INBORN ERRORS OF

METABOLISM
Introduction
• Metabolism: chemical or physical changes undergone by
substances in a biological system.
• Inborn errors of metabolism (IEM)
• IEM are a large group of hereditary biochemical diseases
in which specific gene mutation cause abnormal or missing
proteins that lead to altered function.

• This may produce chemicals that build up in various parts

of the body causing clinical disease.
Categories of IEMs
• Disorders of protein metabolism (eg, amino acidopathies,
organic acidopathies, and urea cycle defects)
• Disorders of carbohydrate metabolism (eg, carbohydrate
intolerance disorders, glycogen storage disorders,
disorders of gluconeogenesis and glycogenolysis)
• Fatty acid oxidation defects
Inheritance of IEMs
• IEM are usually Autosomal recessive.
• Some are x-linked recessive conditions including:
• Agammaglobulinemia.
• Granulomatous disease.
• Hunter’s Syndrome.
• A few inherited as Autosomal dominant trait including:
hyperlipedemia
Approach to the diagnosis of IEMs
• Clinical findings: History and physical examination
• Laboratory tests
 Glucose, Electrolytes, Gas, Ketones, BUN (blood urea nitrogen),
Creatinine.
 Lactate, Ammonia, Bilirubin.
 Amino acids, Organic acids, Reducing subst.
 DNA analysis.
 Neonatal screening
When to suspect an IEM?
Clinical: Labs:
 Vomiting  Metabolic acidosis
 Lethargy  Hypoglycemia
 Failure to thrive  Hyperammonemia
 Seizure  Reducing substances in
 Respiratory manifestation urine
 Coma  Ketonuria
 Cardiomyopathy  Pancytopenia
 Odor
 Abnormal hair
 Dysmorphology
Figure Initial clinical approach
to a full term newborn infant
with a suspected genetic
metabolic disorder. This
schema is a guide to the
elucidation of some of the
metabolic disorders in newborn
infants. Although some
exceptions to this schema
exist, it is appropriate for most
cases.
Figure: Clinical approach to infants
with organic acidemia.
Screening
Diseases Test Age of treatment
PKU, MSUD, Guthrie
1st weeks of life
Thyrosinemia MS/MS1
Propionic acidemia, MS/MS
Methyl malonic acidemia, 1st week of life
Isovaleric acidemia, Enzyme
1st weeks of life
Biotinidase deficiency assessment

Enzyme
Galactosemia 1st days of life
assessment
Urea cycle defects MS/MS 1st days of life

1Tandem mass spectrometry, also known as MS/MS or MS2, is a technique in

instrumental analysis where two or more mass analyzers are coupled together using an
additional reaction step to increase their abilities to analyse chemical samples. A common
use of tandem-MS is the analysis of biomolecules, such as proteins and peptides.
Metabolic Disorders Presenting as Severe
Neonatal Disease
Disorders of Carbohydrate Metabolism
• Galactosemia - presents with severe liver disease, gram
negative sepsis, and/or cataracts
• Enz deficiency: Gal-1-phos uridyl transferase
• Glycogen storage disease type 1a & 1b - presents as
hypoglycemia
• Enz deficiency: Glucose-6 phosphatase (1a), glucose-6-phosphate
translocase (1b)
• Lactic Acidosis - presents as lactic acidosis +/-
hypoglycemia
• Enz deficiency: , Pyr dehydrogenase, Pyruvate carboxylase, etc.
• Hereditary Fructose intolerance - Needs fructose
exposure, hypoglycemia and acidosis
• Enz deficiency: Aldolase B deficiency in the liver, kidney, and small
intestine.
Metabolic Disorders Presenting as Severe
Neonatal Disease
Amino Acid Disorders
• Maple syrup urine disease - presents with odor to
urine and CNS problems
• Enz deficiency: Branched chain ketoacid decarboxylase
• Nonketotic hyperglycinemia - presents with CNS
problems
• Enz deficiency: Glycine cleavage system (See articles in
topic 17)
• Tyrosinemia - Severe liver disease, renal tubular
dysfunction
• Enz deficiency: Fumaryl acetoacetate hydrolase (See
articles in topic 17)
Metabolic Disorders Presenting as Severe
Neonatal Disease
Urea Cycle Defects
• Present with vomiting, lethargy, hepatomegaly,
seizures, hyperammonemia (with no acidosis) and
coma
• Ornithine carbamyl transferase (OTC) deficiency
• Carbamyl phosphate synthetase deficiency
• Citrullinemia: argininosuccinate synthetase deficiency
• Argininosuccinic Aciduria: argininosuccinate lyase deficiency
• Argininemia: Arginase deficiency
Metabolic Disorders Presenting as Severe
Neonatal Disease
• The following present with lethargy, seizures, acidosis, ketonuria
(except MCAD deficiency), hyperammonemia, and/or
hyperglycinemia
4.Organic Acid Defects
• Propionic acidemia: propionyl-CoA carboxylase deficiency
• Methylmalonic acidemia/aciduria: methylmalonyl CoA mutase or
methylmalonyl CoA racemase deficiency
• Isovaleric acidemia - odor of “sweaty feet”: isovaleric acid-CoA
dehydrogenase deficiency
• Medium chain acyl-CoA dehydrogenase deficiency (MCADD):
medium-chain dicarboxylic aciduria (adipic, suberic, and sebacic
acids), hypoketotic hypoglycemia
Phenylketunuria (PKU)
• Phenylketonuria (PKU) is a condition in which the accumulation
of the substrate of the missing enzyme gives rise to a clinical
syndrome. The enzyme concerned is phenylalanine
hydroxylase, which hydroxylates phenylalanine to form
tyrosine
• incidence of approximately 1 in 10 000
• Phenylalanine accumulates in the blood and if the condition is
untreated it results in severe learning difficulties, thought to be
due directly to the effect of excess phenylalanine on the
developing brain.
• The name of the condition derives from the urinary excretion of
phenylpyruvic acid, a phenylketone. This is normally a minor
metabolite of phenylalanine but is produced in excess when the
major metabolic pathway is blocked.
Characteristics of classic PKU:
Elevated phenylalanine:
• Phenylalanine is present in elevated concentrations in tissues,
plasma, and urine.
• These metabolites give urine a characteristic musty (“mousey”)
odor.
• [Note: The disease acquired its name from the presence of a
phenylketone (now known to be phenylpyruvate) in the urine.
CNS symptoms:
• Mental retardation, failure to walk or talk, seizures, hyperactivity,
tremor, microcephaly, and failure to grow are characteristic
findings in PKU.
• The patient with untreated PKU typically shows symptoms of
mental retardation by the age of one year, and rarely achieves an
IQ greater than 50.
• [Note: These clinical manifestations are now rarely seen as a
result of neonatal screening programs.]
Characteristics of classic PKU:
Hypopigmentation :
• Patients with phenylketonuria often show a deficiency of pigmentation
(fair hair, light skin color, and blue eyes).
• The hydroxylation of tyrosine by tyrosinase, which is the first step in the
formation of the pigment melanin, is competitively inhibited by the high
levels of phenylalanine present in PKU.
Neonatal screening and diagnosis of PKU:
• The diagnosis depends on the demonstration of an abnormally
high concentration of phenylalanine in the blood: neonatal
screening for the condition is discussed below.
• The infant with PKU frequently has normal blood levels of
phenylalanine at birth because the mother clears increased
blood phenylalanine in her affected fetus through the placenta.
• Normal levels of phenylalanine may persist until the newborn
is exposed to 24 to 48 hours of protein feeding.
• Thus, screening tests are typically done after this time to avoid
false negatives.
• For newborns with a positive screening test, diagnosis is
confirmed through quantitative determination of phenylalanine
levels.
Neonatal screening and diagnosis of PKU:
• The screening test involves measurement of the concentration
of phenylalanine in a sample of capillary blood taken from a
heel-prick 6–10 days after birth. The delay after birth is to
allow sufficient time for feeding (and hence protein intake) to
become established, and for the effect of maternal clearance
of phenylalanine from the fetal circulation to subside.
• Formerly, the Guthrie test, a microbiological test using a strain
of Bacillus subtilis in conditions such that growth is only seen if
excess phenylalanine is present, was used to detect high
concentrations of phenylalanine, but most laboratories now
use a chromatographic technique. If the screening test is
found to be positive, further, definitive tests are then
performed.