes excretion
• Hemofiltration / Hemodialysis is indicated in cases
unresponsive hyper ammonemia ( more than 500 mg/dl) and
hyperleucinemia ( MSUD)

• Enzyme replacement therapy : ERT is now commercially available for some
lysosomal storage disorders.
Pompe’s disease (Glycogen storage disorder Type II), Gaucher, Muco
polysacharidosis, Fabry disease
 Arginine supplementation in Urea cycle defects, except in Arginase deficiency.
 Sodium benzoate can be used in suspected organic aciduria and Urea cycle
disorders.

• Carntine supplementation: Free carnitine levels are low in organic
acidemias because of increased esterification with organic acid
metabolites.
• Carnitine supplementation may facilitate excretion of these
metabolites.
• Treatment of precipitating factors: Infection should be treated.
Co factor supplementation: Thiamine in MSUD, Vit B 12 in multiple
carboxylase deficiency, Biotin in hypermethionemia, Vit B2 in Glutaric
aciduria

Post mortem diagnosis
 Blood , both clotted and EDTA sample
 Urine Frozen
 Spinal fluid Frozen
 Skin biopsy, Liver and muscle biopsy
 If all of the above could not be done , atleast blood on a filter paper
should be taken and preserved.

References
 Fanaroff and Martin’s Neonatal and Perinatal medicine 10th Edition.
 Avery diseases of the new born ninth edition.
• Cloherty Manual of neonatal care south asian edition

• Inborn Errors of Metabolism Day (IEM Day ) in India is marked
on the 21 November to raise awareness about IEM diseases
that most people will not know of, as well as to improve access
to treatment.
• MERDINDIA organized.

Some facts about IEMS and Genetic Disorders in our country
• 1 in every 500 to1,000 newborns was observed By Inborn errors of Metabolism
• India accounted for a staggering 29 per cent of the global deaths of newborns on their very first day of birth and nearly
40 per cent of neo-natal deaths happening on the first day of birth in India.
• Experts point out that a lot of work has to be done towards improving newborn health in India as nearly 5-15 per cent of
newborns are sick due to metabolic diseases. A major group of these babies is left with irreversible complications of
physical and mental impairment and some die, if affected by severe forms of these conditions.
• Our annual birth rate is 21.76/1000 population. Out of the approximately 25 million new births in India, there are an
estimated 1.6 Million babies born with birth defects including about 620,000 with genetic disorders.
• With no mandatory newborn screening at national/government levels, the country wide burden of genetic disorders
especially the congenital conditions is huge and still unknown..
• The newborn health challenge faced by India is bigger than that experienced by any other country. As India makes
progress in addressing childhood illnesses, reducing newborn deaths remains a critical challenge, making up a
growing percentage of child deaths.
• Today, India accounts for the greatest burden of newborn deaths in the world. An estimated 876,000 newborns die each
year in India alone (2011 estimates) accounting for an estimated 30% of the total global burden of neonatal deaths and
and a staggering 53% of under-5 deaths in India.

• Out of every 100 babies born in this country annually, 6 to 7 have a birth defect.
• In Indian context, this would translate to 1.7 million birth defects annually and would account
for 9.6 per cent of all newborn deaths.
• With a large birth cohort of almost 26 million per year, India would account for the largest share
of birth defects in the world. This would translate to an estimated 1.7 million babies born with
birth effects annually.
• Birth defects account for 9.6% of all new-born deaths and 4% of under five mortality.
Development delays affect at least 10% children.
• India is a single country of multiple cultures and genetic traits. The research and data from one
state does not necessarily apply to another region. The incidence of CAH is thought to be
higher in Southern India; where as incidence of G6PD is thought to be highest in Punjab and
Gujarat.
• Thalassemia has its highest incidence in Guajarati,. Disorders mimicking methyl malonic
acidemia (MMA) is thought to be higher in vegetarians in south India than in north India.
These geographical variations and their understandings are very important in planning the
health programmes of a country.

• 1. In hypermethionemia urine has an odor of
• A. Sweaty feet
• B. Boiled cabbage
• C. Tomcat urine
• D. Maple syrup

• 2. Mild respiratory alkalosis points towards which IEM
• A. Glycogen storage disorders
• B. Pyruvate carboxylase deficiency
• C. Hyperammonemia
• D. Fatty acid oxidation defects

• 3. Acute presentation of MSUD is most effectively managed with
• A. Diet restriction
• B. Total parenteral nutrition
• C. Hemodialysis
• D. No specific intervention needed

• 4. Methyl malonic acidemias treated with large doses of
• A. Pyridoxine
• B. Biotin
• c. Vitamin B 12
• D. Riboflavin

5. Burst suppression pattern in EEG is seen in
• A. Pyridoxine deficiency seizures
• B. Zellweger syndrome
• C. Fatty acid oxidation defects
• D. Non ketotic hyperglycinemia

• 6 Name two conditions where Non ketotic hypoglycaemia is seen
?

• 1. Fatty acid oxidation defects
• 2. Hyperinsulinism
• 3. Galactosemia

approach to inborn error of metabolism dr.mounika

Recommandé

Recommandé

Contenu connexe

Tendances

Tendances (20)

Similaire à approach to inborn error of metabolism dr.mounika

Similaire à approach to inborn error of metabolism dr.mounika (20)

Plus de Dr Praman Kushwah

Plus de Dr Praman Kushwah (20)

Dernier

Dernier (20)

approach to inborn error of metabolism dr.mounika