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 expresses the traits responsible for polymorphism. These variations are heritable differences expressed by our genes and seen in various humans.

1 in 1000 newborns 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 genetic 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. There may be imcomplete penetrance, penetrance, or variable expressivity.

Consequences of this mutation include: low protein synthesis or inactive non-enzyme proteins (e.g. LDL receptors & spectrin); enhanced protein property (e.g. mutant huntingtin in Huntington disease). 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 genetic 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, and they occur in early life.

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
Friedreich 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 genetic 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.

In contrast, X-linked dominant genetic disorders are caused by dominant-disease associated alleles. Transmission occurs from an affected heterozygous female to half her sons & half her daughters. It may also occur from an affected male parent to all his daughters, without affecting the sons. E.g Vit. D-resistant rickets.

Examples include:

Duchenne muscular dystrophy
Hemophilia A & B
Bruton’s agammaglobulinemia
Wiskott-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)
Metabolic block and low amount of end product. 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 by primaquine (in Glucose 6 Phosphate Dehydrogenase G6PD deficiency).

Receptors and transport system defects result in the followings:

Cystic fibrosis: lack of cystic fibrosis transmembrane conductance regulator affects chloride ion transport.
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 normal amount of defective collagen or reduction in amount of normal collagen.
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 disorders arising from defective collagen synthesis or structure. Collagen type V, III, & lyxyl hydroxylase are affected in classical, vascular & kyphoscoliosis types respectively. Lysyl hydroxylase hydroxylates lysine residues during collagen synthesis to form hydroxylysine, which cross-links collagen fibers.

Signs and symptoms: hyperextensible skin; hypermobile joint, fragile skin vulnerable to trauma, hyperextensible thumb, diaphragmatic hernia (CLASSICAL TYPE); rupture of large arteries and colon (VASCULAR TYPE); cornea rupture, retinal detachment, & congenital scoliosis (KYPHOSCOLIOSIS TYPE);

Tay Sachs disease:

Is a lysosomal storage disease that causes GM₂ ganglioside accumulation in many tissues due to severe lack of hexosaminidase A.Gangliosides accumulate in neurons of CNS, ANS & retina, resulting in their destruction. Affects infants leading to death within 3^rd year of life.

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

Using enzyme assays & DNA-based analysis are essential for diagnosis. Disease is common among 1 in 30 Ashkenazi jews, in their carrier states. Death of affected infants occur btw age 2 to 3.

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 including hepatomegaly, splenomegaly; failure to thrive; vomiting; fever; generalized lympadenopathy; psychomotor dysfunction. Type B patients suffer mainly from organ enlargement.

Pathogenesis: lipid laden foam cells of the mononuclear phagocyte system spread widely in organs including spleen, liver e.tc.

Niemann-Pick Type C:

A very common form of Niemann-Pick disease arising from deficient lipid transport protein, for transport of metabolites out of lysosomes to cytoplasm. This results in cholesterol & gangliosides accumulation in lysosomes.

Signs and symptoms: In childhood it presents as muscle dystonia; psychomotor regression; dysarthria, ataxia, vertical supranuclear gaze palsy. Others may include hydrops fetalis, stillbirth, & neonatal hepatitis.

Gaucher disease:

A lysosomal storage disorder that results from a reduction (in type 1 form) or deficiency (in type 2) of glucocerebrosidase. This leads to the accumulation of glucocerebrosides in phagocytes throughout the body, except brain (in type 1) or particularly the brain (in type 2).

Type 1-chronic form affects Ashkenazi jews, while type 2-infantile form doesn’t. Type 3 is the intermediate form. Glycorerebroside is a glycoprotein obtained from cell membranes of senescent erythrocytes or leukocytes.

Signs and symptoms: In type 1 form hepatosplenomegaly, thrombocytopenia, pancytopenia, bone pain and pathologic fracture. In type 2/3 forms there is CNS dysfunction; convulsion; mental deterioration; hepatosplenomegaly; death (especially in type 2). CNS symptoms in type 2 begin in infanthood, while in type 3 they start in early adulthood.

Hurler syndrome

Hurler syndrome MPS-I is a severe form of mucopolysaccharidoses (MPS) deficient of α-L-iduronidase. It affects infants. Lack of this enzyme causes accumulation of mucopolysaccharides (glycosaminoglycans) in cells & tissue organs.

The cells/tissue organs include; macrophages; endothelial cells; fibroblast; spleen; blood vessels; bone marrow; lymph nodes; heart & intimal smooth muscle cells.

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

Pompe disease

This a glycogen storage disease that arises from deficiency of acid maltase (α- glucosidase), a lysosomal enzyme. A deficiency results in lysosomal glycogen accumulation in many organs.

Clinical manifestations: cardiomegaly (commonly noticeable); organ failure and death in early life.

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 spaced nipples; peripheral edema at birth.

Other genetic mutations

Fragile X syndrome: This is a predominantly X-linked dominant disease that affects males than females. In this disease, there is a large expansion of CGG repeats (200-4000).

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: This results from a deletion of paternally active allele on chromosome 15q.

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

Angelman syndrome: This results from a deletion of maternally active allele on chromosome 15q.

Clinical manifestations: mental retardation; ataxia and inappropriate laughter.