This briefly talks about a seminar report based on Inborn Errors of metabolism, the factors that cause inborn errors, pathophysiology and types.

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CHAPTER ONE
1.0 INTRODUCTION TO INBORN ERRORS OF METABOLISM
Inborn Errors of Metabolism (IEM), also known as Congenital/ Inherited Metabolic Diseases are
group of inherited diseases or disorders which leads to defects in the human metabolism. As the
name implies, Inborn Error is defined as birth defects in neonates that are inherited from family
(genetic disorders) and affects metabolism. The cause of IEM is the change in gene that encodes
enzymes leading to defect in enzymatic reaction/activity that affects the normal function of a
metabolic pathway. Due to the deficiency of enzymes, substrates are accumulated which manifests
to more health issues. Most Inherited Metabolic Disorders are rare but life threatening. IEM can
appear at birth or after birth depending on the type of metabolic disorder e.g. phenylketonuria,
albinism, lactose intolerance etc. (Shakya, 2017). Certain symptoms show depending on the
specific metabolic disorder but individuals with the errors usually prefer unusual foods (antipathy
to proteins), may lack energy/ be sluggish. In some cases, signs are muddled with disorders leading
to delayed detection. (Yudkoff, 2017).
During the years, techniques like tandem mass spectrometry and gas chromatography for next
generation sequencing have led to rapid and true diagnosis. Significant progress has been made
for the treatment of inborn errors like special dieting, enzyme replacement therapy, substrate
inhibition and organ transplantation. (Ezgu, 2016). Newborn screening has also been adopted to
detect newborns with fatal but treatable defects to avoid adverse outcome. The use of mass
biochemical testing of neonates was adopted in the 20th
century with the introduction of screening
for phenylketonuria, a rare inborn error of metabolism which is tested by the use of dried blood
sample. Hypothyroidism and other rare inborn errors were included to screening programs.
(Wilcken et al, 2008).
1.1 INHERITANCE
Most of these metabolic disorders are inherited as autosomal recessive though autosomal dominant
and X-linked disorders are present. Family history might reveal a relative who has similar illness,
sibling, paternal aunt, sister or mildly affected father in X-linked disease. Maternal illnesses in
pregnancy can also be associated with specific inborn errors and leads to the presence of metabolic

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disorders in neonates e.g. severe fatty liver of pregnancy and high blood pressure. (Enns et al,
2001). Most metabolic disorders which are mostly recessive genes (parent of the child/children)
are carriers. In other words, a child will be affected if the parent are unaffected carriers (possesses
heterozygous genes). When two carriers of the traits produce children, there is a 25% probability
of having an affected offspring, 25% probability of an unaffected child and 50% chance of having
an unaffected carrier. Autosomal dominant diseases are also inherited when a parent is a carrier
and the other is unaffected. The probability of the offspring being an affected carrier is 50%.
In X-linked disorders, the genes present are X and Y chromosome which determines if an
individual is a female or male (XX and XY respectively). The genetic disorders also affect males
and female differently, the former being affected more than the latter. The males (XY) inherit the
disorder by having a copy of the gene generated from the mother. In males, a change in the X
chromosome is required to cause this disorder. Females with two X chromosomes usually have
two mutated copies of both chromosomes to become an affected person. (Gen, 2014).

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Fig 1: Possible scenarios of Automatic dominant and recessive inheritances respectively
Source: https://learn.genetics.utah.edu/content/disorders/inheritance/

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1.2 GENETIC HISTORY OF INHERITED METABOLIC DISEASES
A British physician, Archibald Edward Garrod (1857-1936) named the term “Inborn Errors of
Metabolism” in 1902. He first discovered Alkaptonuria which were present in humans and later
other metabolic diseases like albinism, pentosuria, cystinuria etc. His works are used in this present
era as landmarks in the Biochemistry and Medicine history. He gave evidence to the metabolism
energetic nature by involving metabolites in normal pathways formed by the Mendelian
inheritance (Scriver, 2008). In other words, Biochemistry is vital and different from organic
chemistry and this led to the discovery of metabolic pathways and the recognition of Mendelian
heredity which explains the term ‘inborn errors of metabolism’ (Scriver, 2001).
Working with his colleague, William Bateson, Garrod was the first to find the Gregor Mendel’s
law of segregation to humans and talked about the role of ethnicity in metabolic diseases
(Rosenberg, 2008). However, his work was not accepted in the 1800s. In 1941, the scientists
George Beadle and Edward Tatum researched on Garrod’s hypothesis further and proposed the
theory of one gene-one enzyme. The theory stated that each gene possesses a genetic code to
synthesize an enzyme. (Shakya, 2017).
1.3 SYMPTOMS & CONSEQUENCES OF INBORN METABOLIC ERRORS
Some inborn metabolic errors are usually obvious at birth or shortly after while others are apparent
until early childhood. The symptoms vary depending on the disorder but mainly, affected
individuals have food intolerance, aversion to food, are tired and have developmental delays. IEM
can cause severe neurological diseases in neonatal period but the most common consequence in
severe cases is brain damage. (Yudkoff, 2017). The infant may perform well until subjected to
infection, dehydration or excessive protein/carbohydrate load.
Problems with feeding happens with sucking and swallowing is mainly associated. Hyperemesis
(vomiting) and seizures may also happen. In neonate carriers, signs and symptoms disappears for
a while and happens in a few weeks while the seriously affected neonates have inevitable
symptoms from sluggishness to coma to death. Some limited signs occur (staring spells,
myoclonus or lethargy). (Enns et al, 2001). Affected individuals with problems in accessing

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glycogen may be normal for a period of time as long they have a regular intake of carbohydrate
but however, changes in dieting will lead to limited access to carbohydrate adequately, leading to
hypoglycemia/seizures. 50% of affected patients have abdominal and mental retardation. Also,
children with IEM have feeding issues, reflux and behavioral issues. (Jeanmonod et al, 2022)
Metabolic reactions work with enzymes which is a catalyst that speeds up biochemical reactions
without being altered in the process. It plays a role in food metabolism (carbohydrate, protein,
fats). The mutated gene that encodes an enzyme leads to defective enzymes. This forms a blockage
to the metabolic pathway, leading to substrate elevation and little/no formation of products in cells.
The consequences of Inborn Error of Metabolisms are:
 Substrate elevation.
 Formation of little/ no product.
 Accumulation of intermediate metabolites
 Disruption of metabolism. (Shakya, 2017).
1.4 PHYSIO-PATHOLOGY CLASSIFICATIONS OF INBORN ERRORS OF
METABOLISM
Inborn Metabolic Errors disturbs the carbohydrate and protein metabolism, beta oxidation and
glycogen storage metabolism. Food is primarily broken down to glucose, which is the primary fuel
to the body system. In this process, other metabolic products are excreted out of the system.
Ingestion of excess glucose is later stored as glycogen in the muscles and liver with the aid of
insulin. This is essential during the period of fasting.
When the body system needs glucose, it is utilized from the glycogen storage, and with the aid of
glucagon, converts glycogen into glucose for energy production. But when the glycogen stores are
depleted, glucose is then generated from amino acids (gluconeogenesis) and beta oxidation to
produce a substrate for Kreb’s cycle. This leads to hypoglycemia (low blood glucose). Interference
of excretion of products leads to accumulation of ammonia in the blood, causing
hyperammonemia. Increased elevation of ammonia to the brain also leads to brain disorders like
hepatic encephalopathy and other several metabolic disorders. (Jeanmonod et al, 2022).

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The different types of IEM can be classified into two major categories which are:
Category 1 - This group of errors affect one functional system (endocrine, coagulation diseases
or immune system disorders), one organ (intestine, erythrocytes, connective tissues and renal
tubules) or function.
Category 2 – This group of errors affect specific biochemical pathways of different organs and
systems. They affect metabolic pathways similar to specific cells or organs (storage errors due to
lysosome catabolic disorders, energy shortage in mitochondrial disorders) or is restricted to one
organ and is detriment to the health (hyperammonemia in urea cycle defect, hypoglycemia in
hepatic glucogenesis). In this category, it is further divided into three groups which are:
• Group 1 – Acute intoxication due to accumulation of unusual compounds leading to metabolic
block. Amino acid catabolic errors (phenylketonuria, maple syrup urine disease, homocystinuria),
sugar intolerance errors (galactosaemia, hereditary fructose intolerance), porphyrias are all under
this group. All the disorders under this group have similar clinical signs; they do not affect fetal
development but show “intoxication” which may be acute (vomiting, coma, liver failure etc.) or
chronic (cardiomyopathy, developmental delay). Food intake, fever, fasting or catabolism are
factors that causes the metabolic attacks.
• Group 2 – This consists of symptoms due to defects in organs with the highest energy production
(liver, heart, muscle, brain and other tissues). Mitochondrial errors and pentose phosphate
pathways are very severe and untreatable. Cytoplasmic energy errors are less severe and treatable.
They include errors of glycolysis, glycogen metabolism, gluconeogenesis and glucose transporter
defects. These errors cause degenerative disorders which remains unsolved.
• Group 3 – This group discusses about the synthesis and catabolism of complex compounds.
They take place in organelles (mitochondria, lysosome, ER and Golgi Apparatus). Manifestations
are usually permanent and progressive and not affected by food ingestion. (Saudubray et al, 2018).

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Fig 2: Pathophysiological Classification of Inborn Errors of Metabolism
Source: https://www.mdpi.com/2075-4418/11/11/2148/htm

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CHAPTER TWO
2.0 TYPES OF INBORN ERRORS OF METABOLISM
Inborn errors are categorized into disorders of carbohydrate metabolism, amino acid metabolism,
organic acid metabolism, lysosomes, urea cycle defects, purine and pyrimidine metabolism etc.
Table 1: Categories of inborn errors of metabolism and examples
Source:https://www.researchgate.net/publication/12688188_Inborn_errors_of_metabolism_a_cli
nical_overview/fulltext/039b25580cf21122b71df1cf/Inborn-errors-of-metabolism-a-clinical-
overview.pdf?origin=publication_detail
2.1 CARBOHYDRATE METABOLISM DISORDERS
Carbohydrate is one of the main sources of energy in the body system and are metabolized into
three monosaccharides; glucose, fructose and galactose. All errors of carbohydrates are gotten
from specific enzymes which are inherited as autosomal recessives. If an enzyme needed to
synthesize a sugar is defective, sugar accumulated in the system which is detriment to the health.
Inborn errors of carbohydrates are grouped into galactosemia, hereditary fructose intolerance
(HFI), hereditary lactose intolerance (HLI), fructosuria and glycogen storage diseases (GSD).
(Shakya, 2017).
Inborn Errors Examples
Disorders of Amino Acids Alkaptonuria, Phenylketonuria, Homocystinuria, Albinism, Maple Syrup Urine
diseases.
Organic Aciduria Propionic Acidemia, Isovaleric Acidemia, Glutaric acidemia type I,
Methymalonic acidemia.
Urea cycle defects Carbamoyl phosphate synthetase deficiency, ornithine transcarbamylase
deficiency, argininemia, citrullinemia.
Fatty acid oxidation Carnitine palmitoyl transferase 1 deficiency, medium chain acyl-CoA
dehydrogenase deficiency, long chain hydroxyacyl-CoA dehydrogenase.
Carbohydrate disorders Galactosemia, glycogen storage diseases, hereditary fructose intolerance,
hereditary lactose intolerance.
2 colors

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2.1.1 GLYCOGEN STORAGE DISEASES
Glycogen is a branched chain polymer consisting of 50,000 residues of glucose, linked by
glycosidic bonds which are α-1.4 glycosidic linkages between the glucose residues and
branchpoints as α-1,6 glycosidic bonds. Glycogen storage occurs mainly in the liver and skeletal
muscles although they can also be stored in the heart, kidney and brain. Glycogen synthesis are
derived from glucose (newly ingested carbohydrate/glycogenesis) or non-carbohydrate
(gluconeogenesis) precursors. Glycogen in muscles give quick source of energy for either
anaerobic or aerobic metabolism and can be exhausted quickly during exercise. Liver glycogen
serves as glucose storage for other tissues when ingested carbohydrates are not readily available
(between meals and fasting period). This is important for the brain which cannot use fatty acid as
fuel. This glycogen stored in the liver can be exhausted in about 12-24 hours. (Roach et al,
2012).
Glycogen storage disorders/ diseases (GSD) are inborn errors of carbohydrate that are passed
down from parent to the offspring/neonate. This inborn error affects the way glycogen is stored
in the body. When the body needs energy, a special protein called enzymes are required to break
down the glycogen to glucose for energy production. A patient with GSD does not have any
enzyme or enough enzyme to break down glycogen to glucose, resulting to the buildup of and
failure to store glycogen. This results to danger to the liver and muscles. There are different types
of GSD but the major ones which affect the liver are:
 Glucose-6- phosphatase deficiency (Type Ia)
 Glucose-6- phosphate transporter deficiency (Type Ib)
 Glycogen Debrancher deficiency (Type III)
 Glycogen branching enzyme deficiency (Type IV)
 Phosphorylase kinase deficiency (Type IX)
The glycogen storage disorders that affect the skeletal muscles are:
 Muscle phosphorylase deficiency (Type V)
 Phosphofructokinase deficiency (Type VII)
 Phosphoglycerate mutase deficiency (Type X)
The glycogen storage disease that affects both cardiac and skeletal muscles are:
 Lysosomal acid Maltase deficiency (Type II) (Stone et al, 2022).
1. Glucose-6-phosphatase deficiency/ Morbius Von Gierke’s disease (Type Ia):
Von Gierke’s disease, also called Glycogenosis Type I is a hereditary glycogen storage disorder
which is an autosomal recessive trait. It is caused by a defect in the gene called G6PC encoded by
the enzyme Glucose-6- phosphatase (G6Pase) which aids in hydrolysis of Glucose-6-phosphate
(G6P) to glucose and inorganic phosphate (Pi), causing elevation or accumulation of glycogen and
enlargement of the liver (hepatomegaly). G6PC, G6P2 and G6P3 are the three subunit-encoding

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genes which make up the enzyme glucose-6-phosphatase. Glucose-6-phosphatase is found in the
smooth endoplasmic reticulum of the liver. Skeletal muscle lack glucose 6 phosphatase and cannot
release glucose to the blood. This incidence which occurs in 1/100,000 persons appears first in
neonates or childhood and is presented earlier with severe hypoglycemia within 3 hours
postprandial. This deficiency reduces the ability of the liver to catabolize glycogen into two
metabolic processes; glycogen to glucose (glycogenolysis) and gluconeogenesis (from non-
carbohydrate precursors) resulting to severe hypoglycemia. (Froissart et al, 2011).
Fig 3: Von Gierke (Glucose 6 phosphatase) deficiency
Source: https://www.researchgate.net/publication/320299103
Clinical Descriptions
Patients with Von Gierke’s disorder may have progressive hypoglycemia (low blood sugar) which
occurs 2 hours after a meal. Signs and symptoms are protruded abdomen due to enlarged liver in
neonatal period (at birth- 3 months). GSD 1 patient may also have lactic acidemia, hyperlipemia
and hyperuricemia (gout). A round like “doll face” is also accompanied with thin limbs. Weak
muscles, low bone mass and growth delays are also frequent symptoms of a GSD I patient. (Kotb,
2015).
Treatment
Prevention of hypoglycemia should be considered by frequent feeding of foods high in
glucose/starch (which are readily digested to glucose). Diet should be 70% carbohydrates, 15%
protein and 15% fats. Gastric infusion of glucose, nocturnal feeding on uncooked cornstarch and
reduced intake of fructose and galactose which increases hyperlactacidemia should also be
adapted for the management of the disorder. (Shakya, 2017).

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2. Glucose-6-phosphate transporter deficiency (Type Ib):
Glucose-6-phosphate is transported from the cytoplasm to the lumen of the endoplasmic reticulum
in livers. G6PT1, G6PT2 and G6PT3 make up G6PT protein. Type Ib is an inherited disorder
caused by the defect in the gene SLC37A4 which encodes the transporter glucose-6-phosphate
transporter 1 (G6PT1) resulting in a defect in the last step of glycogenolysis (conversion of glucose
6 phosphate to glucose).
Clinical Descriptions
The diagnosis of patients with type Ib disease occurs in neonatal periods. Both Type Ia and Ib have
the features of hypoglycemia, hyperlipidemia, hyperuricemia, accumulation of glycogen in the
liver, seizures, hepatomegaly, delayed growth and development, doll-like face with thin limbs,
inflammatory bowel diseases (cramps, fever and abdominal pain). (Stone et al, 2022).
Treatment
Treatment of Type Ia and Type Ib are adapted the same way by introducing small servings of
carbohydrate day and night. Human granulocyte colony stimulating factor is also introduced to
treat infections of patients with this disease which consists of two-three weekly injections. This
treatment must be duly monitored to avoid fatal effects (respiratory distress or death). (Froissart et
al, 2011).
3. Lysosomal acid maltase deficiency/ Pompe Disease (Type II):
This is also an autosomal recessive disease which is inherited from the parent. Lysosomes are tiny
garbage collectors in the cell and recycles substances into smaller parts, which are exported out of
the plasma membrane or reused in the cell. Pompe disease is one of the lysosomal storage diseases
(LSDs) caused by the gene defect encoding the enzyme lysosomal acid-α-1,4-glucosidase (GAA).
GAA is important in hydrolysis of lysosomal glycogen to glucose for energy source. A defect in
the enzyme causes excessive elevation of lysosomal glycogen in the heart, skeletal and smooth
muscles and cytoplasm of tissues, resulting in breakdown and disruption of the cell and organs.
α-Glucosidase
Glycogen
Pompe Disease Glucose
Fig 4: Pompe Disease (Type II).

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Clinical Descriptions
Cardiomyopathy, progressive myopathy and cardiac failures may happen. Hearing loss, breathing
and feeding problems leading to respiratory failures can also appear in infants
Treatment
Enzyme replacement therapy (ERT) or nutritional therapy are the treatments available for patients
with type II. This is accomplished with alglucosidase alfa (Lumizyme®) (Liong, 2014).
4. Glycogen Debrancher Deficiency/ Cori Disease (Type III):
This is an autosomal recessive disorder which is caused by a gene defect AGL encoding the
debranching enzyme (α-1,6-glucosidase) which aids in catabolism of the branched glucose chains
of glycogen. Both phosphorylase and debranching enzymes are necessary for catabolism of
glycogen. GSD III are divided into GSD IIIa, GSD IIIb, GSD IIIc and GSD IIId and are
distinguished by their signs. GSD IIIa and GSD IIIc affect the cardiac muscles, skeletal muscles
and liver while GSD IIIb and GSD IIId affect the liver only. Mutations that cause GSD IIIa and
GSD IIIb lead to non-functional glycogen debranching enzyme while the mutations/defects
causing GSD IIIc and GSD IIId gives production of enzyme with reduced efficiency. This process
leads to partially catabolic reaction of glycogen molecules in the cells causing severe symptoms
in GSD III patients. (Kishnani et al, 2010)
Clinical Descriptions
In early life, GSD III patients with liver problems experience hypoglycemia, hyperlipidemia,
elevated hepatic transaminases and cardiomyopathy. Skeletal myopathy/ weakness occurs in
children and becomes prominent as an adult. Long term complications are liver fibrosis/cirrhosis
and carcinoma which may hinder quality of life.
Treatment
Food should be taken frequently (3-4 hours) to maintain euglycemia in babies/children. Year one
offsprings should take about 1g/kg of cornstarch to prevent hypoglycemia and 3g/kg of protein.
Extra protein supplements are needed also. Oral fructose and sucrose should also be taken for

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increased exercise stamina. Liver transplant is exempted from others except the patients with
severe hepatic cirrhosis/ hepatocellular carcinoma. (Schreuder et al, 2010).
5. Glycogen branching enzyme Deficiency/Andersen Disease (Type IV):
Glycogen branching enzyme deficiency (GBED) is an autosomal recessive defect of the gene
GBE1 [glucan (1,4-α) branching enzyme 1] encoding the branching enzyme of glycogen.
Glycogen branching enzyme is used for the last step of glycogen synthesis. Glycogen is made of
different glucose units which are linked in a straight line or a branched line. Glycogen branching
enzyme comes to play in this process as it is important for storage and makes it easier for catabolic
reaction during fasting state. They are found mostly in horses.
Clinical Descriptions
Defect in the gene encoding the branching enzyme leads to excessive accumulation of glycogen,
giving longer outer branches resulting in tissues and organ damage. (Li et al, 2010). Abortion is a
common sign of GBED. Hypoglycemia, seizures and death are common in this process. Others
are euthanized due to muscle weakness.
Treatment
Treatment is unavailable for GBED patients but euthanasia can be adapted to save cost of care for
foals. (Valberg et al, 2006).
2.1.2. GALACTOSEMIA
Galactosemia is an autosomal recessive disorder which affects how the body metabolizes one of
the simple sugars (galactose). Galactose is a sugar constituent in milk (mother’s milk/ endogenous
galactose or dairy products). It makes up 50% of lactose, a sugar constituent of milk. Three inborn
errors of galactosemia are found which are: Galactose 1-phosphate uridyl transferase (GALT), also
known as classic galactosemia, Galactokinase Deficiency (GALK) and Galactose-6- phosphate
epimerase (GALE). Patients with galactosemia are unable to break down galactose in the body due
the defect in the enzyme Galactose-1-phosphate uridyltransferase (GALT). Intake of galactose

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containing substances in Galactosemic patients results to damage in organs (liver, kidney, brain
and eyes) due to buildup of galactose in the body system.
GALT enzyme is the most common and severe form of galactosemia. It is needed for the milk
sugar, galactose breakdown. Patients with GALT Deficiency can phosphorylate galactose but not
galactose-1-phosphate. This also occurs in Galactokinase (GALK) and Galactose-6-phosphate
epimerae (GALE). In these processes, galactose-1-phosphate and galactose are elevated in the
tissues, blood and urine (galactosuria), leading to alternate pathways product formation of
galactitol and galactonate. Galactitol (alcohol derivative of galactose) accumulation forms in the
eye lens causing swelling, protein precipitation and cataracts.
Fig 5: Galactose Metabolism
Source: https://basicmedicalkey.com/12-carbohydrates-galactose-metabolism/
Clinical Descriptions
The signs and symptoms of GALT deficiency are failure to thrive, hepatic problems, cataracts,
yellowing of the skin, jaundice, hepatomegaly, presence of proteins/amino acids in urine and

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developmental delay. Long term complications include ovarian failure, mental retardation and
poor growth.
Treatment
Strict prevention of meals rich in lactose and galactose in infants should be adopted. For newborns,
lactose free soy-based formulas should be readily available, canned foods should be avoided
except they are dairy free. (Berry et al, 2016).
2.1.3. HEREDITARY LACTOSE INTOLERANCE (HLI)
Lactose is an important form of carbohydrate present in dairy products and a main source of fuel
for mammals. It is usually hydrolyzed by enzyme lactase phlorizin hydrolase (LPH) which are
produced by cells in lining of the small intestine. to glucose and galactose to form a milk lactose.
These two monosaccharides are taken to the enterocytes for energy. Lactase enzymatic activity is
usually high during childhood when milk is the main source of food.
Lactose intolerance is an autosomal recessive genetic condition which impairs the ability of the
body to digest lactose, a sugar found in dairy products. This is caused by the defect in the LCT
gene encoding the enzyme LPH. Due to this defect, the lactose accumulates in the intestine.
Fermentation of bacteria in the intestine occurs resulting to short chain acids and gases (H2) and
CO2).
Clinical Descriptions
Abdominal cramps, watery diarrhea, stomach pain, gases production like hydrogen and carbon
dioxide are signs and symptoms of patients who are lactose intolerant.
Treatment
Foods that are lactose free and fructose free should be recommended to patients who are lactose
intolerant. (Anguita-Ruiz et al, 2020).

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2.1.4 HEREDITARY FRUCTOSE INTOLERANCE (HFI)
Fructose is a monosaccharide present in the body and is used as a sweetener in baby foods,
vegetables, honey and drinks. Fructose intolerance is grouped into hereditary fructose intolerance
and dietary fructose intolerance. Hereditary fructose intolerance leads to symptoms like toxin
ingestion, genetic and metabolic disorders (galactosemia, urea cycle disorders). In diagnosing
hereditary fructose intolerance, the fructose is identified in the urine of an HFI patient. In case of
Dietary Fructose Intolerance, fructose is identified in the gut/stool of patients. The symptoms
presented are nausea, diarrhea, abdominal pain etc. Hereditary fructose intolerance is an autosomal
recessive genetic trait passed from the parent to the offspring. It is caused by an enzyme defect of
aldolase B enzyme (fructose-1,6-bisphosphate Aldolase) which converts fructose-1-phosphate to
dihydroxyacetone phosphate (DHAP) and glyceraldehyde (G3P) in the glycolytic pathway. Due
to the absence of the enzyme, accumulation of fructose-1-phosphate occurs causing danger to the
liver. Defect in Aldolase B causes alternate gluconeogenic pathway since DHAP and G3P cannot
be broken down to yield fructose-1,6-bisphosphate.
Fig 6: Fructose Metabolism
Source: https://www.wikidoc.org/index.php/Fructose

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Clinical Descriptions
The disorder causes jaundice, nausea, vomiting, poor feeding, poor growth, lactic acidosis,
abdominal pain, faintness, hyperuricemia and hypoglycemia. In heterozygous patients, signs and
symptoms are low but some have hyperuricemia, which is also called gout.
Treatment
Patients who are lactose intolerant should remove fructose and sucrose from their diets for effective
treatment. Medications (multivitamins) should also be taken to lower the uric acid level in the
blood so as to reduce gout formation. (Hedge, 2022).
2.2. AMINO ACID METABOLISM DISORDERS
Food is made up of macromolecules (carbohydrates, proteins and fats). Amino acid is a building
block of proteins, enzymes inclusive which are made up of basic amino (-NH2) and acidic
carboxylic (-COOH) functional groups. These functional groups are held by polypeptide bonds.
At the center of each amino acid is an α carbon attached to four groups (hydrogen, α-carboxyl
group, α-amine group and R group/side chain). Proline is an exception as it has a secondary amino
group.
Proteins have 22 kinds of standard amino acid where 9 are essential (found in diets) and the rest
are non-essential (produced by the body). Amino acid metabolic disorders are rare but have
challenging conditions. These defects are caused by inborn errors in the metabolic pathways of a
specific amino acid or more amino acid groups. Examples include phenylketonuria (PKU), Maple
Syrup Urine Disease (MSUD), Homocystinuria (HCU)/ cystathionine-β-synthase deficiency.
(Aliu et al, 2018).
2.2.1. ALKAPTONURIA
This metabolic disorder was the first to be described by Sir Archibald Garrod. He found out about
why the urine of some individuals were black when exposed to air and named the term ‘Inborn
Errors of Metabolism’. It is an autosomal recessive disease caused by the elevation of a reducing

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substance called homogentistic acid (HGA) which affects tyrosine and phenylalanine catabolism.
In other words, the inborn error is caused by the gene defect of the gene encoding a key enzyme,
homogentisate 1,2-dioxygenase (HGD). High level of homogentistic acid in tissues lead to
complications like ochronosis (tissue darkening).
Fig 7: Diagram showing how homogentistic acid accumulation forms alkaptonuria
Source: https://flipper.diff.org/app/items/info/6243
Clinical Descriptions
Signs include pigmentation in connective tissues (particularly the sclera or ear cartilages), arthritis
of joints and spines, kidney stones, swelling on the shoulder joints and numbness in feet and toes.
Treatment
Low protein dieting should be recommended to prevent ochronosis by homogentistic acid
reduction in tissues. Nitisinone may be taken orally to reduce HGA accumulation. (Rana et al,
2015).

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2.2.2. PHENYLKETONURIA (PKU)
This is a disorder of metabolism caused by the defect in the enzyme phenylalanine hydroxylase
which converts phenylalanine to tyrosine. This essential amino acid is toxic to the neural system
and due to this defect, it builds up and forms an alternate pathway which reduces phenylalanine
concentration. It is autosomal recessive in nature.
Clinical Descriptions
Symptoms are seizures, musty body odor and urine smell, nausea, vomiting, eczema like rash,
reduced intellectual disability. PKU neonates rarely have symptoms but have poor eating habits.
Treatment
Phenylalanine strict dieting should be done early for normal development. This will control
hyperactivity in children and raise children’s IQ but does not revert the intellectual disability.
2.2.3. ALBINISM
This is an autosomal recessive disorder caused by the mutation in gene for enzyme tyrosinase
(which coverts tyrosine to 3,4-dihydroxy phenylalanine), resulting in the absence of melanin
(pigment that gives skin, hair and eyes a dark color). This leads to a loss of hair and skin color
(hypomelanosis). (Shakya, 2017). Synthesis of melanin occurs by melanocytes in an organelle
(melanosomes). Melanocytes are present in the iris, hair, skin and inner ear. Albinism is grouped
into ocular albinism (OA) and oculocutaneous albinism (OCA). OCA is caused by absence of
tyrosinase and affected individuals have very fair skin and white/light colored hair. OCA is further
subdivided and are specific in skin, hair and eye color changes. They are: Oculocutaneous
Albinism Type I (OCA1), Type II (OCA2), the most common form of albinism, Type III (OCA3)
and Type IV (OCA4). (Kliegman, 2020).
Type I albinism occurs as a result of the defect in the enzyme Tyrosinase gene, making the gene
non working. It is also called tyrosinase-negative OCA. OCA I is divided into: OCA Ia and OCA
Ib. OCA II is less severe than OCA I and occurs due to mutations in gene MC1R which affects not
the tyrosinase activity but the p polypeptide (Tyrosinase positive). OCA II is subdivided into

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Brown OCA (BOCA). OCA Type III/Red OCA (ROCA) occurs due to mutations in TYRP-1
(Tyrosine related Protein 1) gene. It is mostly present in African descents. This gene is also the
brown locus of the mouse which causes the fur to be brown and not black. OCA IV is caused by
the gene defect of MATP gene and is present in mouse.
Ocular albinism (OA) is a genetic condition that primarily affects the eye only due to reduced color
pigmentation of the iris (colored part of the eye) and retina (light sensitive tissue). It is caused by
the genetic defect of the gene GPR143. This gene plays a role in making protein that pigments
eyes and skin. These mutations of the gene GPR143 reduce/ increase the size of the GPR143
protein, destroying protein functions. This leads to abnormal growth of melanosomes (melanin
storage) in skin cells and retina, causing visual loss and eye abnormalities.
Clinical Descriptions
In OCA I patients, the clinical symptoms are absence of melanin in the hair, skin and eyes,
decreased vision at birth (20/400), photophobia, nystagmus and translucent irises. Patients are
lightly pigmented as a neonate and pigmentation is progressive with age. Freckles may also appear
with exposure to sun. OCA II patients have poor pigmentation and vision improves with age. Eyes
and hair (creamy white) are pigmented. Freckles are limited during birth but gradually progresses
during the third year due to sun exposure. They appear on exposed surfaces of the body (face,
neck, hands) mostly in black individuals.
In BOCA patients, Eumelanin is sparsely present and occurs in African individuals. Clinical
features are dark brown hair, light brown skin and grey eyes. ROCA Patients are usually Black
Americans or black individuals, characterized by reddish hair and skin, reddish brown to brown
eyes. They also have clinical symptoms of decreased visual acuity and photophobia. (Kromberg
et al, 2012). Ocular patients have nystagmus (rotation of the eyes), photophobia and eyes that do
not look in the same direction (strabismus).
Treatment
In albinism patients, refractive errors and visual aids should be done soon. Nystagmus can be cured
by surgical operation also. Hats and sunscreen should be used for protection against ultraviolet
radiation from the sun to reduce the risk of cancer. Regular checks for the skin should be adopted
in affected patients. (Kirkwood, 2009).

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Table 2: Characteristics of the types of albinism
Source: https://www.ajol.info/index.php/eamj/article/download/89473/78965
2.3 FATTY ACID OXIDATION DISORDERS
Fatty acids are biomolecules which are present in all humans and animals and performs different
functions. They are long chains of hydrocarbons divided into: saturated, monosaturated,
polysaturated and trans fats. Fatty acids are majorly present in foods like fruits, vegetable oils,
seeds, animal fat and fish oils (White, 2009). They are important biomolecules as they are energy
sources (via mitochondrial oxidation) when they are released from storage (during fasting) in the
adipose tissue. In the mitochondria, fatty acid oxidation is the primary source of energy, producing
reducing substances flavin adenine dinucleotide (FADH2) and nicotinamide adenine dinucleotide
(NADH+
).
When either mitochondrial oxidation/fatty acid transport via the carnitine transport route is
disrupted, fatty acid -oxidation disorders is formed. (Merritt et al, 2018). Metabolic disorders and
cardiac illnesses are closely related to lipid metabolism disorders that result in excess fat storage

22. 22
in the ectopic tissues (skeletal muscle, liver and heart). These lipid disorders are caused by the
specific lack of enzyme catabolism in lysosomal pathways. Genetic defects in sphingolipids are
the main cause of the numerous lipid metabolic disorders. Sphingolipid is a key component of cell
membrane (brain cells). (Shakya, 2017). The types of fatty acid oxidation disorders are:
2.3.1. MEDIUM-CHAIN ACYL-CoA DEHYDROGENASE DEFICIENCY
(MCAAD)
Medium-chain acyl-coenzyme A dehydrogenase (MCAD) is one of the enzymes involved in
mitochondrial fatty acid β-oxidation, which fuels hepatic ketogenesis, a major source of energy
once hepatic glycogen stores become depleted during prolonged fasting and periods of higher
energy demands. The initial dehydrogenation of acyl-CoAs with a chain length between four and
twelve carbon atoms is carried out by MCAD. Medium-chain fatty acids, their corresponding fatty
acyl glycine- and carnitine-esters, and dicarboxylic acids are among the metabolites that can be
found in bodily fluids (blood, urine, and bile). These metabolites may accumulate and result in
oxidative damage.
Clinical descriptions
MCADD can manifest in infants and toddlers as an infection-related illness that causes vomiting
and poor oral intake before causing hypoketotic hypoglycemia, dehydration, and lethargy. Death
from hyperammonemia and brain edema caused by untreated disease, including sudden deadly
presentations in all age groups, will result from disease progression. Seizures, hepatomegaly and
liver failure occurs and can lead to coma and death.
Treatment
The confirmation of acylcarnitine anomalies in plasma samples is necessary. The most crucial step
in reversing catabolism and maintaining anabolism is administering simple carbohydrates
intravenously, if necessary (glucose tablets or sweetened, non-diet beverages). Fasting should be
avoided; newborns need frequent feedings, while toddlers can be put on a diet that contains very
little fat. They can also get 2 g/kg of uncooked cornstarch at bedtime to ensure adequate glucose
levels overnight. (Matern et al, 1993).

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2.3.2. VERY LONG-CHAIN ACYL-CoA DEHYDROGENASE
DEFICIENCY (VLCADD)
This is an inherited disease which is passed from the parent to the neonate. The first phase of
mitochondrial beta-oxidation of long-chain fatty acids of VLCADD is catalyzed (chain length of
14 to 20 carbons). VLCAD insufficiency is brought on by mutations, in the ACADVL gene. An
enzyme known as very long-chain acyl-CoA dehydrogenase, which is necessary to metabolize a
class of fats known as very long-chain fatty acids, is made by this gene. These fatty acids are
present in diet and the fat tissues of the body. The heart and muscles primarily derive their energy
from fatty acids. Fatty acids are a crucial source of energy for the liver and other tissues during
times of fasting.
A shortfall (deficiency) of the VLCAD enzyme results from variations in the ACADVL gene in
cells. Very long-chain fatty acids cannot be adequately broken down if there is insufficient activity
of this enzyme. Since these lipids are not turned into energy as a result form hypoglycemia. They
also build up in tissues and form damage to the organs in the body system. (Jones et al, 2017).
Clinical Descriptions
In neonates, severe dilated cardiomyopathy hypotonia, hypoglycemia, hepatomegaly and multi
organ failure occurs. In the older children, exercise intolerance and myopathy occurs with muscle
cramps/pain.
Treatment
The significance of early management should be done (e.g., use of IV glucose as an energy source,
monitoring for cardiac rhythm disturbance, and monitoring of rhabdomyolysis) and avoidance of
triggers (fasting, long-chain fats, and irritation of the myocardium). With early, intensive
supportive care and dietary changes, cardiac dysfunction may be treatable. (Leslie, 2009).

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CHAPTER THREE
MINI REVIEW OF INBORN ERRORS OF METABOLISM (IEM)
3.0. CONCLUSION
Essentially, metabolism is the orderly production and utilization of energy. Energy is mostly
required for the basal rate of metabolism (number of calories required for the body to perform
functions like breathing, blood flow and muscle integrity). Glycogen and triglycerides are the
largest energy stores in the body. There are two priorities during fasting: (1) maintaining plasma
glucose levels for cerebral metabolism and other tissues that request glucose, and
(2) the need to mobilize fatty acids from lipid storage and ketone bodies from the liver in order to
liberate energy for all other tissues. Without food, plasma triglyceride, amino acid, and glucose
levels fall, which reduces insulin secretion and increases glucagon release.
Enzymes, which are catalytic proteins, power all metabolic processes. Their main job is to speed
up reactions without changing the nature of the reaction itself. The enzymes have a very specialized
active site that connects to one or more particular substrates and exclusively catalyzes one sort of
reaction. Some enzymes form a relationship with a co-factor (metal ions or coenzyme) required
for the activity of the enzyme.
The majority of IEM are caused by enzyme deficits. For instance, glucose cannot be released from
the liver in Glycogenesis Type I because neither glycogenolysis nor gluconeogenesis can produce
glucose. This leads to hypoglycemia. Some IEMs have a more favorable prognosis than others
depending on all these factors. While many of these kids can live longer lives, many of them also
run the risk of experiencing progressive neurologic abnormalities, learning difficulties, and mental
retardation. In order to effectively manage these patients, primary care physicians must be able to
identify these disorders, treat them while waiting for a formal diagnosis, and refer them to the
proper metabolic expert.

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