Inborn errors of metabolism

1. INBORN ERRORS OF
METABOLISM(IEMs)
DR.OBUMNEME-ANYIM,IJEOMA
CONSULTANT PAEDIATRICIAN,UNTH ENUGU

2. OUTLINE
 INTRODUCTION
 EPIDEMIOLOGY
 CLASSIFICATION
 CLINICAL PRESENTATION
 MANAGEMENT.

3. INTRODUCTION
 Inborn errors of metabolism (IEMs) comprise a group of disorders in which a
single gene defect causes a clinically significant block in a metabolic pathway
resulting in either accumulation of substrate behind the block or deficiency of the
product.
 IEMs cause hereditary metabolic diseases(HMDs) which produce manifestations in
every organ of the body.
 More than 300 human diseases are caused by IEMs.
 Inheritance pattern is usually autosomal recessive but can be X-linked or
autosomal dominant.

4. EPIDEMIOLOGY
 Individually they are rare but collectively, they have a cumulative incidence of 1
:800 in the USA, 40 cases/100,000 live births in a Canadian study and 150 cases per
100,000 in Saudi Arabia
 Race
The incidence within different racial and ethnic groups varies with predominance of
certain inborn errors of metabolism (IEMs) within particular groups (cystic fibrosis, 1
per 1600 people of European descent; sickle cell anemia, 1 per 600 people of African
descent; Tay-Sachs, 1 per 3500 Ashkenazi Jews).
 .

5. EPIDEMIOLOGY…
 Sex
The mode of inheritance determines the male-to-female ratio of affected individuals.
The male-to-female ratio is 1:1 for autosomal dominant and autosomal recessive
transmission. It is also 1:1 for X-linked dominant if transmission is from mother to
child.
 Age
Age for presentation of clinical symptoms varies for individual inborn errors of
metabolism (IEM) from within hours of life to very late in adulthood. The timing of
presentation depends on significant accumulation of toxic metabolites or on the
deficiency of substrate

6. CLASSIFICATION
 IEMs are classified into two categories, according to the clinical
phenotypes.
 Category I
 Diseases that affect a functional or anatomical system. Diagnosis is usually
easy. Defects in the coagulation pathways presents with bleeding.
 Category II
 The biochemical basis affects one metabolic pathway common to a great
number of cells or organs OR is restricted to one organ with humoral and
systemic consequences. Diagnosis is difficult because symptoms are
diverse.
 Three groups have been identified under this category;

7. CLASSIFICATION…..continued
 Group 1
Disturbances in the synthesis or catabolism of complex molecules(
glycoprotein, glycolipids,glycosaminoglycans).
The symptoms are permanent and progressive .
Diseases here are known as Lysosomal disorders or Storage
disorders and Mucolipidosis.
There is progressive accumulation of undigested substrates in the
lysosomes.
Affected tissues are those where the substances are usually
catabolized in great quantity.

8.  They manifest with hepatomegaly or hepatosplenomegaly.
 Dysmorphic features
 Eye, bone and joint involvement.
 CNS involvement

9. GROUP 1
 Lysosomal disorders
1. Mucopolysaccharidosis (mps)
I-H - Hurler
I-HS - Hurler - Scheie
I-S - Scheie
II - Hunter
III - Sanfilippo
IV - Morquio
VI - Maroteaux - Lamy
VII - Sly

10. GROUP 1
2 . Sphingolipidoses
GM1 Gangliosidosis
Tay - Sachs
Sandhoff
Fabry disease
Shindler disease

11. GROUP 1
3. Lactosylceramidosis
Gaucher disease
Farber disease
Nieman-pick disease
Krabbe disease
Metachromatic leukodystrophy
Multiple sulfatase deficiency

12. GROUP 1
 Mucolipidoses
1.Glycoproteinoses: Fucosidosis
Manosidosis,
Sialidosis,
Aspartylglucosaminuria
2.Disturbances of membrane transport
Salla disease
Cystinosis
carnavan disease
Pompe disease
Acid lipase deficiency

13. GROUP 1
3.Peroxisomal biogenesis disorders
Zellweger syndrome
Adrenoleukodystrophy
Refsum disease
Hyperoxaluria, type I

14. CLASSIFICATION…..continued
GROUP 2
 Results from errors of intermediary metabolism leading to acute and
recurrent intoxication OR chronic and progressive accumulation of
metabolites proximal to the block.
 They usually present with metabolic
acidosis,vomiting,lethargy,dehydration.

15. GROUP 2
 Disorders of amino acid metabolism
Cystinuria
Phenylketonuria
Tyrosinemia
Homocystinuria
Non-ketonic hyperglycinemia
Maple syrup urine disease

16. GROUP 2
 Organic aciduria
Isovaleric acidemia
3-methylcrotonyl-CoA carboxylase deficiency
3-methylglutaconic acidemia
3-hydroxy-3-methylglutaric acidemia
Propionic acidemia
Methylmalonic acidemia
Multiple carboxylase deficiency
Glutaric acidemia, type I

17. GROUP 2
 Urea cycle defects
Carbamoyl phosphate synthetase deficiency
Ornithine transcarbamylase deficiency
Citrullinemia
Arginosuccinic aciduria
Argininemia
Lysinuric protein intolerance

18. GROUP 2
 Sugar intolerance
Classical galactosemia
Galactokinase deficiency
Epimerase deficiency
Hereditary fructose intolerance
Hereditary fructose-1,6-biphosphatase deficiency

19. CLASSIFICATION…..continued
 GROUP 3
 Energy deficiency diseases: symptoms results from deficiency in energy
production or utilization as a result of defects in intermediary metabolism
in the liver,myocardium,muscles or brain.
 It includes defects in glycogenosis,glyconeogenesis,congenital
lacticacidemia,fatty acid oxidation and mitochondrial diseases.
 Common symptoms include hypoglycemia,hyperlactemia,severe
generalized hypotonia,myopathy,cardiomyopathy,growth retardation and
circulatory collapse.

20. GROUP 3
 Fatty acid oxidation defects
Medium chain acyl-CoA dehydrogenase deficiency
Long chain acyl-CoA dehydrogenase deficiency
Short chain acyl-CoA dehydrogenase deficiency
Long chain 3-OH-acyl-CoA dehydrogenase deficiency
Multiple acyl-CoA dehydrogenase deficiency (glutaric acidemia,
type II)
Carnitine plasma transport defect
Carnitine palmityl transferase deficiencies

21. GROUP 3
 Mitochondrial disorders
Pyruvate dehydrogenase complex deficiency
Oxidative-phosphorylation (respiratory chain) defects (MERRF)
(MELAS)
Pyruvate carboxylase
Phosphoenolpyruvate carboxykinase deficiency

22. GROUP 3
 Glycogen storage disorders
 Hepatic forms: von Gierke,Pompe, Forbes-Cori disease, Andersen disease
and Hers disease
 Muscle forms: McArdle disease, and Tarui disease.

23. CLINICAL PRESENTATION
 Clues suggesting IEMs include
 Positive family history
 Consanguinity
 Loss of developmental milestones
 History of unexplained neonatal/infant deaths
 Metabolic acidosis with increased anion gap
 Neutropenia and/or thrombocytopenia
 Unusual odor(urine, sweat)
 Poor feeding or onset of symptoms with the institution of feeds.

24. INITIAL APPROACH
 Neonate
 Consider an inborn error of metabolism (IEM) in any critically ill neonate.
 Frequently, the most important clue is a history of deterioration, often life-
threatening, after an initial period of apparent good health ranging from hours
to weeks, usually following an uncomplicated pregnancy and delivery in a term
infant.
 In term infants without risk for sepsis who develop the symptoms of sepsis,
metabolic disease may be nearly as common as sepsis. A negative newborn
screen result does not exclude diagnosis of metabolic disease.

25. INITIAL ASSESSMENT
 Infants and young children (1 month to 5 years)
 Onset of symptoms may coincide with what are normally developmentally
appropriate changes in diet that result in increased intake of protein and
carbohydrates or with increased duration of fasting as infants begin sleeping
through the night.
 A history of recurrent episodes of vomiting, ataxia, seizures, lethargy, coma, or
fulminant (Reye syndrome–like) hepatoencephalopathy.

26.  Infants may appear and act normal between episodes or have a history of poor
feeding, failure to thrive, fussiness, decreased activity and/or developmental
delay, sometimes with loss of milestones.
 With routine illnesses, infants with an inborn error of metabolism (IEM) may
become more severely symptomatic, develop symptoms more rapidly, or
require longer to recover than unaffected children

27. Older children (>5 y), adolescents
 Undiagnosed metabolic disease should be considered in older children (>5 y),
adolescents, or even adults with subtle neurologic or psychiatric abnormalities.
 Many individuals previously diagnosed as having birth injury or atypical forms
of psychiatric disorders or medical diseases, such as multiple sclerosis
migraines, or stroke, actually have an undiagnosed inborn error of metabolism.

28. LABORATORY EVALUATION
 FBC
 SEUCr
 LFT
 PT,APTT
 Blood glucose
 Urine pH.
 Ketones
 Reducing substances
 ECG,CT scan,MRI,ULTRASONOGRAPHY,ECHOCARDIOGRAPHY.

29. LABORATORY ABNORMALITIES IN IEMs
 Metabolic acidosis (increased anion gap)- hallmark of organic acidemia.
 Hypoglycemia
 Hyperammonemia
 Non-ketotic hyperglycemia

30. GOAL OF TREATMENT
Goals of treatment for patients with an inborn error of metabolism
(IEM) are ;
 Prevention of further accumulation of harmful substances,
 Correction of metabolic abnormalities,
 Elimination of toxic metabolites.
 (Even the apparently stable patient with mild symptoms may deteriorate
rapidly with progression to death within hours. With appropriate therapy,
patients may completely recover without sequelae)

31. SPECIFIC IEMs
 Hurler’s disease(MPS I): Results from the build up of heparan and dermatan sulfate.
 Due to deficiency of alpha-L iduronidase
 Inheritance pattern : autosomal recessive
 Frequency: 1:100,000
 Affected individuals are normal at birth, develop symptoms between 3 and 8 years and
die by 10 years.
Clinical features include
 Corneal clouding, hepatosplenomegaly, skeletal deformities (dysostosis multiplex),
coarse facial features, large tongue, prominent forehead, joint stiffness, and short
stature; upper airway obstruction, recurrent ear infections, noisy breathing, and
persistent nasal discharge; hirsutism, hearing loss, hydrocephalus, and mental
retardation
 Management is basically supportive.

32. HUNTER (MPS II)
 Hunter(MPS II)
 X-Linked inheritance
 Deficiency of iduronate-2-sulfatase accumulation of heparan and
dermatan sulphate
 MPS II (severe) – Pebbly ivory skin lesions on the back, arms, and thighs;
coarse facial features, skeletal deformities, and joint stiffness; retinal
degeneration with clear cornea and hydrocephalus, mental retardation,
and aggressive behavior
 MPS II (mild form) – Similar features, but with much slower progression;
normal intelligence and no hydrocephalus; hearing impairment and loss of
hand function

33. Tay Sachs
 Autosomal recessive inheritance pattern
 Caused by mutation in the HEXA gene responsible for the production of
beta hexosaminidase A.
 Absence of the enzyme leads to the accumulation of GM2 ganglioside in
toxic levels in the neurons of the spinal cord and brain.
 Infants with this disorder typically appear normal until the age of 3 to 6
months, when their development slows and muscles used for movement
weaken.
 Affected infants lose motor skills such as turning over, sitting, and
crawling.
 They also develop an exaggerated startle reaction to loud noises.

34.  As the disease progresses, children with Tay-Sachs disease experience
seizures, vision and hearing loss, intellectual disability, and paralysis.
 An eye abnormality called a cherry-red spot, which can be identified with
an eye examination, is characteristic of this disorder. Children with this
severe infantile form of Tay-Sachs disease usually live only into early
childhood.

36. PHENYLKETONURIA
 An autosomal recessive disorder
 Due to the deficiency of enzyme phenylalanine hydroxylase.
 Symptoms result from toxic accumulation of phenylalanine and its metabolites and
deficiency of tyrosine.
 This results in severe progressive intellectual disability, if untreated by diet.
 Newborn screening for PKU has been performed by heel prick since 1969.
Screening for PKU is done with bacterial inhibition assay (Guthrie test)
 A low phenylalanine diet is required.
 Strict compliance to the diet is necessary to reduce or to prevent intellectual
disability.

37. PKU
Other symptoms include;
 Delayed development
 Behavioral, emotional and social problems
 Psychiatric disorders
 seizures
 Hyperactivity
 Poor bone strength
 Skin rashes (eczema)
 A musty odor in the child's breath, skin or urine,
 Fair skin and blue eyes, because phenylalanine cannot transform into melanin
— the pigment responsible for hair and skin tone
 microcephaly

38. GALACTOSEMIA
 Autosomal inheritance pattern
 Enzymes required to metabolize galactose deficient.
3 forms are known:
 Galactose-1 phosphate uridyl transferase deficiency: Classic
galactosemia, the most common and most severe form
 Deficiency of galactose kinase
 Deficiency of galactose-6-phosphate epimerase

40.  vomiting
 jaundice
 poor weight gain
 failure to regain birth weight
 lethargy
 irritability
 seizures
 cataracts
 hepatomegaly
 hypoglycemia

41.  Management involves avoidance of milk both human and cow.
 Use of soy-based milk.

42. MAPLE SYRUP URINE DISEASE (MSUD
 An aminoacidopathy secondary to an enzyme defect in the catabolic pathway of the
branched-chain amino acids; leucine, isoleucine, and valine.
 caused by a deficiency of the BCKD complex(branched-chain alpha-keto acid
dehydrogenase) .
 BCKD complex catalyses the decarboxylation of the alpha-keto acids of leucine,
isoleucine, and valine to their respective branched-chain acyl-CoAs.
 Classic form presents 4-7 days after birth, may be delayed to 2nd week of life by
breastfeeding.
 Symptoms include vomiting, poor feeding, poor weight gain, lethargy and characteristic
urine odour.
 Elevated branch chain amino acids is suggestive
 Detection of alloisoleucine is diagnostic
 Treatment includes dietary restriction and acute treatment of metabolic
decompensations.

43. NEWBORN SCREENING
 Newborn screening identifies conditions that can affect a child's long-term
health or survival.
 Early detection, diagnosis, and intervention can prevent death or disability
and enable children to reach their full potential.
 Each year, millions of babies in the U.S. are routinely screened, using a few
drops of blood from the newborn's heel, for certain genetic, endocrine,
and metabolic disorders, and are also tested for hearing loss and critical
congenital heart defects (CCHDs)
 Newborn screening is non-existent in Nigeria