Genetic Disorders: Causes, Classification: NEET PG Pathology (2023)

Chromosomal disorders are disorders in which entire chromosomes are affected by chromosome number or structure. Monogenic diseases/Mendelian diseases are inherited according to the Mendelian inheritance pattern, while multifactorial inheritance is a disease in which, in addition to genetic factors, environmental factors also play a very important role. Non-Mendelian disorders are disorders that do not follow typical Mendelian inheritance patterns, eg trinucleotide repeat disorders, gonadal spotting.

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Chromosomal Abnormalities:

A disorder in which the structure or number of chromosomes is altered. Chromosomes are large chunks of genetic material (humans have a total of 46 chromosomes). Chromosomes may be lost, duplicated, or changed in some way. Down syndrome: Trisomy 21 (3 copies of Chr. 21 instead of 2) and Turner syndrome: 45, XO (female with only one X chromosome)

Single Gene Disorders/Mendelian Disorders

These disorders have a typical Mendelian inheritance pattern. include:

• Autosomal dominant inheritance (no sex chromosomes involved, somatic chromosomes involved)
• autosomal recessive
• X-linked recessive
• X-linked dominant
• Y-linked disorders: very rare

non-Mendelian diseases

• trinucleotide repeat disorder
• Mitochondrial Diseases / Mitochondrial Inheritance Patterns
• 印记基因
• mosaicism

multifactorial disorder

In these diseases, in addition to genetic factors, environmental and host-related factors also play an important role. Examples include cleft lip, cleft palate, neural tube defects, diabetes, high blood pressure, etc.

Mendelian disease

Monogenic disorders following a typical Mendelian pattern of inheritance:

autosomal dominant genetic disease

Autosomal dominant disorders are those that occur even when one allele of a gene is affected (neither alleles need be affected). In a dominant disorder, one parent is also affected by the same disorder (at least one parent is affected). Examples of autosomal dominant disorders:

• hereditary spherocytosis, hypercholesterolemia
• Elles Danros team
• cartilage plate
• von Willebrand's disease
• pseudohypoparathyroidism
• Myotonic dystrophy (myotonic dystrophy)
• Osteogenesis imperfecta (most types are autosomal dominant)
• Marfan syndrome: Marfan syndrome is clinically characterized by tall stature, increased arm span, arachnids
• intermittent porphyria
• Noonan Syndrome
• Adenomatous polyposis of the large bowel (a precancerous form of colon cancer)
• Neurodermatological disorders - neurofibromatosis and tuberous sclerosis (familial)

autosomal recessive genetic disease

A disorder that occurs only when both copies/alleles of a gene are affected. The disease will only manifest itself in the child if both parents are carriers. Wilson's disease is caused by the ATP 7B gene, which is only manifested when both copies/alleles of the gene are abnormal. In this case, the parents are usually the carriers. If one parent is affected, all children will carry the disease, even if the other parent is normal. Examples of autosomal recessive disorders:

• albinism, black urine
• Beta-thalassemia: If both parents have thalassemia traits, each child has a 25% risk
• cystic fibrosis, congenital adrenal hyperplasia
• Deafness (congenital sensorineural deafness)
• emphysema caused by alpha₁antitrypsin deficiency
• Gaucher disease, galactosemia
• Homocystinuria (classic variety)
• Mucopolysaccharidosis - autosomal recessive inheritance
• Most metabolic disorders are inherited in an autosomal recessive manner.

X-linked recessive disease

These are recessive genetic disorders related to the sex chromosome (X). Tendency: Males are more affected

man woman

46、XY 46、XX

Because males have only one X chromosome, if this chromosome is abnormal, then the disease will manifest itself because there is no other normal copy of the X chromosome. Females have 2 X chromosomes, and even if one X chromosome is affected, the other X chromosome is also affected. A normal copy of the same gene on a different X chromosome. Females are usually not affected by X-linked recessive disorders. All daughters of an affected male are carriers. Since the son receives one Y chromosome from the father and one X chromosome from the mother, there is no detectable inheritance from the father to the son. Father to son excluding X-linked inheritance

Examples of X-linked recessive disorders:

• G6PD (Glucose-6-Phosphate Dehydrogenase) Deficiency: In this condition, red blood cells are easily hemolyzed, so drugs that are notorious for accelerating hemolysis should be avoided in this condition.
• Duchenne muscular dystrophy (DMD)
• Color blindness is more common in men.
• Fabry disease (lysosomal storage disorder)
• Chronic granulomatous disease (CGD - an immunodeficiency condition)
• Hemophilia A y B
• Hunter disease (MPS type 2)
• Agammaglobulinemia/Bruton disease
• Double acting
• Lesch Nyhan Syndrome: This is a self-inflicted disorder in which uric acid builds up in the body.
• Medical History: If the child is affected and has a history of the mother's siblings also having the same disorder.

When can a female exhibit X-linked recessive disorder?

Females have 2 X chromosomes, and even if 1 X chromosome is affected, there is another normal copy of the same gene on a different X chromosome. If a woman has an X-linked recessive disorder, if she has only one X chromosome, which is 45,XO, this may indicate Turner syndrome, which is 45,XO. Usually, in females, one X chromosome is randomly inactivated while the other remains active. Thus, the disease can manifest in females if the X chromosome carrying the abnormal allele remains active while the normal chromosome is inactive.

Pathology-related articles:

X-linked dominant disease

This is more common in women. The female karyotype is 46, XX. The disease manifests itself only when one of the alleles is abnormal/affected. Therefore, if one X chromosome is affected and the other is normal, the disease will continue to manifest. The male karyotype is 46, XY. The condition can be fatal if the only X chromosome in males is affected and they die in utero. All daughters of the affected man were ill, but all sons were normal. There is no father to son. The pedigree does not include X-linked inheritance, ie.

Examples of X-linked dominant disorders:

• Charcot-Marie Dental Disease - Peripheral Neuropathy, Pes cavus
• Alport syndrome (controversial)
• entitlement syndrome
• Rickets: X-linked hypophosphatemic rickets.

genealogy

Schematic diagram showing the inheritance of different genetic traits in different generations in a family.

pedigree chart

Inheritance mode:

for 1^urGenerations: When a woman is affected, all her children will be affected. 2 people^{North Dakota}Generation - A man suffers but not his children, but a woman suffers and all her children suffer. So your explanation is mitochondrial inheritance.

Inheritance mode:

Males are affected but not parents, i.e. the father of the recessive pedigree father is affected. There is no parent-child transmission, so interpretEsX-linked recessive inheritance X-linked recessive inheritance is more common in men, such as hemophilia, Duchenne muscular dystrophy and so on.

non-Mendelian diseases

trinucleotide repeat complex

These diseases are caused by an increase in the number of trinucleotide repeats above a certain threshold. The more repetitions, the greater the severity of the disease.

The "harbinger" phenomenon: In this condition, the symptoms of the disease worsen or appear at an earlier age in the offspring. This is because the number of nucleotides increases with each generation.

example

Fragile X Syndrome

The gene that causes Fragile X syndrome is the FMR-1 mental retardation gene, which is located on the X chromosome:

The premutative stage has no clinical features. In women, it is associated with premature ovarian failure. 10% of women may have intellectual disability/low IQ. It is more common in men.

• clinical manifestations
  • long face
  • big ear
  • large/protruding jaw
  • The upper jaw is highly arched.
  • hyperextended joints
  • mitral valve prolapse
  • Large testes/big testicles: observed in the adolescent age group
  • Intellectual disability (developmental delay, mental retardation)

Mitochondrial disease

All the children of a sick woman are sick. All cells in the body have a nucleus containing nuclear DNA and mitochondria containing mitochondrial DNA present in the cytoplasm.

When the sperm enters the egg, only the head of the sperm enters the egg. The sperm head contains DNA material from the father and the rest of the whole cell comes from the mother. When the zygote forms a complete egg, it comes from the mother and only the sperm head comes from the father, i.e. all the mitochondrial DNA/nuclear material comes from the baby's mother.

Heteroplasmy: presence of wild-type (normal) and mutant mtDNA in the same individual

Threshold effect: minimum percentage of mitochondrial DNA required for disease manifestation

example:

• Karnsell's syndrome
• Leber hereditary optic neuropathy
• MELAS (mitochondrial myopathy, lactic acidosis, stroke-like episodes)
• MERRF (myoclonic epilepsy, red dentate fibers)
• NARP (neuropathy, ataxia, retinitis pigmentosa)
• CPEO (chronic progressive external ophthalmoplegia)
• Pearson syndrome: bone marrow involvement, pancytopenia, pancreatic involvement

imprinted gene

This is due to the specific inactivation of certain genes by the parents. Genomic imprinting refers to changes in the DNA without any changes in the nucleotide sequence. It is the result of epigenetic phenomena. Epigenetic changes are changes in the DNA without changes in the nucleotide sequence. There are differences in gene expression depending on the parent of origin. Epigenetic changes are often the cause of DNA methylation.

Prader-Willi syndrome: it is caused by silencing or imprinting of the paternal gene

Angelman syndrome: This is caused by silencing or imprinting of the maternal gene copy.

example

Mozaika gonad

This is a condition that occurs due to mutations that occur after zygote formation, somatic cells remain intact but gonad/germ cells are affected. If the somatic cells are intact and the individual is asymptomatic, and the gonad cells are affected, many children may be affected.

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