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Mutations &
Inborn Errors of Metabolism

Explore how DNA mutations disrupt enzyme function and cause metabolic diseases: from point mutations to enzyme deficiencies tested on the MCAT.

MCAT Biological Foundations

What Is a Mutation?

A mutation is a permanent change in the nucleotide sequence of DNA. Mutations can occur spontaneously during DNA replication or be induced by mutagens such as UV radiation, chemicals, or viruses.

On the MCAT, understanding mutations means knowing how they alter protein structure and why that matters for metabolism.

Types of Point Mutations

Silent
Nucleotide changes but the same amino acid is coded due to codon degeneracy. No phenotypic effect.
Missense
Nucleotide change causes a different amino acid. Can be conservative (similar) or non-conservative (drastic).
Nonsense
Nucleotide change creates a premature stop codon, yielding a truncated, usually nonfunctional protein.

Frameshift Mutations

Insertions or deletions of nucleotides (not in multiples of 3) shift the reading frame of the mRNA, altering every downstream codon.

Normal: AUG GCA UGC AAU → Met-Ala-Cys-Asn Insert C: AUG CGC AUG CAA → Met-Arg-Met-Gln +C Every codon after the insertion is changed. The protein is completely different from the insertion onward.

The Central Dogma and Enzyme Function

DNA Gene Transcription mRNA Translation Protein / Enzyme Metabolic Function Mutation here → affects all below

Inborn Errors of Metabolism

Inborn errors of metabolism (IEM) are genetic disorders caused by mutations in genes encoding metabolic enzymes. Coined by Archibald Garrod in 1902, these follow the "one gene, one enzyme" hypothesis.

1
Gene mutation leads to an absent or defective enzyme.
2
Substrate accumulates upstream of the blocked step.
3
Product is deficient downstream of the blocked step.
4
Disease symptoms result from toxic buildup, product deficiency, or both.

How a Blocked Enzyme Disrupts a Pathway

Substrate A Enz 1 Intermediate B Enz 2 Product C B Accumulates (Toxic buildup) C Deficient (Missing product) Key: Normal enzyme Defective enzyme

Accumulation vs. Deficiency Diseases

Accumulation Diseases
Toxic substrate builds up. Examples: PKU (phenylalanine), Tay-Sachs (GM2 ganglioside), Gaucher's (glucocerebroside).
Deficiency Diseases
Critical product is missing. Examples: Albinism (no melanin), Cretinism (no thyroid hormone synthesis).

High-Yield IEMs for the MCAT

Disease Enzyme Defect Accumulates Inheritance
PKU Phenylalanine hydroxylase Phenylalanine AR
Tay-Sachs Hexosaminidase A GM2 ganglioside AR
Gaucher's Glucocerebrosidase Glucocerebroside AR
Galactosemia Galactose-1-P uridylyltransferase Galactose-1-P AR
Albinism Tyrosinase Tyrosine (precursor to deficient melanin) AR

Phenylketonuria: PKU in Detail

Phenylalanine PAH Tyrosine Melanin, etc. Phe Accumulates → Intellectual disability Phenylketones in urine Treatment Low-phenylalanine diet

Lysosomal Storage Diseases

A special category of IEMs where lysosomal enzymes are defective. Undigested substrates accumulate inside lysosomes, causing cell dysfunction and organ damage.

Tay-Sachs
Deficient hexosaminidase A. GM2 ganglioside accumulates in neurons. Fatal in early childhood.
Gaucher's
Deficient glucocerebrosidase. Glucocerebroside in macrophages. Hepatosplenomegaly, bone pain.
Niemann-Pick
Deficient sphingomyelinase. Sphingomyelin in reticuloendothelial cells. Cherry-red macula.

How to Identify IEM Problems

1
Locate the defective enzyme in the metabolic pathway described in the passage.
2
Identify what accumulates: the substrate immediately before the blocked step.
3
Identify what is deficient: the product immediately after the blocked step, and all downstream products.
4
Check for alternative pathways: the accumulated substrate may be shunted to abnormal metabolites.
5
Determine inheritance pattern: most IEMs are autosomal recessive. Carriers are unaffected.

Worked Example: Galactosemia

Galactose Galactose-1-P GALT Glucose-1-P Gal-1-P Buildup Liver, brain, eyes

Enzyme Kinetics and IEMs

Many IEM questions connect to enzyme kinetics. A defective enzyme may have altered \( K_m \) or \( V_{max} \):

Reduced \( V_{max} \)
Mutation decreases catalytic efficiency. Less product formed per unit time, even at saturating substrate.
Increased \( K_m \)
Mutation reduces substrate affinity. The enzyme requires higher substrate concentration to reach half-max velocity.
No Activity
Complete loss of function. Nonsense or frameshift mutation: no functional protein produced at all.

Autosomal Recessive Inheritance

Most IEMs follow autosomal recessive inheritance. If both parents are carriers (\( Aa \times Aa \)):

\(A\)
\(a\)
\(A\)
\(a\)
\(AA\)
 Unaffected
\(Aa\)
 Carrier
\(Aa\)
 Carrier
\(aa\)
 Affected Father (Aa) Mother (Aa) Ratio: 25% AA 50% Aa 25% aa

Common Mistakes to Avoid

✕ Confusing Silent and Missense
Silent mutations change a nucleotide but NOT the amino acid. Missense changes the amino acid. Always check the codon table.
✕ Forgetting Substrate Buildup
When an enzyme is blocked, the substrate BEFORE it accumulates: not the enzyme itself, and not the product.
✕ Assuming Dominant Inheritance
Most IEMs are autosomal recessive. Carriers have 50% enzyme activity, which is usually sufficient for normal function.

Mutation Types Summary

Mutation Type DNA Change Protein Effect Severity
Silent 1 base substitution No amino acid change None
Missense 1 base substitution Different amino acid Variable
Nonsense 1 base substitution Premature stop codon High
Frameshift Insertion/deletion All downstream codons altered Very High

Question 1 of 5

A patient with PKU has a deficiency in phenylalanine hydroxylase. Which of the following would you expect to find in this patient's blood?

Question 2 of 5

A single nucleotide deletion occurs in the coding region of a gene. This mutation is most likely to result in:

Question 3 of 5

Tay-Sachs disease results from deficiency of hexosaminidase A. This enzyme normally functions in the:

Question 4 of 5

Two carrier parents (both \(Aa\)) have a child. What is the probability that the child is a carrier but not affected?

Question 5 of 5

A missense mutation in an enzyme's active site most likely affects the enzyme's kinetics by: