Understanding about the biochemical aspects of inborn errors of aminoacid metabolism is important in the field of pediatrics, metabolic medicine and medical genetics. This presentation mainly includes the biochemical aspects, the enzyme defect, clinical features, Screening and diagnostic testing modalities with their reference and management. Recent developments in the field of IEM is also added

1. Inborn Errors of
Aminoacid Metabolism
Dr Sarath Krishnan M P
Junior Resident/Biochemistry
AIIMS Rishikesh
11-10-2021
1

2. ✘ Case of inborn errors of amino acid metabolism
✘ Introduction
✘ Classification
✘ Inborn errors
✘ Screening method
✘ Diagnosis and advanced methods
✘ Treatment
✘ COVID 19 and IEM
✘ Approach to cases of inborn errors of amino acid metabolism
✘ Summary
2

3. 3
CASE :
A one-year-old male child was born to consanguineous parents by NVD.
Birth weight: 3.5kgs.
O/E: Alert and no proper eye to eye contact, Microcephaly, Mild spasticity in
lower limbs, No facial asymmetry, Plantar reflux is raised.
Radiological data presents with cerebral atrophy, bilateral diffuse white
matter changes in MRI scan
Provisional diagnosis to be Metachromatic Leukodystrophy (MLD)/
Aminoaciduria/ Leigh syndrome.

4. 4
Advised for Urine and serum aminoacid test, thyroid hormone stimulating test,
creatinine phosphokinase(CPK), nerve conduction study(NCS), serum lactate
pyruvate tests.
He had kept on physiotherapy and on anti-epileptic medications.
Later when the child visited for the outpatient department with conditions of
global developmental delay, right focal seizures
O/E: Hypopigmented scalp hair, increased tone, deep tendon reflux (DTR)
scoring
He had screened for plasma aminoacid analysis and the method used was
reverse phase HPLC.
Elevated levels of phenylalanine levels 300μmol/L (31-75μmol/L), urine
metabolic screening reports are positive for ferric chloride test.

5. Aminoacids………..
✘ Monomer units of proteins
✘ Contains an amine group, a carboxylic acid group and a side chain specific
to each amino acid
✘ Total 300 known amino acids
✘ 22 standard amino acid
✘ Remaining non-proteinogenic or non-standard amino acids
5

6. Functions of aminoacids!!!!!

7. Inborn errors of aminoacid metabolism
✘ Heterogenous group of disorders
✘ Abnormalities in synthesis, transport and turnover of the aminoacids
✘ Results in aminoacid accumulation and enters into alternate pathway which
results in toxic metabolite formation
7

8. Garrod’s hypothesis
A B C
(Substrate excess) (Product deficiency)
D (Toxic metabolite)
8

9. Classification
✘ Two different ways
○ Based on the defect
 Defective / Deficient enzymes
 Defective transport and storage
○ Based on product / substrate accumulated
 Organic acidemias
 Aminoacidopathies
9

10. Defective Metabolism
✘ Phenylketonuria
✘ Tyrosinemia
✘ Alkaptonuria
✘ Albinism
✘ Maple syrup urine disease – Branched chain aminoacid - IEM
✘ Homocystenemia – Sulphur containing AA – IEM
✘ CPS I deficiency
✘ OTC deficiency
10
Aromatic Aminoacid - IEM
Urea cycle disorders

11. Defective transport
✘ Cystinuria
✘ Cystinosis
✘ Hartnup disease
✘ Lysinuric protein intolerance
11

12. Inborn errors of aromatic aminoacid metabolism
12

13. Metabolism overview
13

14. Phenylketonuria
✘ Also K/a Oligophrenia
Phenylpyruvic Folling Disease
Hyperphenylalaninemia
 AR inheritance
14

15. Classification
15
Type Condition Biochemical defect
I Classical PKU Absent PAH activity
II Persistent hyper phenylalaninemia Low PAH activity
III Transient mild hyper phenylalaninemia Maturational delay of PAH
IV Dihydropteridine deficiency Deficient / Absent DHPR
V Abnormal dihydropteridine function DHPR synthesis defect

16. 16
Phenyl alanine
PAH
Tyrosine Thyroid hormones
Hypothyroidism
Catecholamines
Depression
Decreased CO
Melanin
Albinism
Tyramine
Phenyl pyruvate Increased
phenyl alanine
Phenyl
lactate
Phenyl
acetate
+Glutamine
Phenyl acetyl
glutamine
Mousy odour
Eczema

17. Features
17

18. Laboratory diagnosis
✘ Blood and urinary phenyl alanine levels
✘ Normal levels are
○ Adults: 58±15μM/L
○ Teenagers: 60±13μM/L
○ Childhood: 62±18μM/L
○ Newborn: upto 120μM/L
✘ In untreated cases of PKU blood levels are as high as 2mM/L
18

19. Screening tests
✘ Ferric chloride screening test
✘ Guthrie card test
✘ Tandem mass spectroscopy – Recent Advance
*Phenylketonuria: An Inborn Error of Phenylalanine Metabolism Robin A Williams,1,2,* Cyril DS
Mamotte,2 and John R Burnett1,3,*
19

20. Tandem mass spectrometer
20

21. Confirmatory diagnosis
✘ Southern blotting
✘ Restriction enzyme digestion
✘ Sequencing and multiplex ligation probe amplification.
*Phenylketonuria: An Inborn Error of Phenylalanine Metabolism Robin A Williams,1,2,* Cyril DS
Mamotte,2 and John R Burnett1,3,*
21

22. Treatment
✘ Infant has to fed a diet where there is complete lack of phenylalanine for
the first 7-10days
✘ Pregnant PKU  She is able to prevent her child from PKU symptoms if
she follows a diet low in protein
✘ Phenyl alanine ammonia lyase is combined with low phenyl alanine diet
22

23. Recent Advances!!!!!
✘ Next generation sequencing (NGS) – Confirmatory
✘ Treatment with a BH4 chaperone
✘ Large neutral amino acid (LNAA) therapy
✘ Gene therapy
*Phenylketonuria: A new look at an old topic, advances in laboratory diagnosis, and therapeutic strategies Khalid M. Sumaily and
Ahmed H. Mujamammi
23

24. Tyrosinemia
✘ Group of inherited disorders characterized by increased levels of tyrosine
and their catabolic metabolite in blood and their excretion in urine
✘ Classified into three types
24

25. 25
Type Alternate names Enzyme defect
I Hepato-renal tyrosinemia/ Tyrosinosis Fumaryl acetoacetate
hydrolase deficiency
II Richnar-Hanhart syndrome/ Oregon type
tyrosinemia/ Oculocutaneous type
tyrosinosis
Tyrosine
aminotransferase
deficiency
III Neonatal tyrosinemia 4αOH Phenylpyruvate
oxidase deficiency
Classification

26. Type I Tyrosinemia
✘ K/a Hepato-renal tyrosinemia- deficiency of Fumaryl acetoacetate
hydrolase
✘ AR inheritance
26
*Inhibit porphobilinogen synthase
*Forms Schiff base and increase risk of HCC

27. ✘ Stages-Progress in 3 stages
○ Stage I: Hepatic necrosis and Hypermethioninemia
○ Stage II: Nodular cirrhosis and chronic hepatic insufficiency without
hypermethioninemia
○ Stage III: Also k/a Baber syndrome where renal tubular damage and
hypophosphatemic rickets
✘ Clinical features
○ MR
○ Self mutilation
○ Hepatic failure
○ Cardiomyopathy
27

28. Screening
✘ Tandem mass spectrometry - Measurement of Succinyl acetone
✘ TYR 1
*Newborn screening for Tyrosinemia type 1 using succinylacetone – a systematic review of test accuracy Chris Stinton,1 Julia
Geppert,1 Karoline Freeman,1 Aileen Clarke,1 Samantha Johnson,2 Hannah Fraser,1 Paul Sutcliffe,1 and Sian Taylor-
Phillipscorresponding author1
28

29. ✘ Diagnosis
○ High levels of tyrosine in blood
○ α-Keto gamma methyl butyric acid is present-Cabbage like odour
○ Increased excretion of δ-ALA
○ Prenatal diagnosis: Increased succinyl acetone in amniotic fluid/
Measurement of Fumaryl acetoacetate in cultured amniotic cells
○ Molecular genetic testing for FAH gene mutations – Confirmatory
*Tyrosinemia Type 1 NORD gratefully acknowledges Kshitiz Singh, PhD, Research Fellow, The Children's Hospital of
Philadelphia
29

30. ✘ Treatment
○ Permanent cure: Liver transplantation
○ NITISINONE/ NTBC: Inhibitor of P-OH phenylpyruvate dioxygenase
30

31. Type II Tyrosinemia
✘ Also K/a Richnar-Hanhart syndrome/ Oregon type tyrosinemia/
Oculocutaneous type tyrosinosis– Tyrosine aminotransferase deficiency
✘ AR inheritance
✘ Diagnosis:
○ Presence of skin/ eye lesions along with elevated blood tyrosine levels
✘ Treatment:
○ Dietary restriction of phenylalanine and tyrosine
31

32. Type III Tyrosinemia
✘ Also K/a Neonatal tyrosinemia- Deficiency of 4α-OH Phenylpyruvate
oxidase
✘ AR inheritance
✘ Milder form disease without liver failure
✘ Children with this disorder have mild MR and/or convulsions
✘ HAWKINSINURIA
32

33. Recent Advances!!!!!
33

34. Alkaptonuria
✘ First condition in which mendelian recessive inheritance was proposed
✘ Deficiency of Homogentisate oxidase
34
Homogentisic acid
Homogentisate
oxidase
Maleyl acetoacetate
Benzo quinone acetic
acid
*Binds to collagen fibres
*Darkening of urine
*Calcification of coronary artery and cartilage

35. ✘ Screening tests:
○ Benedict's test
○ FeCl3 test
○ Ammoniacal AgNO3
✘ Diagnostic tests:
○ Estimation of Homogentisate
✘ Treatment:
○ Long term ascorbic acid supplementation
○ NTBC/ NITISINONE
*Measurements of Homogentisic Acid Levels in Alkaptonuria Patients Using an Optimized and Validated Gas Chromatography
Method / Mass Spectrometry September 2014Jordan Journal of Biological Sciences 7(3)
35

36. Recent Advances!!!!!
✘ Enzyme replacement or Gene therapy
✘ Mouse model of AKU is available already
*Alkaptonuria: Current Perspectives. Andrea Zatkova,1 Lakshminarayan Ranganath,2 Ludevit Kadasi1,3. 1Department of Human
Genetics, Biomedical Research Center, Slovak Academy of Sciences, Institute of Clinical and Translational Research, Bratislava,
Slovakia
36

37. Albinism
✘ Spectrum of clinical syndromes characterized by hypomelanosis
✘ Inherited defect in the pigment cells of eye and skin
✘ Gene loci on Chr 11
37

38. ✘ Albinism can be classified in two ways
○ Based on distribution of hypopigmented tissues
■ Oculocutaneous
■ Ocular
○ Based on tyrosinase activity
■ Tyrosinase positive
■ Tyrosinase negative
✘ Clinical features
○ Leads to white hair and skin
○ Lead to skin cancer
○ Photophobia (intolerance to light) and nystagmus ( rapid involuntary
oscillation of the eyeballs)
38

39. ✘ Diagnosis:
○ Detected at birth due to irregular pigmentation
○ Genetic analysis: CVS testing
Amniocentesis
○ Hair from scalp for Tyrosinase activity
○ Radioactive biochemical assay – Recent advance
✘ Treatment
○ NO CURE
○ Only symptomatic management
*Albinism: modern molecular diagnosis SUSAN M CARDEN RAYMOND E BOISSY
PAMELA J SCHOETTKER WILLIAM V GOOD William V Good, MD.
39

40. Inborn errors of branched chain aminoacid metabolism
40

41. Metabolism overview
41

42. Isovaleric acidemia
✘ Classical type of organic acidemia-Prevents normal metabolism of leucine
✘ Deficiency of Isovaleric acid CoA dehydrogenase
✘ AR inheritance
42
Leucine αKeto isocaproic acid Isovaleryl CoA
βMethyl crotonyl CoA
Hydroxy isovalerate
Isovaleryl glycine

43. ✘ Severe and life threatening present in early days of life with distinctive
odour of sweaty foot
✘ Diagnosis
○ Mass spectrometry of urine
○ Increased excretion of Isovaleryl carnitine and Isovaleryl glycine
✘ Treatment
○ Glycine administration in acute episodes
43

44. Methyl butyryl CoA dehydrogenase deficiency
✘ Also K/a Acyl CoA dehydrogenase deficiency/ Methyl butyryl glycinuria
✘ Usually asymptomatic
✘ Certain kids develop developmental delay/ epilepsy
✘ Diagnosi: Plasma and urinary carnitine and glycine conjugates of 2-methyl
butyryl CoA levels are raised
44

45. Propionic acidemia
✘ Also K/a propionic aciduria/ Propionyl CoA carboxylase deficiency/ Ketotic
glycinemia
 Defective PCCA/ PCCB genes
Propionyl CoA carboxylase deficiency
Decreased breakdown of Propionyl CoA to methyl malonyl CoA
Altered metabolism of Valine, Isoleucine, Threonine and methionine
Accumulation of Propionyl CoA, Propionic acid, Ketone bodies, Ammonia
45

46. ✘ Clinical symptoms –present at an early stage with progressive
encephalopathy
○ Poor feeding with developmental delay
○ Vomiting / Dehydration/ Acidosis
○ Hypotonia/ Seizures/ Lethargy
✘ Diagnosis:
○ Urine screened for organic acid – Gas chromatography and mass
spectroscopy
✘ Treatment
○ Low protein diet
○ Carnitine replacement
○ Antibiotics for intestinal washout of propiogenic flora(10days/month)
○ Liver transplant is gaining role in the management
46

47. Recent advances!!!!
✘ Study in mouse model
✘ Alternative for liver transplant
47

48. Methyl malonyl CoA mutase deficiency
✘ Also k/a Methyl malonic acidemia
✘ AR inheritance
48
Deficiency of enzyme leads to increased Methyl malonyl CoA
Inhibition of metabolism of Depletion of ATP, CoA
Propionyl CoA
Propionic acidemia Disruption in biosynthesis of
Myelin, Urea, Glucose

49. ✘ Clinical features:
○ Vomiting/ Acidosis
○ Hyperammonaemia/ Hyper glycinemia
○ Hypoglycaemia
○ Hepatomegaly/ Renal failure
○ Thrombocytopenia and Neutropenia at later stages
○ Hypotonia followed by spasticity
○ Dermatitis
○ Osteoporosis
✘ Outcome of these patients is poor and many of them die by the age of 1
year
49

50. ✘ Lab findings
○ Metabolic acidosis
○ Anaemia
○ Elevated ammonia levels in blood
○ Elevated ketone levels in urine
○ Neutropenia and thrombocytopenia
○ Elevated glycine, methylmalonic acid and propionic acid levels in the
blood and urine
50

51. ✘ Treatment
○ Protein restricted diet and carnitine supplementation
○ Bicarbonate, lipids, glucose and insulin may be indicated during
metabolic crisis episodes
○ Liver transplant or combined liver/ kidney transplant may increase
metabolic control
51

52. Maple syrup urine disease
52

53. ✘ Types:
○ Classical : Little/ No enzyme activity <2%
○ Intermediate: More enzyme activity 3-8%
■ Can tolerate greater amount of leucine
○ Intermittent: Even more enzyme activity 8-15%
○ Thiamine-responsive: Thiamine to increase enzyme activity
✘ Symptoms:
○ Occur in newborns within the first 4-7 days of birth
○ Vomiting/ Dehydration/ Metabolic acidosis
○ Burned sugar smell to urine
○ Could lead to death if not treated, but is manageable
53

54. ✘ Diagnosis:
○ Increased serum levels of leucine, isoleucine and valine along with
their respective ketoacids
○ Tandem mass spectrometry
✘ Treatment:
○ Replacing dietary protein by mixture of amino acids that contain low or
no leucine, isoleucine, and valine
54

55. Recent Advances!!!!!
55

56. Inborn errors of sulphur containing aminoacid metabolism
56

57. Metabolism overview
57

58. Hypermethioninemia
✘ Enzymes defective are
○ Methionine adenosyl transferase I/III deficiency
○ Glycine N-methyl transferase deficiency
○ S-Adenosyl homocysteine hydrolase deficiency
✘ AR/ AD
✘ Clinical features:
○ Remains asymptomatic/ unnoticed
○ Cabbage like odour of breath, sweat and urine
58

59. ✘ Investigations
○ MAT I/III deficiency:
■ Methionine levels are elevated 30times than normal
■ Concentrations of SAH, Total homocysteine and Cystathionine
are elevated
○ GNMT deficiency:
■ Normal concentration of Sarcosine with elevated level of
methionine and SAM
○ SAHH deficiency:
■ Elevated level of dimethyl glycine
59

60. Homocystinuria
✘ Defective enzyme is Cystathionine synthase
✘ AR
60

61. Classification
61
Types Defects
Homocystinuria I Cystathionine β synthase
Homocystinuria II Synthesis of N5-MTHF
Homocystinuria III Deficiency of methyl B12
Homocystinuria IV Defective intestinal
absorption of Vit B12

62. 62

63. ✘ Screening test: Methionine breath test
✘ Diagnosis
○ Plasma and urine levels of Homocysteine and Methionine levels are
raised
○ Silver nitroprusside test
○ Methionine loading test
✘ Treatment
○ Reduce the elevated levels of homocysteine thus preventing its
dreadful complication thrombosis
○ Vit B6 and B12
○ Betaine supplementation
○ PROTEIN RESTRICTED DIET
*Validity and reliability of the 13C-methionine breath test for the detection of moderate hyperhomocystinemia in Mexican adults
Jorge Maldonado-Hernández
63

64. Recent Advances!!!!!
✘ Studies suggest the positive association between ATHEROSCLEROSIS
and Homocystenemia
64

65. Cystathioninuria
✘ Deficiency of Cystathionine γ lyase/ Cystathioninase
✘ No apparent pathology except increased accumulation of cystathionine in
kidney, brain, liver and CSF
✘ Plasma cysteine levels remain normal with mild hyperhomocystinemia
65

66. Inborn errors of Glycine metabolism

67. Metabolism overview
67

68. Glycine encephalopathy
✘ Also k/a non-Ketotic hyperglycinemia
✘ AR
✘ 2nd most common disorder of aminoacid metabolism
✘ Defect lies in glycine cleavage system
✘ Characterised by neurological symptoms and abnormal high levels of
glycine in bodily fluids and tissues especially CSF
68

69. ✘ Classical
○ In first 3 days 2/3rd of infants present with
■ Muscular hypotonia
■ Apnoea and coma
○ Infants who survive the first apnoea attack by 6 months develop
■ Spastic quadriparesis
■ Intractable seizures
■ Severe global retardation
■ CONGENITAL MALFORMATIONS
○ Long term complications are
■ Feeding difficulties, GERD with esophagitis, Gall stones
■ Hip dislocation, Scoliosis, Osteoporosis
69

70. ✘ Mild
○ Less severe mental retardation and less frequent episodes of seizures
○ NO CONGENITAL MALFORMATIONS
○ Characteristic findings: Severe speech retardation and behavioural
problem
✘ Transient
○ Classical clinical and biochemical changes in early infancy but comes
back to normal by 8 weeks of age
○ Outcome being good with slight or no neurological sequelae
70

71. ✘ Diagnosis:
○ Increased concentration of glycine in serum and CSF with an
increased CSF-plasma ratio are pathognomonic features
✘ Treatment
○ Sodium benzoate
○ Dextromethorphan
○ Ketamine
○ Strychnine
○ Diazepam
71
Receptor antagonists

72. Inborn errors of Lysine metabolism

73. Metabolism overview
73

74. Hyperlysinemia
✘ Also k/a Lysine α-keto glutarate reductase deficiency/ α-aminoadipic
semialdehyde synthase deficiency
✘ AR
✘ Clinical features
○ Impaired sexual development
○ Lax ligaments and muscles
○ Mild anaemia
○ Subluxation of lens
○ Comatose due to increase ammonia level in blood
✘ Diagnosis
○ Increased serum lysine, arginine, ammonia are noted
74

75. Inborn errors of Histidine metabolism

76. Metabolism overview
76

77. Histidinemia
✘ Also k/a Histinuria/ Histidase deficiency/ Histidine ammonia lyase
deficiency
✘ AR
✘ Clinical features: Asymptomatic usually, in some MR and developmental
delay
✘ Diagnosis: Increased histidine in blood, urine, CSF with decreased levels of
urocanic acid
✘ Treatment: Specific treatment not necessary
77

78. Urocanic aciduria
✘ Urocanate hydrolase/ Urocanase deficiency
✘ AR
✘ Increased urocanic acid accumulation and its excretion
✘ Histidine levels are normal to slightly elevated
✘ MR and Aggressive behaviour
78

79. Carnosinemia
✘ Also k/a Carnosinase/ Aminoacyl histidine dipeptidase deficiency
✘ AR
✘ Carnosine: Dipeptide formed in muscles and neurons
✘ Lack of enzyme: Accumulated in urine/ CSF/ Blood and Neurons causing
Demyelination and degeneration of axons
79

80. Inborn errors of Proline metabolism

81. Metabolism overview
81

82. Hyperprolinemia
✘ AR-rare
✘ Two types based on the enzyme involved
○ Type I- Proline oxidase
○ Type II- Pyrroline 5 Carboxylase
✘ Mostly asymptomatic but rarely present as seizures, MR, Neurological
problems
✘ No specific treatment
82

83. Inborn errors of Urea cycle

84. Metabolism overview-Urea Cycle
84

85. Carbomyl phosphate synthetase I deficiency
✘ AR- Excess accumulation of NH3 in blood
✘ Clinical features: Symptoms are evident in the first few days of life
○ Early: CPS I enzyme is totally absent
Cerebral damage and hyperammonaemia coma
○ Delay: Partial deficiency
Hyperammonaemia coma stimulating Reye syndrome
Intermittent seizures
Vomiting and Mild abdominal pain
85

86. Ornithine transcarbamoylase deficiency
✘ Most common urea cycle disorder
✘ X-linked recessive disorder
✘ NH3 increase rapidly causing Ataxia, Lethargy and death
✘ GENETICS: OTC deficiency caused by mutations of OTC gene
86

87. ✘ Clinical features: Depending upon the age of onset of OTC deficiency
○ Classical/ Severe/ Early onset
○ Milder/ Late onset
✘ Affected neonates present with
○ Acrodermatitis enteropathica
○ Metabolic encephalopathy
87

88. Secondary orotic aciduria
✘ Orotic aciduria (AKA hereditary orotic aciduria) – Enzyme deficiency
resulting in a decreased ability to synthesize pyrimidines
✘ Elevated urinary orotic acid levels can also arise secondary to blockage of
the urea cycle, particularly in ornithine transcarbamoylase deficiency (OTC
deficiency)
88

89. Citrullinemia
✘ AR
✘ Argininosuccinate synthetase deficiency
✘ Types:
○ Type I: Changes in the kinetic properties of ASS
○ Type II: Low ASS found in liver but not in the kidney
○ Type III: No enzyme activity for ASS
✘ Clinical features:
○ Enuresis
○ Delayed menarche
○ Insomnia
○ Delusions and Hallucinations
89

90. Arginino succinic aciduria
✘ Arginino succinate lyase deficiency
✘ Clinical features:
○ Evident in the first few days of life because of high ammonia or later in
life presenting with sparse/ brittle hair, developmental delay and
tremors
○ Episodic unconsciousness with hepatomegaly
✘ Diagnosis
○ Low arginine along with hyperammonaemia
90

91. Argininemia
✘ Arginase deficiency
✘ AR
✘ Clinical features
○ Evident by the age of 3
○ Stiffness of legs is early presenting feature
○ Slower normal growth with developmental delay
○ Tremors, Seizures
○ MR
○ Rapid increase in NH3 may lead to episodes of irritability, refusal to
eat and vomiting
91

92. Treatment for urea cycle disorders
✘ Low protein diet
✘ IV Sodium benzoate
✘ IV Sodium phenylacetate
✘ Arginine replacement therapy
✘ Dialysis
92

93. N-Acetyl glutamate synthase deficiency
✘ AR
✘ N-Acetyl glutamate – Natural activator of CPS-I synthesized from acetyl
CoA and Glutamic acid
✘ Gene for NAG synthase located on Chr 17
✘ Severe neonatal disorder with fatal consequences if not detected
immediately upon birth
✘ Treatment : Injection of N-carbamoyl-L-glutamate an analogue of NAG
93

94. Inborn errors associated with transport of
aminoacids

95. Cystinuria
✘ AR – Mutation in SLC3A1 and SLC7A9
✘ Cause defective transport protein synthesis in the kidney
✘ Results in lack of proper reabsorption of aminoacids Lysine, Arginine,
Ornithine, Cysteine
✘ Cysteine level increases – will cause Kidney stones
95

96. ✘ Clinical features
○ Symptoms are secondary to the stones formed
✘ Investigations
○ Urine analysis for cysteine crystals
○ Genetic analysis
96

97. Cystinosis
✘ AR
✘ Excessive accumulation of cystine within the cell leading to crystal
formation
✘ Mutation of CTNS gen on Chr 17 which encodes cystinosin the lysosome
cystine transporter that becomes defective
✘ Types
○ Nephropathic
○ Intermediary
○ Non nephropathic/ Ocular
97

98. ✘ Nephropathic
 Present as renal
Fanconi syndrome
 Loss of important
minerals, salts
 Impairs growth and
hypophosphatemic
rickets
 Complete kidney failure
by age 10
✘ Intermediary
 Less severe
 Late presentation
 Clinical features similar
to nephropathic
✘ Ocular
 Growth impairment and
kidney failure not seen
 Only symptom is
photophobia
98

99. Treatment include CYSTEAMINE tablets and eye
drops

100. Lysinuric protein intolerance
✘ Also k/a Dibasic aminoaciduria type2/ Cationic aminoaciduria/ Familial
protein intolerance
✘ AR – Mutation of SLC7A7 gene
✘ Defective transport of Lysine, Ornithine, Arginine from kidneys and
intestine
Restriction of urea cycle due to decreased Ornithine and arginine
Hyperammonaemia leading to coma and death
100

101. ✘ Diagnosis
○ Increased urinary concentration of Lysine, Arginine, Ornithine with
corresponding decrease in plasma
○ Increased orotic acid concentration after protein rich meals
○ High levels of glutamine, glycine, ferritin and LDH
✘ Treatment
○ Oral supplementation of Citrulline
101

102. Hartnup disease
✘ Also k/a pellagra like dermatosis
✘ Defective absorption of non polar aminoacids from intestine and kidney
✘ Mainly Tryptophan
✘ AR – Mutation in SLC6A19 gene
✘ Defective SLC6A19(Na+ dependent and Cl- independent neutral AA
transporter)
Decreased absorption of Tryptophan
Decreased Melatonin/ Serotonin/ Niacin
102

103. ✘ Clinical features
○ Affected individuals remain asymptomatic and present with pellagra
like symptoms only on exposure to triggering factors like sunlight and
stress
○ Short stature with failure to thrive
○ Unsteady gait with episodes
○ Intermittent ataxia
○ Nystagmus
○ Psychiatric problems
103

104. ✘ Diagnosis
○ Excessive amount of amino acids such as tryptophan, lysine, glycine
are excreted but not proline, arginine, hydroxy proline thus
differentiating from generalised aminoacidurias
✘ Treatment
○ High protein diet
○ Daily supplementation with nicotinic acid
○ Avoid sunlight and other aggrevating factors
104

105. COVID-19 and IEM
✘ Study suggestive of metabolic decompensation in IEM
105

106. Approach to a case of inborn errors of aminoacid
metabolism

107. IEM – Index Of Suspicion
✘ Rapid deterioration in an otherwise well infant
✘ Septic appearing infant
✘ Failure to thrive
✘ Regression in milestones
✘ Recurrent emesis/ Feeding difficulty, alterations in respirations, abnormal
urine/ body smell, changing MS/ Lethargy, jaundice, intractable hiccups
✘ Can masquerade like pyloric stenosis
✘ Dietary aversion – Proteins, Carbohydrates
107

108. Inborn errors of aminoacid metabolism associated
with peculiar odour
108
IEM URINE ODOUR
Glutaric acidemia(Type II) Sweaty feet, Acrid
Hawkinsinuria Swimming pool
Isovaleric acidemia Sweaty feet, Acrid
MSUD Maple syrup
Hypermethioninemia Boiled cabbage
Multiple carboxylase deficiency Tomcat urine
Oasthouse urine disease Hops-like
Phenylketonuria Mousey/ musty
Trimethylaminuria Rotten fish
Tyrosinemia Boiled cabbage, Rancid butter

109. Emergency management
✘ ABC’s
✘ Correct hypotension
✘ NPO, Reverse catabolism with
D5-D10
✘ Correct hypoglycaemia
✘ Correct metabolic acidosis
✘ Dialysis
✘ Search and treat for precipitants
✘ Carnitine
✘ Sodium benzoate, Phenylacetate
109

110. Quick algorithms
110

111. Selected presentations/ Diagnostic considerations
111
Infant/ Child with
suspected
metabolic
disease
Respiratory
alkalosis/
Hyperammonaemia
Wide anion gap/
Metabolic acidosis/
Ketonuria/
Hyperammonaemia
Ketones negative/
Encephalopathy
<24hrs old, Burst
suppression EEG
Urea Cycle
Disease
Organic Acidemia
Non Ketotic
Hyperglycinemia

112. To Conclude!!!!!
✘ Inborn errors of metabolism are rare genetic (inherited) disorders in which
the body cannot properly turn food into energy.
✘ The disorders are usually caused by defects in specific proteins (enzymes)
that help break down (metabolize) parts of food.
✘ Researches are taking place for adequate management for IEM
✘ Enzyme replacement/ Gene therapy
✘ Prenatal diagnosis / Screening
112

113. References
✘ Nelson Textbook of Pediatrics - 21st Edition
✘ Harrison principles of internal medicine - 20th edition
✘ Phenylketonuria: An Inborn Error of Phenylalanine Metabolism Robin A
Williams,1,2, Cyril DS Mamotte,2 and John R Burnett1,3
✘ Phenylketonuria: A new look at an old topic, advances in laboratory
diagnosis, and therapeutic strategies Khalid M. Sumaily and Ahmed H.
Mujamammi
✘ Validity and reliability of the 13C-methionine breath test for the detection of
moderate hyperhomocystinemia in Mexican adults Jorge Maldonado-
Hernández
✘ Newborn screening for Tyrosinemia type 1 using succinylacetone – a
systematic review of test accuracy Chris Stinton,1 Julia Geppert,1 Karoline
Freeman,1 Aileen Clarke,1 Samantha Johnson,2 Hannah Fraser,1 Paul
113

114. Thank You