Download - Inborn error of metabolism
Inborn Error of Metabolism
Single gene mutations
Alteration of primary protein structure
Alteration of the amount of protein synthesized
Mild to lethal
Inheritance:
• Most IEM…… autosomal recessive genetic traits
• Urea cycle disorder ornithine transcarbamylase
deficiency…….. X linked
• Some are mitochondrial inheritance
Metabolic disorders can be classified using a
variety of schemes based on:
the clinical presentation
the age of onset
the tissues or organ systems involved
the defective metabolic pathways
Classifications of IEM
Amino acids • Phenylketonuria- Homocystinuria - tyrosinemia
Lipidoses • Tay sach’s disease – Gaucher’s disease –
metachromatic leukodystrophy
carbohydrates • Galactosemia – fructose intolerance –
Glycogen storage disorders
Organic acidemia • Methylmalonic aciduria- propionic aciduria-
maple syrup urine disease
Transport disorders • Cystinuria cystinosis – hypercholesterlemia
(AD)
Peroxisomal disorders
• Adrenoleukodystrophy – zellweger syndrome – chondrodysplasia punctata
Lysosomal storage disorders
• mucopolysaccaridosis
Urea cycle disorders • Ornithine transcarbamylase deficiency-
arginosucciniase deficiency- carbamyl phosphate synthetase deficiency
Metal metabolic disorders
• Wilson’s disease – Menkes disease
Group 1
Anabolism/
catabolism
Lysosomal, Peroxisomal, glycosylation, and cholesterol synthesis defects
some Lysosomal disorders can be efficiently treated by enzyme replacement or substrate reduction therapies
Group 2
intermediary
metabolism
Aminoacidopathies, organic acidurias, urea cycle disorders, sugar intolerances, metal disorders and porphyrias
Acute or chronic intoxications
Neonatal to adulthood
Most …. treatable emergency removal of the toxin by special diets, extracorporeal procedures, cleansing drugs or vitamins
Group 3
energy production/
utilization
Cytoplasmic defects encompass those affecting glycolysis, glycogenosis, gluconeogenesis, hyperinsulinisms, and creatine and pentose phosphate pathways; the latter are untreatable.
Mitochondrial defects include respiratory chain disorders, and Krebs cycle and pyruvate oxidation defects, mostly untreatable, and
disorders of fatty acid oxidation and ketone bodies that are treatable
Clinical presentations:
• Pregnancy:
acute fatty liver of pregnancy- HELLP
syndrome………… long chain 3 hydroxy coenzyme
A dehydrogenase deficiency (LCHADD)
Clinical presentations:
• Sepsis like presentation
• Mental retardation
• Neurological impairment, Seizures,
Encephalopathy, tone abnormalities
• Sudden infant death
• Metabolic acidosis
• Hypoglycemia
• Liver dysfunctions
• Dysmorphic features
• Cardiac disease
• Hydrops fetalis
• Abnormal urine odor
Inborn Errors of Metabolism with hydrops
fetalis
• Lysosomal disorders:
- Mucopolysaccaridosis types I, IVA, VII
- Gaucher disease
- Nieman pick disease type c
- Farber disease
• Hematologic disorders:
- G-6-PD deficiency
- Pyruvate kinase defieciency
• Others:
- Neonatal hemochromatosis
- Respiratory chain disorders
Evaluation
• History, Family history:
parental consanguinity, unexplained neonatal
deaths
• Physical examination:
facial dysmorphism, cataracts, retinopathy,
structural brain anomalies, hypertrophic or dilated
cardiomyopathy, hepatomegaly, multicystic
dysplastic kidneys and myopathy.
Evaluation
Initial Evaluation
CBC
Blood glucose
Plasma ammonia
Plasma lactate,
pyruvate Liver
functions tests
Urine reducing
substances
Urine ketones
Electrolytes, Ca, Mg
2nd line Evaluation
carnitine, acylcarnitine
s, vLCFA enzymes
Magnetic resonance imaging
(MRI)
Magnetic resonance spectroscopy (MRS)
Plasma aminoaci
d analysis Urine
organic acid
analysis
EEG
Mutation analysis
CSF aminoacid analysis
Phenylketonuria Disorder
1:15000 Incidence
Autosomal recessive Inheritance
Phenylalanine hydroxylase (> 98 percent)
Biopterin metabolic defects (< 2 percent)
Metabolic error
Mental retardation, acquired microcephaly Key manifestation
Plasma phenylalanine concentration Key laboratory test
Diet low in phenylalanine Therapy approach
Maple syrup urine disease Disorder
1:150,000 Incidence
Autosomal recessive Inheritance
Branched-chain 3-keto acid
dehydrogenase
Metabolic error
Acute encephalopathy, metabolic
acidosis, mental retardation
Key manifestation
Plasma amino acids and urine organic
acids
Dinitrophenylhydrazine for ketones
Key laboratory test
Restriction of dietary branched-chain
amino acids
Therapy approach
Carbohydrate metabolism Galactosemia Disorder
1:40000 Incidence
Autosomal recessive Inheritance
Galactose 1-phosphate
uridyltransferase (most common);
galactokinase; epimerase
Metabolic error
Hepatocellular dysfunction, cataracts Key manifestation
Enzyme assays, galactose and
galactose 1-phosphate assay,
molecular assay
Key laboratory test
Lactose-free diet Therapy approach
Glycogen storage disease, type Ia
(von Gierke's disease)
Disorder
1:100000 Incidence
Autosomal recessive Inheritance
Glucose-6-phosphatase Metabolic error
Hypoglycemia, lactic acidosis, ketosis Key manifestation
Liver biopsy enzyme assay Key laboratory test
Corn starch and continuous overnight
feeds
Therapy approach
Fatty acid oxidation
Medium-chain acyl-CoA
dehydrogenase deficiency
Disorder
1:15000 Incidence
Autosomal recessive Inheritance
Medium-chain acyl-CoA dehydrogenase Metabolic error
Nonketotic hypoglycemia, acute
encephalopathy, coma, sudden infant
death
Key manifestation
Urine organic acids, acylcarnitines, gene
test
Key laboratory test
Avoid hypoglycemia, avoid fasting Therapy approach
Lactic acidemia
Pyruvate dehydrogenase deficiency Disorder
1:100000 Incidence
X linked Inheritance
E1 subunit defect most common Metabolic error
Hypotonia, psychomotor retardation,
failure to thrive, seizures, lactic acidosis
Key manifestation
Plasma lactate
Skin fibroblast culture for enzyme
assay
Key laboratory test
Correct acidosis; high-fat, low-
carbohydrate diet
Therapy approach
Lysosomal storage
Gaucher disease Disorder
1:60,000; type 1–1:900 in Ashkenazi
Jews
Incidence
Autosomal recessive Inheritance
β-glucocerebrosidase Metabolic error
Coarse facial features,
hepatosplenomegaly
Key manifestation
Leukocyte β-glucocerebrosidase assay Key laboratory test
Enzyme therapy, bone marrow transplant Therapy approach
Fabry's disease Disorder
1:80,000 Incidence
X linked Inheritance
α-galactosidase A Metabolic error
Acroparesthesias, angiokeratomas
hypohidrosis, corneal opacities, renal
insufficiency
Key manifestation
Leukocyte α-galactosidase A assay Key laboratory test
Enzyme replacement therapy Therapy approach
Hurler's syndrome Disorder
1:100000 Incidence
Autosomal recessive Inheritance
α-l-iduronidase Metabolic error
Coarse facial features,
hepatosplenomegaly
Key manifestation
Urine mucopolysaccharides Leukocyte α-
l-iduronidase assay
Key laboratory test
Bone marrow transplant Therapy approach
Organic aciduria
Methylmalonic aciduria Disorder
1:20000 Incidence
Autosomal recessive Inheritance
Methylmalonyl-CoA mutase, cobalamin
metabolism
Metabolic error
Acute encephalopathy, metabolic
acidosis, hyperammonemia
Key manifestation
Urine organic acids Skin fibroblasts for
enzyme assay
Key laboratory test
Sodium bicarbonate, carnitine, vitamin
B12, low-protein diet, liver transplant
Therapy approach
Propionic aciduria Disorder
1:50000 Incidence
Autosomal recessive Inheritance
Propionyl-CoA carboxylase Metabolic error
Metabolic acidosis, hyperammonemia Key manifestation
Urine organic acids Key laboratory test
Dialysis, bicarbonate, sodium benzoate,
carnitine, low-protein diet, liver transplant
Therapy approach
Peroxisomes
Zellweger syndrome Disorder
1:50000 Incidence
Autosomal recessive Inheritance
Peroxisome membrane protein Metabolic error
Hypotonia, seizures, liver dysfunction Key manifestation
Plasma very-long-chain fatty acids Key laboratory test
No specific treatment available Therapy approach
Urea cycle
Ornithine transcarbamylase deficiency Disorder
1:70000 Incidence
X linked Inheritance
Ornithine transcarbamylase Metabolic error
Acute encephalopathy Key manifestation
Plasma ammonia, plasma amino acids
Urine orotic acid
Liver (biopsy) enzyme concentration
Key laboratory test
Sodium benzoate, arginine, low-protein
diet, essential amino acids; dialysis in
acute stage
Therapy approach
Treatment
Prevent Catabolism:
Administration of calories is used in the treatment of
acute episodes to try to slow down catabolism.
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.
Enzyme Replacement Therapy:
Human alpha glucosidase enzyme (pompe’s disease)-
Laronidase (Aldurazyme) enzyme(MPS I)patients-
Fabry-specific enzyme replacement therapy (ERT) with
recombinant alpha-Gal A (Fabrazyme) is safe and
effective, Imiglucerase (Gaucher disease)
Increase the Residual Enzyme Activity:
B12 decreases the urinary levels of methyl malonate by
enhancing activity of Trans Cobalmin II
Reduce Substrate Synthesis:
Inhibition of substrate synthesis has been used as a
strategy for treating glycolipid Lysosomal storage
disease.
Replacement of the End Product:
Hypoglycaemia can be prevented by frequent feeds
during the day and continuous nasogastric feeding
at night, in infancy and early childhood. Raw
cornstarch (2 g/kg every six hours) has been shown
to be effective in preventing hypoglycaemia in older
children with glycogen storage disease type I as
well as decreasing the hyperlipidaemia,
hyperuricaemia, and lactic acidaemia
Transplantation and Gene Therapy:
For the last 25 years, hematopoietic cell
transplantation (HCT) has been used as effective
therapy for selected inborn errors of metabolism
(IEMs), mainly Lysosomal storage diseases and
Peroxisomal disorders. The main rational for HCT in
IEMs is based on the provision of correcting
enzymes by donor cells within and outside the blood
compartment
Prevention
Genetic counselling and prenatal diagnosis:
The samples required are chorionic villus tissue or
amniotic fluid. Modalities available are:
• Substrate or metabolite detection: useful in
phenylketonuria, peroxisomal defects.
• Enzyme assay: useful in lysosomal storage
disorders like Niemann-Pick disease, Gaucher
disease.
• DNA based (molecular) diagnosis: Detection of
mutation in proband/ carrier parents is a
prerequisite.
Neonatal screening: tandem mass spectrometry
Selective screening for inborn errors of metabolism
by tandem mass spectrometry in Egyptian children:
A 5 year report
• A relatively high number of patients (203/3380 (6%))
were confirmed with 17 different types of IEMs.
Averages for age at diagnosis for different disorders
ranged from 2.5 months to 6.6 years with general
developmental delay and irreversible neurological
damage being the most common presenting features
(75.9% and 65.5%, respectively). Amino acid disorders
(127/203 (62.6%)), mainly phenylketonuria (100/203
(49.3%)), were the most encountered, followed by
organic acidemias (69/203 (34%)), while fatty acid
oxidation defects (7/203 (3.4%)) were relatively rare.
88% of patients were born t consanguineous parents.
References
• Talkad S. Raghuveer and et.al. Inborn Errors of
Metabolism in Infancy and Early Childhood: An
Update. American Family Physician j.2006:
17:1981-1990
• Atlas of Metabolic Diseases, 2nd edition
• Ananth N Rao, J Kavitha, Minakshi Koch and
Suresh Kumar V. Inborn Errors of Metabolism:
Review and data from a tertiary care center.
Indian Journal of Clinical Biochemistry, 2009: 24
(3) 215-222
• Anju Gupta. To Err is Genetics: Diagnosis and
Management of Inborn Errors of Metabolism
(IEM)
• Laila A. Selim and et.al. Selective screening for
inborn errors of metabolism by tandem mass
spectrometry in Egyptian children: A 5 year
report. Clinical Biochemistry 47 (2014) 823–828