Diagnosis of Hereditary Diseases

What are Mendelian patterns of inheritance?

Patterns of inheritance that can be described using pedigree diagrams, including autosomal dominant, autosomal recessive, and sex-linked traits.

What types of diseases are discussed in molecular diagnostics?

Inherited diseases, their causes, and symptoms.

What laboratory methods are used to detect single-gene disorders?

Examples include genetic testing techniques designed to identify specific mutations.

What is non-Mendelian inheritance?

Inheritance patterns that do not follow Mendel's laws, including mitochondrial disorders and trinucleotide repeat expansion diseases.

How does genomic imprinting affect disease phenotype?

Genomic imprinting can influence the expression of genes based on their parental origin, affecting disease outcomes.

What are the three categories of genetic influences on diseases?

Genetic (inherited), environmental (somatic), and multifactorial (polygenic + somatic).

What is the most frequently observed transmission pattern in genetic disorders?

Autosomal recessive (AR) is the most common transmission pattern.

What is a loss of function mutation?

A mutation that usually displays a recessive phenotype and depends on the type of protein affected.

What is a gain of function mutation?

A mutation that is less common and results in new properties of the mutant allele, typically displaying a dominant phenotype.

What are dominant negative patterns?

Patterns observed when loss of function occurs in multimeric proteins, affecting the overall phenotype.

What is loss of heterozygosity (LOH)?

The loss of the normal allele, revealing the mutant allele, often due to somatic mutations or deletions.

Why are males more likely to develop X-linked recessive disorders?

Males are hemizygous for X-linked genes, meaning they have only one copy of the X chromosome.

What is the phenotype in heterozygous states for autosomal recessive disorders?

The mutant phenotype is not observed in the heterozygous (normal/mutant) state.

What is required for an abnormal phenotype to be expressed in autosomal recessive disorders?

The mutation must be homozygous (mutant/mutant) to show the abnormal phenotype.

What is the significance of X-linked mutations?

X-linked mutations are usually recessive and can lead to abnormal phenotypes in hemizygous males.

What is the role of environmental factors in genetic mutations?

Environmental factors can lead to somatic mutations that affect gene expression and disease phenotype.

What is the relationship between polygenic traits and multifactorial diseases?

Multifactorial diseases arise from the interaction of multiple genes (polygenic) and environmental factors.

What are examples of non-Mendelian inheritance?

Mitochondrial disorders and trinucleotide repeat expansion diseases.

What does variable expressivity refer to in genetics?

A single genetic mutation results in a range of phenotypes.

Define genetic heterogeneity.

The same phenotype results from mutations in different genes, including diseases with multiple genetic components.

What is penetrance in genetics?

The presence of a mutation without the predicted phenotype.

How many genetic disorders are known?

Over 4,000 genetic disorders are known, with more being discovered.

What types of cells do mutations in germ cells affect?

Mutations in germ cells result in inherited diseases.

What is the result of mutations in somatic cells?

Mutations in somatic cells can result in cancer and some congenital malformations.

What is a congenital disease?

A disease present at birth, which is not always inheritable, such as spina bifida.

Name a disorder caused by structural protein mutations.

Sickle cell anemia, Marfan syndrome, or muscular dystrophy.

What is familial hypercholesterolemia?

A disorder caused by mutations in cell surface receptor proteins.

What is phenylketonuria?

A disorder caused by mutations in enzymes.

What are lysosomal storage diseases?

Disorders resulting from incompletely digested macromolecules due to loss of enzyme function.

What is Factor V Leiden?

A mutation in the coagulation factor V gene that causes hypercoagulation and increases the risk of deep venous thrombosis.

What is hemochromatosis?

An autosomal recessive disorder that causes over-absorption of iron, leading to damage in various organs.

What is cystic fibrosis?

An autosomal recessive disease causing severe lung damage and thick, sticky secretions due to a mutation in the CFTR gene.

What is the most frequently observed mutation in cystic fibrosis?

A 3-bp deletion that removes a phenylalanine from position 508 (F508del).

What is the role of the HFE gene in iron absorption?

HFE codes for a protein that helps intestinal cells sense iron stores; its dysfunction leads to excessive iron absorption.

What diagnostic methods are used for detecting genetic mutations?

Methods include direct sequencing, PCR, and various hybridization/amplification techniques.

What is the significance of the prothrombin gene mutation?

A mutation in the prothrombin gene increases the risk of thrombosis and is tested for in labs.

What is the most common mutation in the HFE gene?

The C282Y mutation.

What are the symptoms of hemochromatosis?

Pancreas, liver, and skin damage, heart disease, and diabetes.

What is the purpose of therapeutic phlebotomy in hemochromatosis?

To reduce excess iron levels in the body.

What are cytochrome P-450 enzymes primarily involved in?

They influence steroid, amino acid, and drug metabolism.

How many reported variations of CYP-450 enzymes exist?

Over 30 reported variations.

What is the significance of CYP1A2 and the CYP2 and CYP3 families?

They are considered the most important in drug metabolism.

Where are the genes coding for cytochrome P-450 enzymes located?

Throughout the genome.

What is gonadal mosaicism?

A somatic mutation in germ-line cells (gonads).

What is genomic imprinting?

Nucleotide or histone modifications that do not change the DNA sequence.

What is nucleotide repeat expansion?

Increased allele sizes that disrupt gene function.

What is mitochondrial inheritance?

Maternal inheritance of mitochondrial genes.

What is the length of the mitochondrial DNA genome?

16,569 base pairs containing 37 genes.

What diseases can mutations in mitochondrial genes cause?

Diseases in muscle and nervous system, such as Kearns-Sayre syndrome and MELAS.

What is homoplasmy?

All mitochondria in a cell are the same.

What is heteroplasmy?

Some mitochondria are normal while others have mutations.

What is the relationship between mitochondrial mutation severity and mitochondrial distribution?

The severity of the disease phenotype depends on the amount of mutant and normal mitochondria present.

What are triple repeats in genetics?

Short tandem repeats (STRs) with 3-bp repeating units.

What is Fragile X Syndrome associated with?

CGG expansion in the noncoding region of the FMR-1 gene.

What is the genetic cause of Huntington's Disease?

A trinucleotide repeat expansion in the Huntingtin (Htt) gene.

What is the inheritance pattern of Huntington's Disease?

Autosomal dominant, requiring only one affected allele from either parent.

What are common symptoms of Huntington's Disease?

Abnormal body movements (chorea), lack of coordination, and mental decline.

What is the prevalence of Huntington's Disease in Western European descent?

Affects 1 out of 20,000 people.

What is the typical age of onset for symptoms of Huntington's Disease?

Commonly noticeable in a person's forties, but can occur at any age.

What is the full mutation threshold for Fragile X Syndrome?

More than 2000 CGG repeats.

How is the full mutation of Fragile X Syndrome detected?

Southern blot is required due to the large size of the mutation.

What is the significance of allele-specific PCR in genetic testing?

It is used to test for particular polymorphisms.

What are some disorders associated with mitochondrial mutations?

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS).

What is a trinucleotide repeat?

A sequence of three nucleotides that repeats, such as CAG, which is associated with certain genetic disorders.

What amino acid is coded by the CAG codon?

Glutamine

What is a polyglutamine (polyQ) expansion?

A condition where a sequence of 40 or more CAG repeats produces a mutated form of the protein Htt.

What is the normal form of the Htt protein associated with CAG repeats?

A sequence of fewer than 36 glutamine amino acid residues.

How does the number of CAG repeats affect Huntington's Disease (HD)?

The greater the number of CAG repeats, the earlier the onset of symptoms.

What is the inheritance probability of Huntington's Disease for children of an affected parent?

Every child has a 50% chance of inheriting the faulty copy of the gene.

What does a negative blood test for Huntington's Disease indicate?

The individual does not carry the expanded copy of the gene, will never develop symptoms, and cannot pass it on to children.

What does a positive blood test for Huntington's Disease indicate?

The individual carries the expanded copy of the gene, will develop the disease, and has a 50% chance of passing it on to children.

What is required for a full pathological diagnosis of Huntington's Disease?

A neurological examination and/or demonstration of cell loss, especially in the caudate nucleus, supported by cranial CT or MRI scan findings.

What is the role of nutrition in the treatment of Huntington's Disease?

Most HD sufferers need two to three times the calories than the average person to maintain body weight.

What is the significance of EPA in Huntington's Disease treatment?

EPA, an Omega-III fatty acid, is currently in FDA clinical trials and may slow or possibly reverse the progression of the disease.

What are some promising agents in initial experiments for treating Huntington's Disease?

Dopamine receptor blockers, creatine, CoQ10, Minocycline, exercise, antioxidant-containing foods, and antidepressants.

What is gene silencing in the context of Huntington's Disease?

A theoretical treatment approach that could halt disease progression by silencing the gene responsible for HD.

What is CCHS and its association with other conditions?

CCHS is a rare pediatric disorder characterized by inadequate breathing while asleep, often associated with Hirschsprung's disease.

What gene mutation is associated with CCHS?

A polyalanine expansion of the paired-like homeobox (PHOX2b) gene.

What is Prader-Willi Syndrome and its genetic cause?

A disorder caused by regional deletion or mutation in the paternally inherited chromosome 15, leading to symptoms like mental retardation and obesity.

What is Angelman Syndrome and its genetic cause?

A disorder caused by regional deletion or mutation in the maternally inherited chromosome 15, leading to symptoms like ataxia and seizures.

What is the role of methylation in gene silencing?

Methylation of C residues can affect phenotype without changing the DNA sequence.

What are complex traits in genetics?

Traits influenced by multiple loci and/or environmental factors, lacking a distinct inheritance pattern.

What are quantitative traits?

Complex traits with phenotypes defined by thresholds, such as obesity or diabetes.

What molecular methods can detect point mutations?

PCR, PCR-RFLP, SSP-PCR, and Southern blot.

What are non-Mendelian patterns of inheritance?

Inheritance patterns exhibited by nucleotide repeat expansions, mitochondrial mutations, gonadal mosaicism, and genomic imprinting.

What ethical concerns may arise from nonsymptomatic diagnosis?

The potential for raising ethical concerns when the disease phenotype is not yet expressed.