Biochemistry of PKU and Galactosemia

Introduction to Genetic Diseases

• Genetic disorders are far more common than appreciated
• Lifetime frequency is estimated at 670/1000
• 50% of spontaneous abortions are due to chromosomal abnormalities in early gestation
• Approximately 1% of newborns have a gross chromosomal abnormality

Genetic Information Storage

• Genetic information is stored in DNA
• The typical normal human cell contains 46 chromosomes (23 pairs): 22 homologous pairs of autosomes and 1 pair of sex chromosomes (XX or XY)
• Members of a chromosome pair carry matching genetic information, though they can have slightly different forms (alleles)
• Each chromosome is composed of a long DNA molecule bound to histones and proteins
• A DNA molecule is composed of two long complementary chains of deoxyribonucleotides.

DNA Structure

• Two DNA strands twist around each other to form a double helix
• Each deoxyribonucleotide comprises a nitrogenous base (adenine, guanine, cytosine, or thymine) bound to deoxyribose and phosphate

DNA Functions

• Provides genetic information for protein synthesis
• Transmits genetic information to daughter cells and offspring

Genes, Codons, and Proteins

• The portion of DNA required for protein production is called a gene
• Gene transcription is regulated by promoter or enhancer regions
• Three consecutive nucleotides form a codon, each specifying a single amino acid
• The sequence of amino acids in a protein is determined by the sequence of codons in mRNA, which is determined by the sequence of nucleotides in DNA

Transmission of Genetic Information

• Genetic information is transmitted to daughter cells during mitosis (somatic cells) and meiosis (germ cells)

Terminology

• Hereditary disorders: disorders inherited from parents
• Congenital disorders: present at birth
• Genotype: genetic constitution (genome)
• Phenotype: expressed characteristics

Mutations

• Permanent change in the DNA's primary nucleotide sequence
• Can occur spontaneously during cell division or environmentally by mutagens (radiation, viruses, chemicals)
• Mutations in germ cells cause hereditary diseases
• Three categories of mutation:
• Genome mutations: loss or gain of a whole chromosome; often incompatible with survival
• Chromosomal mutations: rearrangement of genetic material within a chromosome; usually incompatible with survival; exemplified by translocations
• Gene mutations: single base mutations (more common); or they may affect a large portion of a gene; cause most hereditary diseases; types include point mutations (single base changes), deletions/insertions, and expansion of repeat sequences (trinucleotide repeats)

Point Mutations

• Single base substitutions
• Types include:
• Silent mutations: no change in amino acid sequence
• Missense mutations: change in one amino acid
• Nonsense mutations: change to a stop codon, terminating protein synthesis;

Deletions/Insertions (Gene Mutations)

• Can occur within coding or non-coding sequences
• Deletions or insertions of 1 or 2 bases lead to frameshift mutations, altering the reading frame of the genetic code
• Deletions or insertions of 3 or multiples of 3 bases do not cause frameshifts but can result in abnormal protein missing one or more amino acids

Expansion of Repeat Sequences (Gene Mutations)

• Show amplification or expansion of a sequence of 3 nucleotides
• Normally repeated 20-30 times
• Trinucleotide repeat mutation is when the sequence expands to more than 100 repeats
• Mechanism leading to the increase in repeats and how this leads to disease is poorly understood; examples are Huntington's disease and fragile X syndrome

Categories of Genetic Disease

• Mendelian disorders: single-gene defects; follow known Mendelian inheritance patterns
• Chromosomal disorders: abnormalities in chromosome structure or number
• Multifactorial disorders: caused by multiple genes and environmental factors
• Diseases with non-classic inheritance patterns: atypical inheritance

Autosomal Dominant Disorders

• Manifested in the heterozygous state
• 50% chance of inheriting the abnormal allele from an affected parent
• Can show reduced penetrance, with inherited mutant gene but no phenotype
• Commonly show variable expressivity
• Pathogenesis: often loss-of-function mutations (reduced regulatory protein amount), or gain-of-function mutations (toxic mutant protein)
• Many show delayed onset and symptoms first appear in adulthood

Autosomal Recessive Disorders

• Phenotype usually only observed in the homozygous state
• Affected siblings often have normal parents
• The chance of each pregnancy resulting in a homozygous affected child = 25% (parents heterozygous)

X-Linked Disorders (Recessive)

• Located on the X chromosome
• Generally recessive, but rarely dominant
• In heterozygous females, random X-inactivation may lead to partial expression of the trait
• Affected males cannot transmit the disease to their sons.

Biochemical Basis of Single-Gene Disorders

• Genetic defects can lead to formation of abnormal proteins or reduced gene product output
• Phenotypic effects can be direct (abnormalities in encoded protein) or indirect (interactions of the mutant protein with other normal proteins)

Mechanisms in Single-Gene Disorders

• Enzyme defects and consequences (accumulated substrate)
• Defects in membrane receptors and transport systems
• Alterations in the structure, function, or quantity of non-enzyme proteins

Enzyme Defects and Consequences

• Mutation can result in defective or reduced enzyme synthesis, leading to a metabolic block
• Three major consequences:
• Accumulation of the substrate
• Decreased production of the end product needed
• Failure to inactivate a tissue damaging substrate

Defects in Receptors and Transport Systems

• Examples: Familial hypercholesterolemia (defects in LDL receptor function); Cystic fibrosis (defects in chloride ion transport)

Alterations in Structure, Function, or Quantity of Nonenzyme Proteins

• Examples: Hemoglobinopathies (sickle cell disease, thalassemia); osteogenesis imperfecta; muscular dystrophies; Ehlers-Danlos syndrome (EDS)

Disorders Associated with Defects in Structural Proteins

• Marfan syndrome: autosomal dominant; affects fibrillin-1; leads to skeletal, ocular, and cardiovascular abnormalities
• Ehlers-Danlos syndrome (EDS): defects in collagen synthesis or structure; various types resulting in variable clinical presentations such as hyperextensibility of joints.

Diseases Associated with Mutations in Receptor Proteins or Channels

• Familial hypercholesterolemia: impaired LDL receptor function; elevated cholesterol

Disorders Associated with Defects in Enzymes

• Phenylketonuria (PKU): autosomal recessive; deficiency of phenylalanine hydroxylase (PAH); causes elevated phenylalanine and lack of tyrosine leading to intellectual disability and other problems
• Galactosemia: autosomal recessive; deficiency of galactose-1-phosphate uridyltransferase (GALT); causes accumulation of galactose and galactose-1 phosphate; severe outcomes in the absence of treatment

Lysosomal Storage Diseases

• Lysosomes contain hydrolytic enzymes; breakdown complex substrates to soluble products
• Inherited lack of an enzyme results in storage of partially degraded metabolites within lysosomes
• Examples: Tay-Sachs disease; Niemann-Pick disease types A, B, and C; Gaucher disease

Tay-Sachs Disease

• Deficiency of hexosaminidase A
• GM2 ganglioside accumulates in nervous system causing damage
• Symptoms develop in infancy and are progressive, often leading to death

Niemann-Pick Disease

• Deficiency of acid sphingomyelinase results in varying degrees of illness
• Sphingomyelin accumulation in cells
• Type A: severe, with rapid deterioration in infancy
• Type B: less severe, with organomegaly but no neurological problems
• Type C: distinctive; involves lipid transport defects; cholesterol accumulation

Gaucher Disease

• Deficiency of glucocerebrosidase
• Glucocerebroside accumulates in macrophages; leading to hepatosplenomegaly, bone problems
• Three clinical variants (type 1, 2, 3); clinical features vary based on the type and severity or the loss of function

Mucopolysaccharidoses (MPS)

• Defective degradation of mucopolysaccharides (part of the extracellular matrix)
• Accumulation within various tissues, including the heart valves and subendothelial arterial deposits
• Various clinical variants characterized by specific enzyme deficiencies and varying degrees of severity

Glycogen Storage Diseases (Glycogenoses)

• Inherited deficiencies of enzymes involved in glycogen synthesis or degradation cause glycogen accumulation in tissues.
• Types with different tissue localization.
• Varying degrees of severity and presentation

Crystal-Induced Arthritis

• Endogenous crystals can trigger arthritis (urate, calcium pyrophosphate dehydrate, and basic calcium phosphate)
• Gout (urate crystals); Pseudogout (calcium pyrophosphate dehydrate crystals)

Gout

• Marked by transient attacks of acute arthritis, initiated by urate crystals deposited within and around joints
• Hyperuricemia (high blood uric acid) is a necessary but not sufficient factor for causing gout
• Results from reduced excretion, or in a smaller percentage of cases from overproduction of uric acid

Other Diseases

• Many other pediatric diseases have genetic origins
• Prenatal developmental errors can cause structural defects

This quiz explores the biochemical mechanisms behind phenylketonuria (PKU) and galactosemia, including enzyme roles and metabolic pathways. Test your understanding of the symptoms, causes, and therapeutic approaches related to these metabolic disorders.