Inborn errors of metabolism

Md. Nahian Rahman
M.Sc (Nutrition and Food
Science)
INFS,University of Dhaka.

“Inborn errors of metabolism”
inborn error : an inherited (i.e. genetic)
disorder
metabolism : chemical or physical changes
undergone by substances in a biological
system
“any disease originating in our chemical
individuality”

Garrod’s hypothesis
Product
deficiency
substrate excess
toxic metabolite
A
D
B
C

Small molecule
disease
• Carbohydrate
• Protein
• Lipid
• Nucleic Acids
Organelle disease
• Lysosomes
• Mitochondria
• Peroxisomes
• Cytoplasm

Acute life threatening illness
• encephalopathy - lethargy, irritability, coma
• vomiting
• respiratory distress
Seizures, Hypertonia
Hepatomegaly (enlarged liver)
Hepatic dysfunction / jaundice
Odour, Dysmorphism, FTT (failure to
thrive), Hiccoughs

Index of suspicion
• eg “with any full-term infant who has no
antecedent maternal fever or PROM
(premature rupture of the membranes) and
who is sick enough to warrant a blood culture
or LP, one should proceed with a few simple
lab tests.
Simple laboratory tests
• Glucose, Electrolytes, Gas, Ketones, BUN
(blood urea nitrogen), Creatinine
• Lactate, Ammonia, Bilirubin, LFT
• Amino acids, Organic acids, Reducing subst.

Most IEM’s are recessive - a negative
family history is not reassuring!
CONSANGUINITY, ethnicity, inbreeding
neonatal deaths, fetal losses
maternal family history
• males - X-linked disorders
• all - mitochondrial DNA is maternally inherited
A positive family history may be helpful!

CAN YOU EXPLAIN THE SYMPTOMS?
Timing of onset of symptoms
• after feeds were started?
Response to therapies

General – dysmorphisms (abnormality in
shape or size), ODOUR
H&N - cataracts, retinitis pigmentosa
CNS - tone, seizures, tense fontanelle
Resp - Kussmaul’s, tachypnea
CVS - myocardial dysfunction
Abdo - HEPATOMEGALY
Skin - jaundice

ANION GAP METABOLIC ACIDOSIS
Normal anion gap metabolic acidosis
Respiratory alkalosis
Low BUN relative to creatinine
Hypoglycemia
• especially with hepatomegaly
• non-ketotic

Metabolic diseases are individually rare,
but as a group are not uncommon.
There presentations in the neonate are
often non-specific at the outset.
Many are treatable.
The most difficult step in diagnosis is
considering the possibility!

An inherited enzyme deficiency leading to
the disruption of normal bodily
metabolism
Accumulation of a toxic substrate
(compound acted upon by an enzyme in
a chemical reaction)
Impaired formation of a product normally
produced by the deficient enzyme

Type 1: Silent Disorders
Type 2: Acute Metabolic Crises
Type 3: Neurological Deterioration

Do not manifest life-threatening crises
Untreated could lead to brain damage and
developmental disabilities
Example: PKU (Phenylketonuria)

Error of amino acids metabolism
No acute clinical symptoms
Untreated leads to mental retardation
Associated complications: behavior
disorders, cataracts, skin disorders, and
movement disorders
First newborn screening test was
developed in 1959
Treatment: phenylalaine restricted diet
(specialized formulas available)

 Life threatening in infancy
Children are protected in utero by maternal
circulation which provide missing product
or remove toxic substance
Example OTC (Urea Cycle Disorders)

Appear to be unaffected at birth
In a few days develop vomiting,
respiratory distress, lethargy, and may
slip into coma.
Symptoms mimic other illnesses
Untreated results in death
Treated can result in severe
developmental disabilities

Examples: Tay Sachs disease
Gaucher disease
Metachromatic leukodystrophy
DNA analysis show: mutations

Nonfunctioning enzyme results:
Early Childhood - progressive loss of
motor and cognitive skills
Pre-School – non responsive state
Adolescence - death

Partial Dysfunctioning Enzymes
-Life Threatening Metabolic Crisis
-ADH
-LD
-MR
Mutations are detected by Newborn
Screening and Diagnostic Testing

Dietary Restriction
Supplement deficient product
Stimulate alternate pathway
Supply vitamin co-factor
Organ transplantation
Enzyme replacement therapy
Gene Therapy

Life long treatment
At risk for ADHD
LD
MR
Awareness of diet restrictions
Accommodations

Inborn errors of metabolism
Definition:
Inborn errors of metabolism occur from a group of rare genetic
disorders in which the body cannot metabolize food components
normally. These disorders are usually caused by defects in the enzymes
involved in the biochemical pathways that break down food components.
Alternative Names:
Galactosemia - nutritional considerations; Fructose intolerance -
nutritional considerations; Maple sugar urine disease (MSUD) - nutritional
considerations; Phenylketonuria (PKU) - nutritional considerations;
Branched chain ketoaciduria - nutritional considerations

Background:
Inborn errors of metabolism (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.
An understanding of the broad clinical manifestations of IEMs
provides the basis for knowing when to consider the diagnosis.
Most important in making the diagnosis is a high index of suspicion.
Successful emergency treatment depends on prompt institution of
therapy aimed at metabolic stabilization.

A genetically determined
biochemical disorder in which a
specific enzyme defect produces a
metabolic block that may have
pathologic consequences at birth
(e.g., phenylketonuria) or in later life
(e.g., diabetes mellitus); called also
enzymopathy and genetotrophic
disease.

Metabolic disorders testable on Newborn Screen
Congenital Hypothyroidism
Phenylketonuria (PKU)
Galactosemia
Galactokinase deficiency
Maple syrup urine disease
Homocystinuria
Biotinidase deficiency

Classification
Inborn Errors of Small molecule Metabolism
Example: Galactosemia
Lysosomal storage diseases
Example: Gaucher's Disease
Disorders of Energy Metabolism
Example Glycogen Storage Disease
Other more rare classes of metabolism error
Paroxysmal disorders
Transport disorders
Defects in purine and pyrimidine metabolism
Receptor Defects

Categories of IEMs are as follows:
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)
Lysosomal storage disorders
Fatty acid oxidation defects
Mitochondrial disorders
Peroxisomal disorders

Pathophysiology:
Single gene defects result in abnormalities in the synthesis or
catabolism of proteins, carbohydrates, or fats.
Most are due to a defect in an enzyme or transport protein, which
results in a block in a metabolic pathway.
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.
Nearly every metabolic disease has several forms that vary in age of
onset, clinical severity and, often, mode of inheritance.

Frequency:
In the US: The incidence, collectively, is estimated to
be 1 in 5000 live births. The frequencies for each individual
IEM vary, but most are very rare. Of term infants who
develop symptoms of sepsis without known risk factors, as
many as 20% may have an IEM.
Internationally: The overall incidence is similar to
that of US. The frequency for individual diseases varies based
on racial and ethnic composition of the population.

Mortality/Morbidity:
IEMs can affect any organ system and usually do affect
multiple organ systems.
Manifestations vary from those of acute life-threatening
disease to subacute progressive degenerative disorder.
Progression may be unrelenting with rapid life-threatening
deterioration over hours, episodic with intermittent
decompensations and asymptomatic intervals, or insidious with
slow degeneration over decades.

Adenine phosphoribosyltransferase deficiency

The normal function of adenine phosphoribosyltransferase
(APRT) is the removal of adenine derived as metabolic waste from the
polyamine pathway and the alternative route of adenine metabolism to
the extremely insoluble 2,8-dihydroxyadenine, which is operative when
APRT is inactive. The alternative pathway is catalysed by xanthine
oxidase.

Hypoxanthine-guanine phosphoribosyltransferase (HPRT,
EC 2.4.2. 8)
HGPRTcatalyses the transfer of the phosphoribosyl
moiety of PP-ribose-P to the 9 position of the purine ring of
the bases hypoxanthine and guanine to form inosine
monophospate (IMP) and guanosine monophosphate
(GMP) respectively.
HGPRT is a cytoplasmic enzyme present in virtually
all tissues, with highest activity in brain and testes.

The salvage pathway of the
purine bases, hypoxanthine
and guanine, to IMP and
GMP, respectively,
catalysed by HGPRT (1) in
the presence of PP-ribose-
P. The defect in HPRT is
shown.

The importance of HPRT in the normal interplay between
synthesis and salvage is demonstrated by the biochemical and clinical
consequences associated with HPRT deficiency.
Gross uric acid overproduction results from the inability to
recycle either hypoxanthine or guanine, which interrupts the inosinate
cycle producing a lack of feedback control of synthesis, accompanied by
rapid catabolism of these bases to uric acid. PP-ribose-P not utilized in
the salvage reaction of the inosinate cycle is considered to provide an
additional stimulus to de novo synthesis and uric acid overproduction.

The defect is readily detectable in
erythrocyte hemolysates and in
culture fibroblasts.
HGPRT is determined by a gene on
the long arm of the x-chromosome
at Xq26.
The disease is transmitted as an X-
linked recessive trait.
Lesch-Nyhan syndrome
Allopurinal has been effective
reducing concentrations of uric
acid.

Phosphoribosyl pyrophosphate synthetase (PRPS, EC 2.7.6.1)
catalyses the transfer of the pyrophosphate group of ATP to ribose-5-
phosphate to form PP-ribose-P.
The enzyme exists as a complex aggregate of up to 32 subunits,
only the 16 and 32 subunits having significant activity. It requires Mg2+,
is activated by inorganic phosphate, and is subject to complex regulation
by different nucleotide end-products of the pathways for which PP-ribose-
P is a substrate, particularly ADP and GDP.
Phosphoribosyl pyrophosphate synthetase superactivity

PP-ribose-P acts as an allosteric regulator of the first specific
reaction of de novo purine biosynthesis, in which the interaction of
glutamine and PP-ribose-P is catalysed by amidophosphoribosyl
transferase, producing a slow activation of the amidotransferase by
changing it from a large, inactive dimer to an active monomer.
Purine nucleotides cause a rapid reversal of this process,
producing the inactive form.
Variant forms of PRPS have been described, insensitive to
normal regulatory functions, or with a raised specific activity. This
results in continuous PP-ribose-P synthesis which stimulates de novo
purine production, resulting in accelerated uric acid formation and
overexcretion.

The role of PP-ribose-P in the de novo synthesis of IMP and adenosine
(AXP) and guanosine (GXP) nucleotides, and the feedback control normally
exerted by these nucleotides on de novo purine synthesis.

Purine nucleoside phosphorylase (PNP, EC 2.4.2.1)
PNP catalyses the degradation of the nucleosides inosine,
guanosine or their deoxyanalogues to the corresponding base.
The mechanism appears to be the accumulation of purine
nucleotides which are toxic to T and B cells.
Although this is essentially a reversible reaction, base
formation is favoured because intracellular phosphate levels normally
exceed those of either ribose-, or deoxyribose-1-phosphate.
The enzyme is a vital link in the 'inosinate cycle' of the purine
salvage pathway and has a wide tissue distribution.
Purine nucleotide phosphorylase deficiency

The necessity of purine nucleoside phosphorylase (PNP) for the normal catabolism and
salvage of both nucleosides and deoxynucleosides, resulting in the accumulation of
dGTP, exclusively, in the absence of the enzyme, since kinases do not exist for the other
nucleosides in man. The lack of functional HGPRT activity, through absence of substrate,
in PNP deficiency is also apparent.

The importance of adenosine deaminase (ADA) for the catabolism of dA, but not A, and
the resultant accumulation of dATP when ADA is defective. A is normally salvaged by
adenosine kinase (see Km values of A for ADA and the kinase, AK) and deficiency of
ADA is not significant in this situation
Adenine deaminase deficiency

The role of AMPDA in the deamination of AMP to IMP, and the recorversion of the
latter to AMP via AMPS, thus completing the purine nucleotide cycle which is of
particular importance in muscle.
Myoadenylate deaminase (AMPDA) deficiency

Purine and pyrimidine degradation

PRPP synthesis
1=ribokinase 2=ribophosphate pyrophosphokinase 3=phosphoribosyl transferase

Salvage pathway of purine
PRPP Purine ribonucleotide
purine PPi
Adenine + PRPP Adenylate + PPi
(AMP)
Mg 2+
APRTase
Catalyzed by adenine phosphoribosyl transferase (APRTase)

IMP and GMP interconversion
Hypoxanthine + PRPP Inosinate + PPi
( IMP)
Mg 2+
HGPRTase
Guanine + PRPP Guanylate + PPi
(GMP)
Mg 2+
HGPRTase
HGPRTase = Hypoxanthine-guanine phosphoribosyl transferase

purine reused
1=adenine phosphoribosyl
transferase
2=HGPRTase

Formation of uric acid from hypoxanthine and xanthine catalysed
by xanthine dehydrogenase (XDH).

Intracellular uric acid crystal under polarised light (left) and under non-polarised light
(right)
With time, elevated levels of uric acid in the blood may lead to deposits around
joints. Eventually, the uric acid may form needle-like crystals in joints, leading to
acute gout attacks. Uric acid may also collect under the skin as tophi or in the
urinary tract as kidney stones.

Additional Gout Foot Sites: Inflamation In Joints Of Big Toe, Small Toe And Ankle
Gout-Early Stage: No Joint Damage
Gout-Late Stage: Arthritic Joint

The UMP synthase (UMPS) complex, a bifunctional protein comprising the enzymes
orotic acid phosphoribosyltransferase (OPRT) and orotidine-5'-monophosphate
decarboxylase (ODC), which catalyse the last two steps of the de novo pyrimidine
synthesis, resulting in the formation of UMP. Overexcretion formation can occur by the
alternative pathway indicated during therapy with ODC inhibitors.
Hereditary orotic aciduria

Dihydropyrimidine dehydrogenase (DHPD) is responsiblefor the catabolism of the end-products of
pyrimidinemetabolism (uracil and thymine) to dihydrouracil and dihydrothymine. A deficiencyof
DHPD leads to accumulationof uracil and thymine. Dihydropyrimidine amidohydrolase (DHPA)
catalysesthe next step in the further catabolism of dihydrouraciland dihydrothymineto amino acids. A
deficiencyof DHPA results in the accumulation ofsmall amounts of uracil and thymine togetherwith
larger amounts of the dihydroderivatives.

The role of uridine monophosphate hydrolases (UMPH) 1 and 2 in
the catabolism of UMP, CMP, and dCMP (UMPH 1), and dUMP
and dTMP (UMPH 2).

CDP-choline phosphotransferase catalyses the last step in the synthesis
of phosphatidyl choline. A deficiency of this enzyme is proposed as the
metabolic basis for the selective accumulation of CDO-choline in the
erythrocytes of rare patients with an unusual form of haemolytic
anaemia.
CDP-choline phosphotransferase deficiency

WHAT IS TYROSINEMIA?
Hereditary tyrosinemia is a genetic inborn error of metabolism
associated with severe liver disease in infancy. The disease is inherited in an
autosomal recessive fashion which means that in order to have the disease,
a child must inherit two defective genes, one from each parent. In families
where both parents are carriers of the gene for the disease, there is a one in
f o u r r i s k t h a t a c h i l d w i l l h a v e t y r o s i n e m i a.
About one person in 100 000 is affected with tyrosinemia globally.

HOW IS TYROSINEMIA CAUSED?
Tyrosine is an amino acid which is found in most animal
and plant proteins. The metabolism of tyrosine in humans takes
p l a c e p r i m a r i l y i n t h e l i v e r.
Tyrosinemia is caused by an absence of the enzyme
fumarylacetoacetate hydrolase (FAH) which is essential in the
metabolism of tyrosine. The absence of FAH leads to an
accumulation of toxic metabolic products in various body tissues,
which in turn results in progressive damage to the liver and
k i d n e y s.

WHAT ARE THE SYMPTOMS OF TYROSINEMIA?
The clinical features of the disease ten to fall into two categories, acute and chronic.
In the so-called acute form of the disease, abnormalities appear in the first month of life.
Babies may show poor weight gain, an enlarged liver and spleen, a distended abdomen,
swelling of the legs, and an increased tendency to bleeding, particularly nose bleeds.
Jaundice may or may not be prominent. Despite vigorous therapy, death from hepatic
failure frequently occurs between three and nine months of age unless a liver
transplantation is performed.
Some children have a more chronic form of tyrosinemia with a gradual onset and less
severe clinical features. In these children, enlargement of the liver and spleen are
prominent, the abdomen is distended with fluid, weight gain may be poor, and vomiting
and diarrhoea occur frequently. Affected patients usually develop cirrhosis and its
complications. These children also require liver transplantation.

Figure 1: the structures of tyrosine, phenylalanine and homogentisic acid

This excess can be caused by an increase in production by the body, by under-elimination
of uric acid by the kidneys or by increased intake of foods containing purines which are
metabolized to uric acid in the body. Certain meats, seafood, dried peas and beans are
particularly high in purines. Alcoholic beverages may also significantly increase uric acid
levels and precipitate gout attacks.

Pyruvate kinase (PK) deficiency:
This is the next most common red cell enzymopathy after G6PD
deficiency, but is rare. It is inherited in a autosomal recessive pattern
and is the commonest cause of the so-called "congenital non-
spherocytic haemolytic anaemias" (CNSHA).
PK catalyses the conversion of phosphoenolpyruvate to pyruvate with
the generation of ATP. Inadequate ATP generation leads to premature
red cell death.
There is considerable variation in the severity of haemolysis. Most
patients are anaemic or jaundiced in childhood. Gallstones,
splenomegaly and skeletal deformities due to marrow expansion may
occur. Aplastic crises due to parvovirus have been described.

Blood film: PK deficiency:
Characteristic "prickle cells" may be seen.

A female baby was delivered
normally after an uncomplicated
pregnancy. At the time of the
infant’s second immunization, she
became fussy and was seen by a
pediatrician, where examination
revealed an enlarged liver. The
baby was referred to a
gastroenterologist and later
diagnosed to have Glycogen
Storage Disease Type IIIB

Disorder Affected Tissue Enzyme Inheritance Gene Chromosome
Type 0 Liver Glycogen synthase AR GYS2[125] 12p12.2[121]
Type IA Liver, kidney, intestine Glucose-6-phosphatase AR G6PC[96] 17q21[13][94]
Type IB Liver Glucose-6-phosphate transporter (T1) AR G6PTI[57][104] 11q23[2][81][104][155]
Type IC Liver Phosphate transporter AR 11q23.3-24.2[49][135]
Type IIIA Liver, muschle, heart Glycogen debranching enzyme AR AGL 1p21[173]
Type IIIB Liver Glycogen debranching enzyme AR AGL 1p21[173]
Type IV Liver Glycogen phosphorylase AR PYGL[26] 14q21-22[118]
Type IX Liver, erythrocytes, leukocytes Liver isoform of -subunit of liver and muscle
phosphorylase kinase
X-Linked PHKA2 Xp22.1-p22.2[40][68][162][165]
Liver, muscle, erythrocytes,
leukocytes
Β-subunit of liver and muscle PK AR PHKB 16q12-q13[54]
Liver Testis/liver isoform of γ-subunit of PK AR PHKG2 16p11.2-p12.1[28][101]

Type 0
Type I
Type II
Glycogen Storage Diseases
Type IV
Type VII

 Deficiency of debranching enzyme in the
liver needed to completely break down
glycogen to glucose
 Hepatomegaly and hepatic symptoms
• Usually subside with age
 Hypoglycemia, hyperlipidemia, and
elevated liver transaminases occur in
children

 Amylo-1,6-glucosidase
• Isoenzymes in liver, muscle and heart
• Transferase function
• Hydrolytic function

The two forms of GSD Type III are caused
by different mutations in the same
structural Glycogen Debranching Enzyme
gene

The gene consists of 35 exons spanning at
least 85 kbp of DNA
The transcribed mRNA consists of a 4596
bp coding region and a 2371 bp non-
coding region
Type IIIa and IIIb are identical except for
sequences in non-translated area
The tissue isoforms differ at the 5’ end

Approximately 16 different mutations
identified
Most mutations are nonsense
One type caused by a missense mutation

 The GDE gene is located
on chromosome 1p21, and
contains 35 exons
translated into a
monomeric protein
 Exon 3 mutations are
specific to the type IIIb,
thus allowing for
differentiation

Inborn errors of metabolism
Autosomal recessive disorder
Incidence estimated to be between
1:50,000 and 1:100,000 births per
year in all ethnic groups
Herling and colleagues studied
incidence and frequency in British
Columbia
• 2.3 children per 100,000 births per year

 Single variant in North African Jews in Israel
shows both liver and muscle involvement (GSD
IIIa)
• Incidence of 1:5400 births per year
• Carrier frequency is 1:35

G g
G
g
GG Gg
Gg gg
GG = normal
Gg = carrier
Gg = GSD
Both parents are carriers in the case.

Clinical Features
• Hepatomegaly and fibrosis in childhood
• Fasting hypoglycemia (40-50 mg/dl)
• Hyperlipidemia
• Growth retardation
• Elevated serum transaminase levels
(aspartate aminotransferase and alanine aminotransferase > 500 units/ml)
Common presentation

• Splenomegaly
• Liver cirrhosis
Clinical Features
Less Common

Galactosemia is an inherited disorder that affects the way the body breaks down
certain sugars. Specifically, it affects the way the sugar called galactose is broken
down. Galactose can be found in food by itself. A larger sugar called lactose,
sometimes called milk sugar, is broken down by the body into galactose and glucose.
The body uses glucose for energy. Because of the lack of the enzyme (galactose-1-
phosphate uridyl transferase) which helps the body break down the galactose, it then
builds up and becomes toxic. In reaction to this build up of galactose the body makes
some abnormal chemicals. The build up of galactose and the other chemicals can cause
serious health problems like a swollen and inflamed liver, kidney failure, stunted
physical and mental growth, and cataracts in the eyes. If the condition is not treated
there is a 70% chance that the child could die.

Lysomal storage diseases
The pathways are shown for the formation
and degradation of a variety of
sphingolipids, with the hereditary metabolic
diseases indicated.
Note that almost all defects in sphingolipid
metabolism result in mental retardation and
the majority lead to death. Most of the
diseases result from an inability to break
down sphingolipids (e.g., Tay-Sachs,
Fabry's disease).

Inborn errors of metabolism

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