INBORN ERRORS OF

METABOLISM
Dr Oluyomi Esan (FWACP)
OUTLINE

 Objectives
 What are IEM?

 Epidemiology

 Pathophysiology

 Classification

 General features

 Diagnosis

 Principles of treament

 Common examples of IEM

 Resources
OBJECTIVES

 At the end of the lecture you should able :

 To define inborn errors of metabolism

 To discuss the features,pathophysiology,

diagnosis and principles of treatment of
inborn errors of metabolism.
 Discuss the very common IEM
WHAT ARE IEM?

 Genetic Disorders that affect the metabolism of

food.
 An Inherited enzyme deficiency causing the
disruption of normal bodily metabolism which leads
to an accumulation of toxic substrates or Impaired
formation of a product normally produced by the
deficient enzyme
Epidemiology
The number of identified inborn errors of
metabolism is growing with increased awarness and screening
procedure of infants.
 The incidence, collectively is estimated to be 1 in 5000 live births.
The frequencies for each individual IEM vary, but most are very rare
There are over 1500 IEM identified.
IEMs individually are rare but collectively are common.
 Presentation can occur at any time, even in adulthood.
Diagnosis does not require extensive knowledge of biochemical
pathways or individual metabolic diseases.
HOW OF IEM?

C
A
substrate excess B product deficiency

toxic metabolite
D
PATHOPHYSIOLOGY

 The majority are due to defects of single genes that code for
enzymes that facilitate conversion of various substances
(substrates) into others (products).
 Most are autosomal recessive traits.
 This means that the child must inherit the non-working gene from
both parents to be seriously affected.
 Effects are due to toxic accumulations of substrates before the
block, intermediates from alternative metabolic pathways, and/or
defects in energy production and utilization caused by a
deficiency of products beyond the block.
 Food not broken down properly may produce chemicals that build
up in various parts of the body causing medical problems and
learning disorders.
 Nearly every metabolic disease has several forms that vary in age
of onset, clinical severity and, often, mode of inheritance.
 There are missing or defective enzymes necessary to metabolize
the food eaten.
CLASSIFICATION
 Disorders of carbohydrate metabolism
 E.g., glycogen storage disease
 Disorders of amino acid metabolism
 E.g., phenylketonuria , maple syrup urine disease, glutaric acidemia type 1
 Disorders of organic acid metabolism (organic acidurias)
 E.g., alcaptonuria
 Disorders of fatty acid oxidation and mitochondrial metabolism
 E.g., medium chain acyl dehydrogenase deficiency (glutaric acidemia type 2)
 Disorders of porphyrin metabolism
 E.g., acute intermittent porphyria
 Disorders of purine or pyrimidine metabolism
 E.g., Lesch-Nyhan syndrome
 Disorders of steroid metabolism
 E.g., congenital adrenal hyperplasia
 Disorders of mitochondrial function
 E.g., Kearns-Sayre syndrome
 Disorders of peroxisomal function
 E.g., Zellweger syndrome
 Lysosomal storage disorders
 E.g., Gaucher's disease
 E.g., Niemann Pick disease
GENERAL FEATURES
 Growth failure, failure to thrive, weight loss
 Ambiguous genitalia, delayed puberty precocious puberty
 Developmental delay, seizures, dementia, encephalopathy, stroke
 Deafness, blindness, pain agnosia
 Skin rash, abnormal pigmentation, lack of pigmentation, excessive hair growth,
lumps and bumps
 Dental abnormalities
 Immunodeficiency, thrombocytopenia, anemia, enlarged spleen, enlarged
lymph nodes
 Many forms of cancer
 Recurrent vomiting, diarrhea, abdominal pain
 Excessive urination renal failure, dehydration, edema
 Hypotension, heart failure, enlarged heart, hypertension, myocardial infarction
 Hepatomegaly, jaundice, liver failure
 Unusual facial features, congenital malformations
 Excessive breathing (hyperventilation), respiratory failure
 Abnormal behavior, depression, psychosis
 Joint pain, muscle weakness, cramps
 Hypothyroidism, adrenal insufficiency, hypogonadism, diabetes mellitus
DIAGNOSIS: SCREENING TESTS
 Ferric chloride test(Abnormal metabolites in
urine)
 Ninhydrin paper chromatography(Abnormal
aminoacid patterns)
 Guthrie bacterial inhibition assay. (amino acids
in excessive amounts in blood)
 Quantitative plasma amino acids

 Mass spectrometry: Urine organic acids

DIAGNOSIS: DIAGNOSTIC TESTS
1. Tissue biopsy : liver, muscle, brain, bone
marrow
2. Skin biopsy and fibroblast cultivation for
specific enzyme testing
3. Specific DNA testing
LABORATORY STUDIES FOR AN INFANT
SUSPECTED OF
HAVING AN INBORN ERROR OF METABOLISM
 Complete blood count with differential (CBC-diff)
 Urinalysis (U/A)
 Blood gases
 Serum electrolytes
 Blood glucose
 Plasma ammonia
 Urine reducing substances
 Urine ketones if acidosis or hypoglycemia present
 Plasma and urine amino acids,
 quantitative Urine organic acids
 Plasma lactate
 PRINCIPLES OF TREATMENT
 Dietary Restriction
 Supplement deficient product

 Stimulate alternate pathway

 Dialysis

 Supply vitamin co-factor

 Bone marrow or organ transplantation

 Enzyme replacement therapy

 Gene Transfer

 Treatment of symptoms and complication

 Prenatal diagnosis and avoidance of pregnancy or

abortion of an affected fetus
Some common
examples of Inborn
Errors of metabolism
PHENYLKETONURIA(PKU)
 Incidence 1:15000
 First known genetic disorder caused by enzyme
deficiency
 Mutation occur in both alleles of the gene for
PAH found on ch.12, >500 mutations
 Causes a buildup of the amino acid
phenylalanine cannot be synthesized in the body
(ie an essential AA).
 Excess phe is normally converted to tyrosine,and
eliminated from the body.
 Without the enzyme that converts it to tyrosine,
phe builds up in the blood and is toxic to the
brain, causing mental retardation.
 A normal blood phenylalanine level is about 1
mg/dl.In classic PKU, levels may range from 6 to
80mg/dl, but are usually >30mg/dl.
SYMPTOMS
 50% of untreated infants have early symptoms, such as:
 Vomiting, irritability, an eczema-like rash, and a mousy
 Odor to the urine
 Some may also have subtle signs of nervous system
function problems,
 Such as: increased muscle tone, and more active muscle
tendon reflexes.
 Later, severe brain problems occur, such as: mental
retardation and
 Seizures.
 Other commonly noted features in untreated children
include:
 Microcephaly, prominent cheek and upper jaw bones with
widely spaced teeth,
 Poor development of tooth, and decreased body growth.
MAJOR CLINICAL FEATURES

 Mental Retardation
 Agitated behavior

 EEG abnormalities

 Hyperactive reflexes

 Muscular hypertonicity

 Inability to talk

 Inability to walk

 Tremors

 Seizures
DIAGNOSIS
 Abnormal Guthrie test at birth
 High Phe and tyrosine levels

 Plasma Phe level> 10mg/dl

 Increased urine Phe metabolites

 Normal concentration of the cofactor

tetrahydrobiopterin
 Goal of treatment is to maintain the blood level
of phe between 2 and 10 mg/dl.
 Diet can have some phenylalanine but in much
lower amounts than normal.
 High protein foods, such as: meat, fish, egg,
cheese, milk, dried beans, and ground nuts are
avoided.
 Instead, measured amounts of cereals, starches,
fruits, and vegetables, along with a milk
substitute are usually recommended.
TREATMENT
 Nutritional Treatment
 • Restrict the food sources of phenylalanine

 • Supplement the tyrosine

 • Provide adequate calories, protein, fats and

 carbohydrates, vitamins and minerals for

meeting
 energy needs, growth and development.
TYROSINEMIA

 Associated with severe liver disease in

infancy
 Autosomal recessive inheritance.

 About one person in 100 000 is affected

with tyrosinemia globally.
 Caused by an absence of the enzyme
Fumaryl Acetoacetate Hydrolase (FAH)
which is essential in the metabolism of
tyrosine
NIEMANN–PICK DISEASE

 Caused by deficiency of an enzyme acid

sphingomyelinase needed to break down certain
lipids which results in harmful quantities of fatty
substances, or lipids, accumulate in the spleen,
liver, lungs, bone marrow, and brain.

 Autosomal recessive inheritance

ALKAPTONURIA
 Genetic disorder of phenylalanine and tyrosine
metabolism.
 Causes urine to turn black when exposed to air
 Autosomal recessive inheritance.
 Toxic tyrosine byproduct called homogentisic acid or
alkapton accumulates in the blood and is excreted in
urine in large amounts.
 Causes damage to cartilage (ochronosis, leading to
osteoarthritis) and heart valves as well as
precipitating as kidney stones.
 People with alkaptonuria typically develop arthritis,
particularly in the spine and large joints, beginning in
early adulthood
 Common in slovakia and the Dominican Republic
LESCH–NYHAN SYNDROME

 Caused by deficiency of the enzyme hypoxanthine-guanine

phosphoribosyl transferase (HPRT).
 Associated with 3 major clinical elements: Overproduction of uric
acid, neurologic disability, and behavioral problems.
 Overproduction of uric acid is associated with hyperuricemia. If left
untreated, it can produce nephrolithiasis with renal failure, gouty
arthritis, and solid subcutaneous deposits known as tophi.
 The neurologic disability is dominated by dystonia but may include
choreoathetosis, ballismus, or pyramidal signs, such as spasticity and
hyperreflexia.
 The behavioral problems include cognitive dysfunction and aggressive
and impulsive behaviors. Patients with the classic syndrome also
develop persistent and severe self-injurious behavior.

 Treatment of the condition is limited. Allopurinol is useful to control

the overproduction of uric acid and reduces the risk of nephrolithiasis
and gouty arthritis
ACUTE INTERMITTENT PORPHYRIA
 Autosomal dominant inheritance
 Diseases involves defects in heme metabolism and
that results in excessive secretion of porphyrins and
porphyrin precursors.
 Manifests itself by abdomen pain, neuropathies, and
constipation, but, unlike most types of porphyria,
patients with AIP do not have a rash.
 Results from defects in the enzyme porphobilinogen-
deaminase. This enzyme speeds the conversion of
porphobilinogen to hydroxymethylbilane.
 Main problems neurologic damage that leads to
peripheral and autonomic neuropathies and
psychiatric manifestations.
GAUCHER'S DISEASE
 The disease is caused by a recessive mutation in a gene located on
chromosome 1
 lipid accumulates in cells and certain organs.
 Most common of the lysosomal storage diseases.
 Deficiency of the enzyme glucocerebrosidase .
 The enzyme acts on a fatty substance glucocerebroside .
 When the enzyme is defective, the substance accumulates,
particularly in cells of the mononuclear cell lineage. Fatty material
can collect in the spleen, liver, kidneys, lungs, brain and bone
marrow.
 Symptoms may include enlarged spleen and liver, liver malfunction,
skeletal disorders and bone lesions that may be painful, severe
neurologic complications, swelling of lymph nodes and (occasionally)
adjacent joints, distended abdomen, a brownish tint to the skin,
anemia, low blood platelets and yellow fatty deposits on the white of
the eye (sclera). Persons affected most seriously may also be more
susceptible to infection.
 Some forms of Gaucher's disease may be treated with enzyme
replacement therapy.
GLYCOGEN STORAGE DISEASE

 Characterized by defects in the processing of

glycogen synthesis or breakdown within muscles,
liver, and other cell types.
 GSD has two classes of cause: genetic and
acquired. Genetic GSD is caused genetically
defective enzymes involved in these processes.
 McArdle disease: Glycogen storage disease type V
is the most common type of glycogen storage
disease.
 McArdle disease is an autosomal recessive
disorder caused by mutations in the gene that
encodes myophosphorylase, an enzyme that is
essential for glycogenolysis.
CONGENITAL ADRENAL HYPERPLASIA

 The term congenital adrenal hyperplasia encompasses a

group of autosomal recessive disorders, each of which
involves a deficiency of an enzyme involved in the synthesis
of cortisol,aldosterone, or both.

 enzymes mediating the biochemical steps of production of

cortisol from cholesterol by the adrenal glands
 Most of these conditions involve excessive or deficient
production of sex steroids and can alter development of
primary or secondary sex characteristics in some affected
infants, children, or adults.

 Approximately 95% of cases of CAH are due to 21-

hydroxylase deficiency.
ZELLWEGER SYNDROME

 A group of rare, genetic, multisystem disorders

that were once thought to be separate entities.
 It is one of a family of disorders called
leukodystrophies
 Zellweger syndrome is the most severe form;
neonatal adrenoleukodystrophy is the
intermediate form; and infantile Refsum disease
is the mildest form.
 Characterized by the reduction or absence of
peroxisomes in the cells of the liver, kidneys, and
brain.
MAPLE SYRUP URINE DISEASE
 An aminoacidopathy secondary to an enzyme defect
in the catabolic pathway of the branched-chain amino
acids leucine, isoleucine, and valine.
 Accumulation of these 3 amino acids and their
corresponding keto acids leads to encephalopathy and
progressive neurodegeneration in untreated infants.
 Early diagnosis and dietary intervention prevent
complications and may allow for normal intellectual
development.
 In 1954, Menkes et al reported a family in which 4
infants died within the first 3 months of their lives
because of a neurodegenerative disorder. The urine of
these infants had an odor resembling maple syrup
(burned sugar) Therefore, this disorder was called
maple sugar urine disease and, later, maple syrup
urine disease.
HOMOCYSTINURIA

 Affects the metabolism of the amino acid

methionine.
 Autosomal recessive inheritance.

 Leads to a multisystemic disorder of the

connective tissue, muscles, CNS, and
cardiovascular system.
 Characterized by an accumulation of
homocysteine in the serum and an increased
excretion of homocysteine in the urine