"Complex Genetic Disorders Notes"

Complex Genetic Disorders

Multifactorial Complex Disorders

• Generally arise later in life.
• Divided into 3 categories:
  • Dichotomous (binary traits): A person is either affected or unaffected.
  • Several classes of phenotype: Measured using metric values; referred to as Meristic Traits.
  • Continuous: No discrete measurable meristic traits are observed.

Quantitative Traits

• The overall phenotype depends on the value of the Meristic trait.
• Individuals may have a mutation, but the effect may be below a THRESHOLD, affecting whether the person is affected or not.
• Genes of this nature are referred to as Quantitative Trait Loci (QTL).

Binary and Continuous Traits

• More alleles mean more possible combinations, even more possible genotypes ultimately reaching a Gaussian distribution.

Falconer's Polygenic Threshold Model

• For dichotomous non-Mendelian characters.
• Liability to the condition is polygenic and normally distributed (upper curve).
• People whose liability is above a certain threshold value are affected.
• Their siblings (lower curve) have a higher average liability than the population mean, and a greater proportion of them have a liability exceeding the threshold.
• Therefore, the condition tends to run in families.

Locating QTLs

• Case-control association studies: Non-random occurrence between alleles and phenotypic traits using candidate genes.
  • Mostly SNPs are used for these studies to test for association.
• Genome Scans: An unbiased approach to find genes that may be causal to a phenotypic trait.
  • Mostly a set of polymorphic markers (tandem repeats like microsatellite DNAs) are used.
• Other tests:
  • Linkage disequilibrium test
  • Affected Sib pair linkage analysis

Neural Tube Defects (NTDs)

• Developmental defects in neural tube development during early embryonic development.
• Nutritional disorders: Problems with folate metabolism.
• Genetic causes: From genome-wide studies, chromosomes 2, 7, and 10 are identified as harboring candidate risk loci for spina bifida.

Developmental Defects in NTDs

• Normally, the embryo goes through a very rapid phase of cell differentiation (formation of different cell types) and morphogenesis (movement and spread of cells to achieve certain shapes) in the first 28 days post-fertilization.

Stages of Early Embryonic Development: Week 1-2

• Includes stages such as the development of the ovarian follicle, menstrual phase, ovulation, fertilization, zygote division, morula, and the formation of the blastocyst.

Stages of Early Embryonic Development: Week 3-6

• Beginning of Neural tube development: Primitive streak
• Includes stages such as the formation of the trilaminar embryo, neural plate, neural groove, somites, and the development of various organs and structures.

Stages of Fetal Development: Week 11-38

• Rapid growth and expansion of all cell types (very high Mitotic load).
• Covers the period from the eleventh week to full term.

What Happens During NTD?

• During neurulation (formation of the neural tube and neural plate), the neural tube starts to close from the cranial and caudal direction until a small opening is left on both ends.
• This establishes a blood vascular system from the brain to the developing spinal cord.
• Currently, 5 sites of closure are thought to be involved in neural tube closure.
• Failure to fuse/close at site 1 leads to Spina bifida cystica (NTD).

What is Spina Bifida?

• A midline defect of the bone, skin, spinal column, and/or spinal cord.

Myelomeningocele

• Lumbosacral presentation of Spina Bifida.
• Types:
  • Mild
  • Moderate
  • Severe
• Spina Bifida Cystica
• Spina Bifida Occulta (hidden)
  • With myeloschisis - No lumbar deficits
  • Both muscular and neural tissues displaced
  • Spinal cord exposed
  • Defect hidden under the tuft of hair because the neural folds failed to fuse at week 4 of development.

Severity of Spina Bifida

• Depends on the extent of the defect in spinal cord displacement.
• Motor and neurologic deficits are proportional to the severity.

Incidence and Prevalence

• Incidence: 1/1000
• Prevalence:
  • Increased incidence in families of Celtic and Irish heritage (genetic or environmental?)
  • Increased incidence in minorities (genetic or environmental?)

Risk Factors for Spina Bifida

• Folic acid deficiency: Lack of folic acid increases the risk of spina bifida and other neural tube defects.
• Some medications: Anti-seizure medications, such as valproic acid (Depakene), seem to cause neural tube defects when taken during pregnancy, perhaps because they interfere with the body's ability to use folic acid.
• Diabetes: The risk of spina bifida increases with diabetes, especially when the mother's blood sugar is elevated early in her pregnancy. Much of this risk is preventable by careful blood sugar control and management.
• Obesity: There's a link between pre-pregnancy obesity and neural tube birth defects, including spina bifida. Obese women may have more babies with spina bifida possibly because of nutritional deficits from poor eating habits or because they may have diabetes.

Diagnosis and Detection

• Amniocentesis AFP - indication of abnormal leakage
• Blood test Maternal blood samples of AFP
• Ultrasonography For locating back lesion vs. cranial signs

Differential Diagnosis

• Of Aneuploidies versus NTDs by Triple screening

  Anomaly	AFP	hCG	UE3
  NTDs	Increased	Normal	Normal
  Trisomy 21	Decreased	Increased	Decreased
  Trisomy 18	Decreased	Decreased	Decreased

• NTDs = neural tube defects; AFP = alpha-fetoprotein; hCG = human chorionic gonadotropin; uE3 = unconjugated estriol.

Prognosis

• Spina bifida is a static, non-progressive defect with worsening from secondary problems.
• The prognosis for a normal life span is generally good for a child with good health habits and a supportive family/caregiver.

Impairments Associated with Spina Bifida

• Physiological changes below the level of the lesion generally include:
  • abnormal nerve conduction, resulting in: somatosensory losses, motor paralysis, including loss of bowel and bladder control changes in muscle tone (flaccid to normal to spastic)
• Anatomical changes below the level of lesion:
  • musculoskeletal deformities (scoliosis) joint and extremity deformities (joint contractures, club foot, hip subluxations, diminished growth of non-weight bearing limbs) osteoporosis abnormal or damaged nerve tissue

Medical Management

• Surgical closure of back lesion 24-48 hrs after birth with shunt insertion within 6 months
• In-utero surgery to repair the NTD

In-Utero Surgery

• For Repairing myelomeningocele.

Summary of In-Utero Surgery

• Prenatal surgery for myelomeningocele reduces the need for a shunt or death and improves motor outcomes at 30 months but is associated with maternal and fetal risks

Epidemiological Studies

• Have identified risk factors for NTDs
  • Among environmental factors, folate status plays a key role in determining NTD risk
  • Genetic factors in the causation of NTDs indicate that folate-related genes could be NTD candidate genes genes involved in the one carbon metabolism
  • Nutritional disorders-

Significances of Nucleotides

• Precursors for DNA and RNA synthesis
• Essential carriers of chemical energy, especially ATP
• Components of the cofactors NAD+, FAD, and coenzyme A
• Formation of activated intermediates such as UDP-glucose and CDP-diacylglycerol.
• cAMP and cGMP, are also cellular second messengers.

Degradation of Nucleic Acid

• Nucleoprotein breaks down into Nucleic acid and Protein, then Nucleic acid degrades to Nucleotide which becomes Nucleoside and eventually broken down into Base and Ribose.

Ribonucleotide Synthesis

• Begins with ribose 5-phosphate converted to PRPP (5-phosphoribosyl-1-pyrophosphate), which involves glutamine, glycine,