Genetics of Metabolic Disorders

BIDZINA CHACHKHIANI
 Inherited metabolic disorders
Inherited metabolic disorders are genetic conditions that result in metabolism problems. Most people with
inherited metabolic disorders have a defective gene that results in an enzyme deficiency. There are hundreds
of different genetic metabolic disorders, and their symptoms, treatments, and prognoses vary widely.

What Is Metabolism?
Metabolism refers to all the chemical reactions taking place in the body to convert or use energy. A few
major examples of metabolism include:
-Breaking down the carbohydrates, proteins, and fats in food to release energy.
-Transforming excess nitrogen into waste products excreted in urine.
-Breaking down or converting chemicals into other substances and transporting them inside cells.

Metabolism is an organized but chaotic chemical assembly line. Raw materials, half-finished products, and
waste materials are constantly being used, produced, transported, and excreted. The "workers" on the
assembly line are enzymes and other proteins that make chemical reactions happen.
 Causes of Inherited Metabolic Disorders

In most inherited metabolic disorders, a single enzyme is either not produced by the body at all or is
produced in a form that doesn't work. The missing enzyme is like an absentee worker on the assembly line.
Depending on that enzyme's job, its absence means toxic chemicals may build up, or an essential product
may not be produced.

The code or blueprint to produce an enzyme is usually contained on a pair of genes. Most people with
inherited metabolic disorders inherit two defective copies of the gene -- one from each parent. Both parents
are "carriers" of the bad gene, meaning they carry one defective copy and one normal copy.

The original cause of most genetic metabolic disorders is a gene mutation that occurred many, many
generations ago. The gene mutation is passed along through the generations, ensuring its preservation.

Each inherited metabolic disorder is quite rare in the general population. Considered all together,
inherited metabolic disorders may affect about 1 in 1,000 to 2,500 newborns. In certain ethnic
populations, such as Ashkenazi Jews (Jews of central and eastern European ancestry), the rate of inherited
metabolic disorders is higher.
 Types of Inherited Metabolic Disorders

Hundreds of inherited metabolic disorders have been identified, and new ones
continue to be discovered. Some of the more common and important genetic
metabolic disorders include:

Lysosomal storage disorders,

Galactosemia,
Maple syrup urine disease,
Phenylketonuria (PKU),
Alkaptonuria,
Glycogen storage diseases,
Mitochondrial disorders,
Friedreich ataxia,
Metal metabolism disorders …
 Diseases Involving Enzymes

• Enzymes are the biological

catalysts that mediate, with great
efficiency, the conversion of a
substrate to a product
• The diversity of substrates on
which enzymes act is huge and is
reflected in the fact that the
human genome contains more
than 5000 genes that encode
enzymes
• Not surprisingly, therefore, there
are hundreds of human enzyme
defects, or enzymopathie
• The best-known groups of
inborn errors of metabolism, the
hyperphenylalaninemias, which
arise from deficient activity of
phenylalanine hydroxylase.
Several other enzyme defects of
significance are then briefly
examined
 Inborn errors of metabolism

• Inheritable change of an allele can reveal itself as a modification in the

structure and function of that specific allele product
• Even a single amino acid replacement in a protein may have important
clinical consequences
• Many of the earliest described inherited anomalies were biochemical
defects, or inborn errors of metabolism, resulting from enzymatic deficiencies
• The consequence of an enzyme deficiency is the direct impairment of a
specific metabolic pathway

NEWBORN SCREENING
In the US all states screen for:
1. PKU
2. Congenital hypothyroidism
3. Galactosemia
4. Sickle cell disease (only selected populations in some states)
 Alkaptonuria
• The first example of recessive
inheritance occurred in patients
excreting “black urine.” From an
analysis of family histories,
Archibald Garrod concluded that this
anomaly, known as alkaptonuria,
appeared when affected children
inherited one defective gene from each
parent
• In an alkaptonuric individual, the
enzyme is absent or deficient
and homogentisic acid accumulates,
since its conversion to acetoacetic acid
is blocked or reduced. The excess
homogentisic acid is then eliminated in
urine. Urine containing homogentisic
acid, on exposure to air, gradually
darkens
 AMINOACIDOPATHIES
Inborn errors of metabolism (IEMs) have been classified into different categories and one class of IEMs,
characterized by the physiological disturbances of amino acids is called as aminoacidopathies.

Out of 91 treatable IEM, thirteen disorders are amino acid related. Aminoacidopathies can be detected by
chromatography and mass spectrometry based analytical techniques .

Phenylketonuria (PKU),
Maple Syrup Urine Disease (MSUD),
Homocystinuria/Methylene Tetrahydrofolate Reductase (MTHFR) deficiency,
Tyrosinemia type II,
Citrullinemia type I and type II,
Argininosuccinic aciduria, Carbamoyl Phosphate Synthetase I (CPS) deficiency,
Argininemia (arginase deficiency),
Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome,
N-Acetylglutamate Synthase (NAGS) deficiency,
Ornithine Transcarbamylase (OTC) deficiency, and
Pyruvate Dehydrogenase (PDH) complex deficiency.
 Phenylalanine metabolism

Phenylalanine is the starting point

for a series of reactions essential in
metabolism. Reflected in this
pathway of reactions are several
inherited defects:
• phenylketonuria,
• albinism,
• tyrosinemia,
• alkaptonuria
All are recessive, and the
heterozygote typically produces
sufficient enzyme and is considered
“normal”
 The Molecular Defects in the Phenylalanine
Hydroxylase Gene

• A striking degree of allelic heterogeneity at the PAH locus—more than 400 different mutations
worldwide—has been identified in patients with hyperphenylalaninemia associated with classic PKU,
variant PKU, and non-PKU hyperphenylalaninemia
• The great majority of PAH alleles are individually rare mutations that impair PAH enzymatic activity and
lead to hyperphenylalaninemia, although benign polymorphisms or less common benign variants have also
been identified
• Six different mutations account for about two thirds of known mutant chromosomes in populations of
European descent. Notably, six other mutations are responsible for slightly more than 80% of PAH
mutations in Asian populations. The remaining disease-causing mutations are individually rare
• In all populations, there is substantial genetic heterogeneity in the PAH mutant population. Owing to the
high degree of allelic heterogeneity at the locus, most PKU patients in most populations are compound
heterozygotes
• Certain PAH mutations in homozygous patients have been associated with phenotypes ranging all the way
from classic PKU to non-PKU hyperphenylalaninemia. Thus, it is now clear that other unidentified
biological variables—undoubtedly including modifier genes—generate variation in the phenotype seen with
a specific genotype. This observation, which has now been recognized to be a common feature of many
single-gene diseases, highlights the fact that even monogenic traits like PKU are not genetically simple
disorders
 Defects in Tetrahydrobiopterin Metabolism

It was initially believed that all children with hereditary hyperphenylalaninemia had a primary deficiency
of PAH
• In about 1% to 3% of these patients, the PAH gene is normal, and their hyperphenylalaninemia is the
result of a genetic defect in any one of several different genes involved in the formation or recycling of the
cofactor of PAH, BH4
• The association of a single phenotype, such as hyperphenylalaninemia, with mutations in different
genes is an example of locus heterogeneity
• As illustrated by mutations in the genes encoding the PAH protein and the biopterin cofactor pathways,
the proteins encoded by genes that manifest locus heterogeneity generally act at different steps in a single
biochemical pathway
• BH4 deficient patients were first recognized because, despite the successful administration of a
lowphenylalanine diet, they developed profound neurological problems in early life. This poor outcome is
due in part to the requirement for the BH4 cofactor of two other enzymes, tyrosine hydroxylase and
tryptophan hydroxylase. Both of these hydroxylases are critical for the synthesis of monoamine
neurotransmitters such as dopa, norepinephrine, epinephrine, and serotonin
Deficiency phenylalanine hydroxylase and mental
retardation

• The increased concentration of phenylalanine leads, in turn, to an increased rate of formation of

phenylpyruvic acid, which is excreted in the urine.
• Excess phenylpyruvic acid in sweat accounts for the unusual “mousy” body odor of PKU patients
• Phenylpyruvic acid is a competitive inhibitor of the pyruvate dehydrogenase complex, which is
important in glucose metabolism and subsequently in synthesis of fatty acids and cholesterol.
This may contribute to the lack of myelin formation and mental retardation in these individuals
• Phenylalanine will also interfere with hydrophobic amino acid transport across the blood-brain
barrier. It competes for the same active transport system as does leucine, an important
component of myelin
• Postmortem studies of PKU infants with microcephaly suggest that the decreased brain size is due
to a decreased amount of myelin and a reduction in other protein components of the brain
 Tyrosine Metabolism
• Many genes are involved in the production of pigment of skin and hair
• The best-described condition affecting pigment production is classic albinism, which results from a
lack of tyrosinase
• Individuals with classic PKU may demonstrate pale skin and hair coloration that might suggest
albinism

• Tyrosinemia types I and II are rare but can be detected by molecular analysis
• Type I, also known as hepatorenal tyrosinemia, is potentially fatal
• Present in either acute or chronic form, it is associated with liver failure or with liver
dysfunction and renal nephropathy.
• Type II, also known as oculocutaneous tyrosinemia, usually presents during the first year as eye
irritations in the form of photophobia, conjunctivitis, or pain resulting from tyrosine crystals within the
cornea. Skin lesions begin as blisters on fingertips and toes; later keratotic plaques appear on palms and
soles. Both types result from the accumulation of tyrosine. Mental retardation may occur in these
individuals, but it is unclear whether it results from elevated tyrosine or is secondary to the enzyme
deficiency.
• About 1 in 40,000 people have some form of OCA1.
 Homocystinuria and Hyperhomocystinuria
• Methionine is an essential amino acid that is converted to cysteine
• These amino acids are the only two sulfur-containing amino acids in protein synthesis, and therefore, the
roles they play in synthetic pathways are critical

• An intermediate in the methionine-to-cysteine pathway is homocysteine, a thiol compound

required to regenerate methionine
• Classic homocystinuria is a recessive metabolic disorder due to deficiency of cystathionine β-
synthase (CBS) that produces increased urinary homocystine and methionine
• Two other enzymes may result in hyperhomocystinuria: methionine synthase and 5,10-
methylenetetrahydrofolate reductase
 Homocystinuria and Hyperhomocystinuria

Classic homocystinuria results from a deficiency of cystathionine β-synthase (CBA)

 Homocystinuria and Hyperhomocystinuria

• Clinical manifestations of homocystinuria include lens dislocation (ectopia lentis), excessive height and
length of limbs, and vascular abnormalities that may lead to myocardial infarction, stroke, or
pulmonary embolism
• Lens dislocation is the primary symptom leading to diagnosis in 80% of patients with undiagnosed
homocystinuria; it is usually diagnosed between ages 4 and 6

• There are two forms of homocystinuria: vitamin B6 responsive and vitamin B6 nonresponsive
• Pyridoxine (B6) responsiveness is the ability to enhance transsulfuration of homocysteine upon
pyridoxine administration. Vitamin B6– responsive homocystinuria is typically milder than the
nonresponsive form
• Pyridoxine responsiveness determined by a challenge test is defined as a decrease of total homocysteine
below 50 μmol/L, whereas nonresponsiveness is no change in plasma total homocysteine after a dose of up
to 10 mg/kg of pyridoxine per day administered for at least 2 weeks
• About 40% of homocystinuria patients respond to B6 supplementation. Those who fail to respond require
a diet restricted in methionine.
Thank you!