How to identify the implications of genetic disorders

The human gene and genetic disorders

The human gene is a complex structure through which all human traits can be confirmed. The study of genetics has made us understand the source of our identity and variations among humans. About 0.5% of our DNA epresses the traits responsible for polymorphysm. These variations are heritable differences expressed by our genes and seen in various humans.

1 in 1000 newborn develop various chromosomal abnormalities. These abnormalities are because of morphological and numerical changes seen in autosomal and sex chromosomes. Every 5 in 100 young adults below 25 years has illnesses that arise from genetic disorders from single gene mutation.

Mutations are abnormal changes that affect the DNA sequences of single gene. These mutations can occur in germ cells or somatic cells. Mutations in gametes are inherited by the offspring. Somatic cell mutations lead to cancer or congenital changes. Types of mutations include: autosomal dominant disorder; autosomal recessive disorder; X-linked disorder.

Autosomal dominant disorders

These disorders are expressed in their heterozygote states (Tt). Females and males are equally affected. An offspring has 1 in 2 chances of being affected. Consequences of this mutation include: lower productive capacity of genes; absent or inactive non-enzyme proteins; enhanced protein property. Examples include:

Huntington disease
Neurofibromatosis
Tuberous sclerosis
Myotonic dystrophy
Polycystic kidney disease
Familial polyposis coli
Hereditary spherocytosis
Von Willbrond disease
Achondroplasia
Osteogenesis imperfecta
Acute intermittent porphyria
Classical Ehlers-Danlos syndrome (type I/II)
Marfan’s syndrome

Autosomal recessive disorders

Male and female parents have traits of the disease (Tt x Tt), and are unaffected. The disease expresses itself in a homozygous recessive state (tt). Offsprings have 25% chances of having the disease. Consequence of this mutation: absence of enzyme proteins; abnormal or absent transport proteins.

Examples include:

Cystic fibrosis
Homocystinuria
Galactosemia
Sickle cell disease
Thalassemias
Wilson disease
Hemochromatosis
α-1 antitrypsin deficiency
Alkaptonuria
Freidrich ataxia
Neurogenic muscular atrophies
Spinal muscular atrophy
Phenylketonuria
Glycogen storage diseases
Lysosomal storage diseases
Ehlers-Danlos syndrome (type 6) (Kyphoscoliosis)
Congenital adrenal hyperplasia
Albinism

X-linked recessive disorders

They are a group of disorders that can be transmitted through mutated sex chromosome, X. These disorders express commonly in males, and daughters are carriers from father with the disease.

Examples include:

Duchenne muscular dystrophy
Hemophilia A & B
Bruton’s agammaglobulinemia
Wiskot-Aldrich syndrome
Glucose-6 phosphate dehydrogenase
Lesch-Nyhan syndrome
Diabetes insipidus
Chronic granulomatous disease
Hunter syndrome (MPS type II)

Enzyme defects result in the followings:

Toxic substance accumulation in tissues. An example is in galactosemia (deficient galactose-1-phosphate uridyltransferase)
Insoluble macromolecules accumulate in lysosome vacuoles. An example is lysosomal storage diseases (deficient lysosomal enzymes)
Final product abscence. An example is in albinism (lack of tyrosinase causes deficient melanin)
Destruction of tissues. An example is in lung emphysema (deficient inhibitory action of α-1 antitrypsin on neutrophil elastase)
Drug-induced hemolytic anemia (deficient Glucose 6 Phosphate Dehydrogenase G6PD)

Receptors and transport system defects result in the followings:

Cystic fibrosis: lack of cystic fibrosis transmembrane conductance regulator
Familial Hypercholesterolemia: Lack of Low-Density Lipoprotein Receptor to transport cholesterol intracellularly.

Defects to the structure & quantity of non-enzyme proteins cause the followings:

Sickle cell disease: results from abnormal change in structure & function of β-globin chain.
Osteogenesis imperfecta: results from abnormal changes in the structures of collagen fiber.
Hereditary spherocytosis: Results from abnormal changes in the structure of spectrin molecules.
Muscular dystrophies: This results from abnormal changes in the structure of the dystrophin molecule.
Thalassemias: A reduction in amount of structurally normal α/β globin chain leads to thalassemia.

We shall discuss about selected examples of gene mutation next:

Marfan syndrome

This is a connective tissue disorder arising from abnormal fibrillin-1 synthesis. its prevalence is 1 in 5000 in the population.

Signs & symptoms include: too tall; long extremities; long fingers, toes; hyperextensible thumb; pigeon breast deformity; pectus excavatum; bilateral lens dislocation (ectopia lentis); dilation of ascending aorta; aortic dissection.

Ehlers-Danlos syndromes:

This is a heterogenous group of disorder arising from defective collagen synthesis.

Signs and symptoms: hyperextensible skin; hypermobile joint; fragile skin vulnerable to trauma; hyperextensible thumb; diaphragmatic hernia; rupture of large arteries and colon; cornea and retinal detachment; kyphoscoliosis.

Tay Sachs disease:

Is a lysosomal storage disease resulting from lack of hexosaminidase α- subunit. Affects 1 in 30 Ashkenazi jews. Gangliosides accumulate in tissues like CNS neurons. Affects infants leading to death within 3^rd year of life.

Signs and symptoms: motor incoordination; reduction in alertness; motor and mental deterioration; muscular flaccidity; cheery-red spot of eye macula; blindness.

Niemann-Pick disease (Type A & B):

This is a lysosomal storage disorder in which sphingomyelin accumulates in tissue lysosomes. This accumulation arises from deficient sphingomyelinase. Type A affects infants and can result in death within 3 years of life. Type B patients do survive into adulthood. Both affect Ashkenazi jews.

Signs and symptoms: For Type A, there is extensive neurologic damage; organ enlargement. Example splenomegaly. Type B patients suffer mainly from organ enlargement.

Niemann-Pick Type C:

A very common form of Niemann-Pick disease arising from deficient lipid transport protein. This results in cholesterol accumulation in lysosome.

Sings and symptoms: In childhood it presents as muscle dystonia; psychomotor regression; dysarthria, ataxia, vertical supranuclear gaze palsy. Complication of hydrops fetalis, stillbirth in fetus.

Gaucher disease:

A lysosomal storage disorder that occurs in phagocytic cells of tissues. A deficiency or reduction of glucocerebrosidase leads to accumulation of glucocerebrosides in tissues. Type 1 form affects Ashkenazi jews. Type 2/3 forms don’t.

Signs and symptoms: In type 1 form hepatosplenomegaly, thrombocytopenia, pancytopenia, bone pain and pathologic fracture. Type 2/3 forms affect CNS resulting in convulsion; mental deterioration; hepatosplenomegaly; death. CNS symptoms in Type 2 begins in infanthood. Type 3 CNS symptoms starts in early adulthood.

Hurler syndrome

Hurler syndrome MPS-I is a severe form of mucopolysaccharidoses (MPS) deficient of α-1-iduronidase. It affects infants. Lack of this causes accumulation of mucopolysaccharides in macrophages, endothelial cells, fibroblast, & intimal smooth muscle cells of organ tissues.

Signs and symptoms: Coarse facial features; mental retardation; joint stiffness; clouding of cornea; hepatosplenomegaly; cardiovascular complications, & death.

Pompe disease

This a lysosomal storage disease that results is glycogenosis in tissues. Glycogen accumulates in tissue lysosomes arising from deficiency in acid maltase, resulting in organ failure and dearth in early life. Cardiomegaly is a noticeable feature.

Autosomal chromosomal disorders

These disorders include: Edward syndrome trisomy 18, Patau syndrome trisomy 13, and Down syndrome trisomy 21.

Down syndrome trisomy 21: With female karyotype 47, XX, +21, this presents as Epicanthic folds with flat facial profile; abundant neck skin; simian crease on palm; hypotonia; umbilical hernia; intestinal stenosis; gap between first and second toe; acute leukemia; congenital heart defects. There is an incidence of 1 in 700 births, and an average life expectancy of 47 years.

Patau syndrome, trisomy 13: With female karyotype 47, XX, +13, this presents as cleft palate; rocker-bottom feet; microphthalmia; polydactyly; microcephaly; mental retardation; congenital heart defects; renal defects; umbilical hernia. There is an incidence of 1 in 15000 births, with an average life expectancy of 1 year.

Edward syndrome, trisomy 18: With male karyotype 47, XY, +18, this presents as: micrognathia; prominent occiput; lower ears; short neck; overlapping fingers; rocker-bottom feet; mental retardation; congenital heart defects; renal defects; There is an incidence of 1 in 8000 births, with an average life expectancy of 1 year.

Sex chromosome disorders:

Klinefelter syndrome: This is a common cause of hypogonadism in male, with a karyotype 47, XXY. It has an incidence of 1 in 1 in 660 male births.

Clinical manifestations include: abnormally long legs, elongated body; mitral valve prolapse; lower IQ; small testes and penis; lack of pubic hair, deep voice & beard; gynecomastia; type 2 diabetes; higher breast cancer risk.

Turner syndrome: The cause of hypogonadism in females, with karyotype 45, X. It has an incidence of 1 in 3000 female births.

Clinical manifestations include: webbed neck; low posterior hairline; short stature; loss of oocytes and infertility; amenorrhea; pigmented nervi (skin moles); coarctation of aorta; cubitus valgus; broad chest and widely shaped nipples; peripheral edema at birth.

Other genenetic mutations

Fragile X syndrome: This is an X-linked disease which can be recessive or dominant depending on male or female transmission. In this disease, there is a long repeating sequence of three nucleotides. This frequently affects males compared to females.

Clinical manifestations include: mental retardation; low IQ; large testes; long face with large mandible; large everted ears; high arched palate; mitral valve prolapse.

Prader Willi syndrome: There is a point mutation in paternal allele and deletion, leading to 2 copies of maternal autosomal chromosomes.

Clinical manifestations include: mental retardation; short stature; intense hyperphagia; hypogonadism; small hands and feet; obesity.

Angelman syndrome: A point mutation in maternal allele causes its deletion, resulting in double paternal autosomal chromosomes.

Clinical manifestations: mental retardation; ataxia and inappropriate laughter.