Non-Mendelian Inheritance: Single-Gene Disorders

Single-Gene Disorders with Non-classical Patterns of Inheritance

• Focuses on genetic disorders that deviate from Mendelian inheritance
• Includes gonadal mosaicism, mitochondrial mutations, genomic imprinting, and trinucleotide repeats

Introduction to Non-Mendelian Inheritance

• Single-gene disorders adhering to Mendelian inheritance have aided in identifying genes and pathways linked to genetic diseases
• Molecular analysis can predict disease status in Mendelian inheritance
• Many abnormalities display familial recurrence and a genetic component, but do not follow Mendelian patterns
• Identifying causative genes for non-Mendelian diseases poses difficulty because of uncertainty in prenatal prediction

Non-Mendelian Inheritance Examples

• Gonadal mosaicism
• Mitochondrial mutations
• Genomic imprinting
• Trinucleotide repeats

Gonadal Mosaicism

• Refers to new mutations arising in germ line cells
• Mutated cells become eggs or sperm carrying the mutation- creating a heritable phenotype
• Can result in "unusual" pedigrees
• May be suspected when phenotypically normal parents have multiple affected children, e.g., osteogenesis imperfecta

Gonadal Mosaicism Arises from New Mutation

• Dominant disease phenotypes have been inherited from unaffected parents
• Mutation only present in germ cells of first-generation parents, but inherited in all cells of offspring

Osteogenesis Imperfecta (OI)

• Also known as brittle bone disease
• Genetic disorder marked by bones fracturing without apparent reason
• A classification helps describe the severity of OI in affected individuals
• Can be only a few fractures or hundreds in someone's lifetime
• OI hinders the body's ability to create strong bones
• In dominant (classical) OI, deficient or poor-quality type I collagen results from a mutation in type I collagen genes
• In recessive OI, mutations in other genes interfere with collagen production
• Most cases of OI (85-90%) is caused by a dominant genetic defect.

Prevalence of Osteogenesis Imperfecta

• At least eight recognized forms (I-VIII)
• Type I is the mildest, type II is the most severe
• Affects ~6-7 per 100,000 people across the globe
• Types I and IV are the most common, affecting 4-5 per 100,000 people
• Occurs uniformly among males and females from all racial groups

OI Symptoms

• Weak bones contribute to increased risk of fractures in all people with OI
• Often presents with below-average height (short stature)
• Severity of the disease varies greatly
• Includes blue sclera, multiple bone fractures, loose joints, muscle weakness, deafness, spinal curvature

Severe OI Symptoms

• Occurs because type I collagen found in ligaments
• Loose joints (hypermobility)
• Flat feet
• Poor teeth
• Bowed limbs, kyphosis, and scoliosis

OI Treatment

• There is no cure for OI
• Treatments are available to manage the symptoms
• Goal: diminish fractures, enhance function, promote general health
• Involves an interdisciplinary team: primary care doctors, orthopedists, endocrinologists, geneticists, rehabilitation specialists, neurologists, pulmonologists
• Treatment options consists of fracture care, physical therapy, surgery, medication, lifestyle adjustments, and mobility aids

Healthy Lifestyle for Managing OI

• Healthy lifestyle consists of safe exercise and proper nutrition
• Adequate vitamin D and calcium, but not excessive doses
• Maintaining a healthy weight reduces stress on bones, heart, and lungs, improving mobility
• Avoid smoking, second-hand smoke, excessive alcohol/caffeine, and steroid medications to maintain bone density

Mutations in Mitochondrial Genes

• Mitochondria have their own circular DNA genome consisting of 16,569 base pairs
• Mitochondrial genetics differ due to: strictly maternal inheritance, cellular polyploidy, and a deviation from genetic code
• These features dictate functional consequences of pathogenic mtDNA mutations

Mitochondrial Genome and Function

• Human mtDNA contains 37 essential genes for normal mitochondrial function
• There are no introns in mtDNA genes
• Mitochondrial genome has a high mutation rate

Mitochondrial Inheritance

• Each human somatic cell hosts 200-1700 mitochondria
• Mitochondria divide and distribute to daughter cells
• Mitochondria pass from egg to zygote, with sperm negligibly contributing mitochondria
• All cells in an individual contain multiple copies of identical mitochondria derived from mother

Cause of Mitochondrial Disease

• Mutations in the mitochondria
• Mitochondria controlled by both mitochondrial and nuclear genomes
• Mutations within either DNA result in a respiratory chain deficiency
• Manifested in energy-demanding organs, muscle, and the nervous system
• Result in a variety of muscular and neurological disease syndromes

Mitochondrial Disease

• Develop when body's mitochondria fail
• Severely affect organ systems because of its high energy demands
• The brain, heart, liver, skeletal muscles, kidneys, endocrine and the respiratory systems require the most energy
• Includes LHON (Leber's Hereditary Optic Neuropathy) and MELAS( Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes).
• 1 in 4000 people has mitochondrial diseases

Symptoms of Mitochondrial Disease

• Poor growth
• Muscle weakness/poor coordination
• Sensory problems
• Reduced mental functions
• Organ disease
• Dementia
• Respiratory problems
• Hypoglycaemia
• Apnoea
• Lactic acidosis
• Seizures
• Gastro-intestinal disorders
• Developmental delays
• Movement disorders
• Stroke
• Diabetes
• Brain atrophy

Leber's Hereditary Optic Neuropathy (LHON)

• LHON patients go through fast, sudden, and painless vision loss in both eyes in their late teens or early 20s
• Men more commonly affected than women
• Women tend to develop the disorder later in life and be more severely affected
• Some individuals with LHON may also have a multiple sclerosis-like condition

LHON Treatment

• Currently no approved treatment or cure
• Management focuses on easing symptoms and rehabilitation
• Anecdotally, some patients self-medicate with antioxidant food supplements
• Some patients adopting a healthy lifestyle by eliminating smoking and reducing or eliminating alcohol, incorporating fresh foods and regular exercise.

LHON Mutations

• Approximately 1 in 10,000 have the mutation
• Males carrying a mutation have a 40% chance of developing symtpms while women have only 10% chance
• There are three common mtDNA mutations

Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS)

• Systemic condition
• Particularly affects nervous system and muscles
• Typical onset in the first decade of life
• Symptoms include encephalomyopathy, mitochondrial myopathy, and stroke-like episodes

MELAS Clinical Manifestations

• A wide range of clinical symptoms: diabetes mellitus, cardiomyopathy, migraines, and deafness
• 1.6 per 10,000 are affected
• The mtDNA gene MTTL1 has the most common mutation amongst MELAS patients
• Diabetes appears to be the most common manifestation

MELAS Treatment

• Various supportive measures available, but no controlled trial have shown efficacy
• Long-term benefits are still unknown
• Improvements may be related to nutritional status and hydration
• The following medications have been used: Menadione (vitamin K-3), phylloquinone (vitamin K-1), and ascorbate, Riboflavin and Nicotinamide

Other Conditions Related to mtDNA

• Cyclic vomiting syndrome
• Kearns-Sayre syndrome
• Nonsyndromic hearing loss
• Maternally inherited diabetes and deafness (MIDD)
• Neuropathy, ataxia, and retinitis pigmentosa (NARP)

Genomic Imprinting

• Responsible for cell-specific gene expression
• Most non-imprinted genes, maternal copy functionally is equivalent to the paternal copy
• Imprinted genes differ from maternal and paternal alleles
• Imprinting inactivates either maternal or paternal allele

Imprinting Selective Inactivation

• An imprinted gene is only expressed in the male/female gene
• The gene becomes haploid- one allele works

Trinucleotide Repeats

• The genes contain trinucleotide repeats, like CAGCAGCAG
• Genes have ~dozen repeats- isn't likely to create a problem
• The expansion of repeats is associated with several different diseases and expands with DNA replication
• Repeat expansions increases with cell division and successive generations with the repeats

Trinucleotide Repeats Mechanism

• The altered DNA occurs when trinucleotide repeats increase to a larger number of copies
• The gene may not work as it should
• Carrying an increased number of copies does not always alter the function
• These people are "premutation carriers."
• When they pass these mutations to their offspring, the extra repeats cause instability- those genes expand much more
• The offspring have the "full mutation." an example of a trinucleotide repeat disorder is Fragile X Syndrome
• The Fragile X Syndrome cases intellectual disability, this range from mild to severe
• Is most typical that males are more severely more affected than females, while FXS in childhood are not always specific

Fragile X Syndrome

• Males more severely impacted
• Symptoms in childhood aren't specific to the condition
• May consist of autism, Prader-Willi syndrome, or attention deficit-hyperactivity disorder (ADHD)
• No current cure

Fragile X Syndrome Causes

• FMR1 is located on X chromosome.
• CGG is repeated
• The affected sequence from FMR1 (5 to 45 trinucleotide) can cause many issues with the X chromosome adding more mutated sequence due to the X chromosome
• Premutation carriers have about 55 to 200 trinucleotide
• People with FXS full mutation have over 200 repeats.

Symptoms of Fragile X Syndrome

• Delays in motor skills
• Language delays
• Austism behavior
• Troubled memory
• Long narrow face structure
• Hyperactivity

Other Triplet Expansion Disorders

• Huntington Disease (HD)
• Spinobulbar Muscular Atrophy (SBMA)
• Spinocerebellar Ataxias
• Dentatorubro-Pallidoluysian Atrophy (DRPLA)
• Fragile XE Mental Retardation (FRAXE)
• Friedreich Ataxia (FRDA)
• Myotonic Dystrophy
• Spinocerebellar Ataxias