This document provides an overview of inborn errors of metabolism (IEM). It defines IEM as genetic disorders affecting biochemical pathways. The document classifies IEM into 3 main categories: intoxication disorders involving toxic metabolite accumulation, energy metabolism defects, and disorders of complex molecules/organelles. Symptoms of acute and chronic presentation are described. The document outlines diagnostic testing including blood/urine screens and specialized tests. Principles of management are discussed including supportive care. Specific clinical manifestations involving the neurological, hepatic, cardiac and ocular systems are also reviewed.

1. INBORN
METABOLIC
ERROR
Prepared by : Laxmi Dahal
M. Sc. Nursing
B-19
12/9/2022 1

2. INTRODUCTION
• Also known as congenital metabolic diseases or inherited
metabolic diseases.
• Inborn error : an inherited (i.e. genetic) disorder
Metabolism : chemical or physical changes undergone by
substances in a biological system
• IEM is a conditions caused by the genetic errors related to
synthesis, metabolism, transport or storage of biochemical
compounds.
• It results in the accumulation or deficiency of a specific
metabolite.
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3. Introduction
• The majority are due to defects of single genes that code
for enzymes that facilitate conversion of various substances
(substrates) into others (products).
• These disorders are individually rare, but collectively
common, and manifest at any time from the fetal life to old
age.
• Early recognition of signs and symptoms, prompt evaluation
and management results in optimal outcome.
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4. Introduction
• inborn errors of metabolism: Archibald Garrod (British
physician,1857–1936), in 1908.
• "one gene-one enzyme" hypothesis,
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6. Epidemiology
• The prevalence of IEM in various countries shows a
prevalence varying between 1 in 800 to 1 in 5000
• British Columbia: estimated 1 in 2,500 births,
• Mexican study: incidence of 3.4: 1000 live newborns
and a carrier detection of 6.8:1000 NBS.
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7. Research Article
Research topic: Case reports of metabolic disorders from Nepal
Conducted by: Arti Sharma Pandey
• The prevalence of metabolic disease in Nepal is largely
unknown. Some consideration has been given by the nepalese
government for high prevalence of congenital disorders in
some populations.
• enzymatic deficiencies disorders have not been considered as
a class of diseases where timely diagnosis and intervention
might be possible.
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8. Research article
Methods
• A search for case reports on metabolic disorders listed
according to International Classification of Diseases −11 was
performed using the google search engine.
Results
• A total of 443 cases have been discovered presented in the
literature. This does not include disorders that might be due to
lifestyle and behaviour. Most of the reported cases have been
identified based on clinical acumen, radiological and
histopathological findings.
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9. Research article
Conclusions
• Glucose 6 phosphate dehydrogenase deficiency, Wilson's
disease and lysosomal disorders should be considered for
early diagnosis through newborn screening along with the
acknowledged disorders hypothyroidism and
hemoglobinopathies in Nepal.
• Early intervention in these disorders can significantly reduce
morbidity and mortality in infancy.
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10. CLASSIFICATION
Intoxication group
Defects of energy
metabolism
Disorders of complex
molecules
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11. 1. Intoxication group
disorders of intermediary metabolism, with accumulation
of toxic compounds resulting in acute or progressive
symptoms.
- Aminoacidopathies (e.g. phenylketonuria, maple syrup
urine disease),
- organic acidurias,
- urea cycle defects,
- disorders of carbohydrate and copper metabolism and
- porphyrias
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12. Intoxication group
- Symptoms are precipitated by catabolic state (fever,
infections, immunization, dehydration or fasting),
- sudden onset and non-specific physical findings.
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13. 2. Defects of energy metabolism
deficient energy production or utilization within liver, muscle,
heart and brain. E. g:
- mitochondrial disorders,
- disorders of glycolysis, glycogen metabolism and
gluconeogenesis, and
- hyperinsulinism.
Failure to thrive, hypoglycemia with high lactate, hepatomegaly,
hypotonia, cardiomyopathy, myopathy, neurological symptoms
and circulatory collapse may occur.
Sudden onset and non-specific physical findings.
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14. 3. Disorders of complex molecules
Molecules involving organelles. E.g:
- lysosomal storage diseases,
- peroxisomal disorders,
- antitrypsin deficiency and
- congenital disorders of glycosylation.
Symptoms are progressive and permanent and do not have
precipitating factors. Most disorders have multisystem
involvement.
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15. Disorders of complex molecules
- Common features include developmental delay,
organomegaly, coarse facies and arthropathy.
- Gradual onset with slow progression, and have characteristic
findings that enable a specific clinical diagnosis.
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16. Major categories of IEM
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17. Major categories of IEM
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18. Major categories of IEM
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19. Clinical Suspicion
• The diagnosis of IEM is often delayed, and requires a high
index of suspicion.
• Symptoms are often nonspecific, leading to evaluation for
other disorders.
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21. Acute presentation
• Neonates are normal at birth since the small intermediary
metabolites are eliminated by the placenta during fetal life.
• Disorders of glucose, protein and fat breakdown usually
present early; premature neonates with transient
hyperammonemia of newborn (THAN) and term babies
with glutaric acidemia type II may present on the first day
of life.
• Early onset of symptoms is associated with severe disease.
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22. Acute presentation
• An important clue to diagnosis is unexpected deterioration
after normal initial period in a full term baby.
• Neonates may present with:
 lethargy,
 poor feeding,
 persistent vomiting,
 seizure, tachypnea,
 floppiness and
 body or urine odor
Conditions such
as sepsis, HIE &
hypoglycemia
should be
excluded.
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23. Acute presentation
Older children show acute unexplained, recurrent episodes of:
- altered sensorium,
- vomiting,
- lethargy progressing to coma,
- stroke or stroke-like episodes,
- ataxia,
- psychiatric features,
- exercise intolerance,
- abdominal pain,
- quadriparesis or arrhythmias
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24. Acute presentation
• Asymptomatic more than 1 year and patients are normal in
between the episodes.
• Intercurrent illness, high protein intake, exercise, fasting and
drug intake may precipitate symptoms.
• Encephalopathy occurs with little warning in previously
healthy individuals, progresses rapidly, may be recurrent and is
not associated with neurological deficits.
• Physical examination shows altered sensorium, apnea or
hyperpnea and hypotonia.
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25. Laboratory investigation
Metabolic screening:
- Blood glucose,
- Electrolytes,
- Lactate,
- pH,
- Bicarbonate and
- Ammonia
 Done in: urea cycle disorders, organic acidurias, energy
deficit disorders
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26. Laboratory investigation
Urine metabolic screen
- pH,
- ketones and reducing substances
 Done in : PKU, organic aciduria/maple syrup urine disease
and homocystinuria.
 Biochemical screening may be normal in asymptomatic
patients.
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27. Specialized tests
• Quantitative Plasma Amino acids analysis by High
Performance (HPLC),
• Acylcarnitine profile on plasma or dried blood spot by
Tandem Mass Spectrometry (TMS) and
• Urinary organic acids by Gas Chromatography
Spectrometry (GCMS)
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28. Other tests
• Examinations of cerebrospinal fluid,
• Chest X-ray,
• Echocardiography,
• Ultrasound abdomen,
• Computed tomography and magnetic resonance
imaging of the head and
• Electroencephalogram (EEG) are required in
specific cases.
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31. Biochemical Autopsy
• severely ill or dying child with suspected but undiagnosed
IEM, for confirmation of diagnosis.
• Specimens obtained: before or within 1 to 2 hours of death.
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33. Principles of Management
• Treatment is symptomatic, supportive and often instituted
empirically.
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35. CHRONIC AND PROGRESSIVE
PRESENTATION
• variable but insidious onset from birth to adulthood. Some
useful clues are:
 Unexplained developmental delay with or without seizures,
 organomegaly, - coarse facies,
 cataract, - dislocated lens,
 chronic skin lesions,
 abnormal hair or urine color, and
 failure to thrive .
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36. Neurologic findings
- developmental delay
- progressive psychomotor retardation,
- seizures,
- ataxia,
- spasticity,
- variable hearing and visual impairment, and
- extra pyramidal symptoms
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37. Neurologic findings
• Severe irritability, impulsivity, aggressiveness,
hyperactivity and abnormal behavior are common.
• Complex partial or myoclonic seizures which is often resistant
to therapy.
• involvement of grey and white matter (narrowing the
diagnosis)
 Movement disorders: intermittent or progressive (ataxia,
dystonia, choreoathetosis and Parkinsonism).
 Muscular disorders: myopathy (progressive) are usually due
to defects in energy metabolism.
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38. Hepatic presentations
• un-conjugated or conjugated jaundice,
• hypoglycemia and course of the disease and are often
resistant to therapy.
• hepatomegaly with or without hepatocellular dysfunction.
GSD types I and III, lysosomal storage disorders, galactosemia,
GSD IV and III, Niemann-Pick type B and alpha -antitrypsin
deficiency, tyrosinemia, galactosemia, hereditary fructose
intolerance and Wilson disease.
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39. Cardiac manifestations
occur in
- fatty acid oxidation defects,
- mitochondrial disorders,
– GSD type: II,
– methylmalonic acidemia,
– Fabry disease,
– Kearns-Sayre syndrome,
– familial hypercholesterolemia,
– mucopolysaccharidoses and
– GM1 gangliosidosis.
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40. Dysmorphic features
 Zellweger syndrome, glutaric aciduria type 2 and storage
syndromes.
 Renal manifestations:
- patients with cystinosis, galactosemia, hereditary fructose
intolerance and tyrosinemia (renal tubular acidosis);
progressive renal failure is common m cystinosis.
- Enlarged kidneys are seen in patients with GSD type I.
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41. Ocular findings
- Cataract: galactosemia, peroxisomal disorders, Lowe
syndrome and Wilson disease; lens dislocation is seen in
homocystinuria.
- Corneal abnormalities: mucopolysaccharidoses, Wilson
disease and Fabry disease.
- Cherry-red spots: lysosomal storage diseases (Tay-Sachs
disease, GMJ gangliosidosis and Niemann-Pick disease).
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42. Skin findings
- eczematous rash with alopecia: biotinidase deficiency
- Angiokeratoma: Fabry disease, but are also seen in
fucosidosis and beta- mannosidosis.
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44. Laboratory Investigations
- Peripheral smear : vacuolated lymphocytes in neuronal
ceroid lipofuscinosis, fucosidosis and sialidosis;
acanthocytosis in abetalipoproteinemia and Hallervorden Spatz
disease.
• Adrenal insufficiency
• Neuroimaging, electrophysiological studies and skeletal
survey are useful for various neurodegenerative and storage
disorders.
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45. Laboratory Investigations
• Bone marrow aspirate
• Enzyme assays
• DNA molecular testing is the most specific form of diagnostic
testing and is useful for prenatal diagnosis.
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46. Management
• A multidisciplinary team of metabolic specialists, pediatric,
neurologists, clinical geneticist, cardiologist, orthopedic surgeon
and physiotherapist is required to minimize the supportive care in
these patients.
• enzyme replacement
• enzyme enhancement/ organ transplant
• substrate reduction
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47. Management
• Since most IEMs are inherited in an autosomal recessive
manner, the risk of recurrence in subsequent pregnancies in
25%.
• Few disorders show X- linked, autosomal dominant and
mitochondrial inheritance.
• Prenatal diagnosis is possible by enzyme assays or mutation
testing on fetal DNA, obtained through amniotic fluid or
chorionic villus biopsy.
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48. Galactosemia
• Galactosemia is an
inherited disorder
characterized by an
inability of the body
to utilize
galactose.
• Galactosemia means
"galactose in the
blood".
The main source of
galactose in the diet is
milk products.
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49. Features
• Infants usually have feeding problems and do
not grow as they should.
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50. Management
• Galactosemia is treated by removing
foods that contain galactose from the
diet.
• Untreated galactosemia will result in a
harmful build-up of galactose and
galactose-1- phosphate in the
bloodstream and body tissues.
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51. BREASTFEEDING ?????
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52. Research article
Topic: To Breastfeed or Not: PKU, Galactosemia, Other
Rare Disorders and Possible Misdiagnosis
- Galactosemic baby, soon after birth have profuse
vomiting, poor weight gain, wasting and lethargy.
- This usually prompts them to seek medical attention and
testing.
- There is no intermediate or partial breastfeeding
option for these infants.
- They must be totally weaned promptly and fed a
galactose-free formula such as Nutramigen. With cup /
spoon.
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53. Disorder of Amino acid metabolism
Phenylketonuria (PKU)
• autosomal recessive metabolic genetic disorder.
• Phenylalanine is found naturally in the breast milk of
mammals
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56. BREASTFEEDING????
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57. To Breastfeed or Not: PKU, Galactosemia,
Other Rare Disorders and Possible
Misdiagnosis
• According to Riordan and Auerbach, "Breastfeeding an
infant with PKU is not contraindicated as was
previously believed.
• Human milk has relatively low levels of phenylalanine"
when compared with cow's milk formulas.
• Miller and Chopra and others recommend that total or
partial breastfeeding should be encouraged in the PKU
infant.
• In addition, these infants should have their phenylalanine
blood levels monitored regularly.
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58. Research article
Topic: The management of breast feeding among infants with
phenylketonuria
Conducted by: L. McCabe, A. E. Ernest, M. R. Neifert, S.
Yannicelli, A. M. Nord, P. J. Garry & E. R. B. McCabe
Journal of Inherited Metabolic Disease
Summary :Treatment for phenylketonuria (PKU) involves using
low phenylalanine or phenylalanine-free formulas and
supplementation with sufficient phenylalanine for normal growth
and development. Eighteen infants with phenylketonuria who
received breast milk as their primary phenylalanine source were
compared with ten other infants with PKU who received their
phenylalanine primarily from infant formulas.
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59. Research article
• There were no significant differences between breast-fed
and formula-fed infants for serum phenylalanine, serum
tyrosine, length, weight, head circumference,
haematocrit, haemoglobin, serum iron, total iron binding
capacity, percentage iron saturation, ferritin, plasma zinc
and total calorie intake.
• Breast-fed infants did show lower mean corpuscular
volume at 3 months and 6 months of age. Breast-fed
infants had lower phenylalanine intake at 2, 4, 5 and 6
months of age. Breast-fed infants at 1, 2, 3, 4, 5 and 6
months of age had lower protein intake. Breast feeding
may be continued in the newly diagnosed
phenylketonuric infant without any apparent
adverse nutritional consequences.
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60. REFERENCES
• Inborn errors of metabolism [Internet]. En.wikipedia.org. 2020 [cited 8 September
2020]. Available from: https://en.wikipedia.org/wiki/Inborn_errors_of_metabolism
• disease M. Maple syrup urine disease: MedlinePlus Medical Encyclopedia
[Internet]. Medlineplus.gov. 2020 [cited 8 September 2020]. Available from:
https://medlineplus.gov/ency/article/000373.htm#:~:text=Maple%20syrup%20urine
%20disease%20(MSUD)%20is%20inherited%2C%20which%20means,these%20c
hemicals%20in%20the%20blood.
• Wu F, Wang J, Pu C, Qiao L, Jiang C. Wilson’s Disease: A Comprehensive Review
of the Molecular Mechanisms. International Journal of Molecular Sciences.
2015;16(12):6419-6431.
• Wilson's disease - Diagnosis and treatment - Mayo Clinic [Internet].
Mayoclinic.org. 2020 [cited 8 September 2020]. Available from:
https://www.mayoclinic.org/diseases-conditions/wilsons-disease/diagnosis-
treatment/drc-20353256
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61. REFERENCES
• 5. [Internet]. 2020 [cited 8 September 2020]. Available from:
https://www.researchgate.net/publication/273144908_To_Breastfeed_or_N
ot_PKU_Galactosemia_Other_Rare_Disorders_and_Possible_Misdiagnosi
s [accessed Sep 06 2020]. Available from:
https://www.researchgate.net/publication/273144908_To_Breastfeed_or_N
ot_PKU_Galactosemia_Other_Rare_Disorders_and_Possible_Misdiagnosi
s [accessed Sep 07 2020].
• https://www.researchgate.net/publication/273144908_To_Breastfeed_or_N
ot_PKU_Galactosemia_Other_Rare_Disorders_and_Possible_Misdiagnosi
s [accessed Sep 06 2020].
• Available from:
https://www.researchgate.net/publication/273144908_To_Breastfeed_or_N
ot_PKU_Galactosemia_Other_Rare_Disorders_and_Possible_Misdiagnosi
s [accessed Sep 07 2020].
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