Category Archives: Genetics

Progeria

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Progeria

Among the rarest people in the world are those with progeria, or accelerated aging disease. While leaving intelligence intact, progeria ages the body many times faster than normal, leaving teens with frail bodies of people nearing 100 years old.


First described by Dr. Jonathan Hutchinson in 1886 and Dr. Hastings Gilford in 1904.

Also known as Hutchinson-Gilford Progeria Syndrome is an extremely rare genetic disease. In this disease the aging process of the body accelerates much faster than what it does in normal humans. This process of aging gallops to about seven times the normal rate. Because of this accelerated aging, a child of ten years would have a look of 70 years old. He or she may also have similar respiratory, cardiovascular, and arthritic conditions that a 70-year-old would have.

There is no cure for this disease. The exact cause is unknown, but it is believed due to a single abnormal (mutant) gene. Normally for each gene there are two copies, one from each parent. Progeria is considered to be the result of a dominant mutation because the gene in question has one normal copy and one abnormal copy, as opposed to a recessive mutation in which both copies are abnormal. Because neither parent carries or expresses the mutation, each case is believed to represent a sporadic new mutation which happens at the time of conception.

Progeria affects between 1 in 8 million (approx.) children, with a total reported incidence of just over 100 in the century since it’s been identified. There are currently between 30 and 40 known cases worldwide of Progeria. Children from all races and cultures from around the world have been affected.

Because of the lack of a specific laboratory test at this time, the diagnosis must be based on the physical appearance of the individual. The diagnosis is usually made in the first or second year of life when skin changes and failure to gain weight become apparent.

Features

  • Dwarfism.
  • Small face and jaw in relation to size of head.
  • Delayed tooth formation.
  • Wrinkled and aged-looking skin.
  • Stiffness of joints. Hip dislocation.
  • Baldness
  • Pinched nose.
  • Mental growth is equivalent to other children of the same age.
  • Most children with Progeria live no longer than their early teenage years, though one or two have lived to be as old as 20 or 21.
  • Generalized atherosclerosis and cardiovascular problems.
  • Children suffering from this disease tend to have remarkably similar appearance in spite of being of different racial background.

Research indicates that a chemical (hyaluronic acid) may be found in greatly elevated levels in the urine of Hutchinson-Gilford Progeria Syndrome patients. The same abnormality has been found in Werner Syndrome, which is sometimes called ‘progeria of the adult’.

It is now believed that the mechanism that plays a role in the disease Progeria causing accelerated aging of those suffering from this disease may be playing a role in normal aging as well.

A study led by Dr. Francis Collins, director of the National Institute of Health, suggests aging may not simply be a gradual wearing out of cells.

 

Osteogenesis Imperfecta

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Osteogenesis Imperfecta

Synonyms:

  • Brittle Bone Disease
  • Ekman-Lobstein Disease
  • Lobstein Disease (Type I)
  • OI
  • Vrolik Disease (Type II)

OI occurs about once in every 10,000 births and the incidence is about the same worldwide.

Osteogenesis Imperfecta is a group of disease characterized by extremely fragile bones that break easily often without any apparent cause. This disease is due to the abnormality of the connective tissue and it is a genetic disorder. In most cases, the various forms of osteogenesis imperfecta are inherited as Autosomal dominant traits.

The mutation is found on the COL1A2 gene on the long arm of chromosome 7 and/or the COL1A1 gene on the long arm of chromosome 17.
Four main types of OI have been identified. OI type I is the most common and the mildest form of the disorder. OI type II is the most severe. The symptoms of OI vary greatly from case to case and even among members of the same family. A person may have just a few or several hundred fractures in a lifetime.

Some of the features seen in patients of OI are

  • Stature is may be normal in mild forms. But in severe form (Type II ) body stature is small with underdeveloped lungs.
  • Type II variety is lethal shortly after birth.
  • Loose joints and low muscle tone.
  • Tendency towards spinal curvature.
  • Brittle teeth.
  • Sclera (white of eye) has blue, purple or gray tint.
  • Hearing loss may be present starting in 20s or 30s.
  • Collagen may be normal in Type I with amount less than normal. In other types the collagen in improperly formed.
  • Triangular face.

Most cases of OI are caused by autosomal dominant genetic defect. Some children with OI inherit the disorder from a parent. Other children are born with OI even though there is no family history of the disorder. In these children, the genetic defect occurred as a spontaneous mutation. A person with OI has 50% chance of passing the disorder to his or her children.

The prognosis for this disease depends on various factors especially the severity of the symptoms. Despite disability most of the persons lead productive life.

There is no cure yet for this disease. The main management involves around managing symptoms, preventing fractures, developing optimal bone and muscle mass, maximizing mobility.

Rodding surgery is frequently used in OI patients. In this procedure metal rod is inserted through the length of long bones to prevent and correct deformities and strengthen the bones.

Persons with OI should exercise as much as possible. The best exercise is swimming and walking. It is advisable to maintain healthy weight have nutritious diet and avoid intoxicants.

Russell-Silver Syndrome

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Russell-Silver Syndrome

Russell-Silver Syndrome is a very rare genetic disorder. Most cases of Russell-Silver Syndrome are the result of new genetic changes (mutations) that occur randomly for no apparent reason. A rare form of Russell-Silver Syndrome is thought to be inherited as an X-linked dominant genetic trait.

The incidence of this disease is uncertain yet. The estimated number of people who develop this condition varies greatly. Some say it affects about 1 in 3,000 people. Other reports say it affects 1 in 100,000 people. Males and females are equally affected.

Some features seen in this syndrome : –

  • Growth delays, which starts before birth ( intrauterine growth retardation)
  • Overgrowth of one side of the body (hemihypertrophy or asymmetry)
  • Unusual characteristic facial features.
  • Affected infants may be low birth weight. Growth delays and immature bone development continue after birth.
  • Asymmetry or overgrowth of one side of the body is obvious at birth. Asymmetry may affect the head, trunk, arms, and/or legs.
  • Characteristic facial features may include a triangular-shaped face with a small, pointed chin; an abnormally prominent forehead (frontal bossing)
  • Precocious sexual development, Cryptorchidism
  • Bluish discoloration of the outer membranes covering the eyeballs (blue sclera)
  • Unusually small, wide mouth; downturned corners of the mouth; and/or an abnormally small jaw .
  • Permanent fixation of the fifth fingers in a bent position. webbing of the second and third toes. Vertebral abnormalities, Absent sacrum, Absent coccyx
  • Coffee-colored patches on the skin (cafe-au-lait spots)
  • Abnormalities of the kidney and urinary tract.
  • Hepatocellular carcinoma

Marfan syndrome

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Marfan syndrome 

Marfan syndrome is a rare hereditary disorder of connective tissue which causes connective tissue to be weaker than normal.

For people with the Marfan syndrome, weak connective tissue causes problems of the skin, muscles, ligaments, heart, eyes, blood vessels, and bones.

It is estimated that about one in 10,000 people has the Marfan syndrome.

People affected by the Marfan syndrome are most often unusually tall and slender, with particularly long arms, legs, and fingers in comparison to the rest of their body.
Symptoms may not be apparent until adulthood.

The Marfan syndrome follows a pattern of inheritance called “autosomal dominant inheritance.” “Autosomal” means the inheritance is linked to any chromosome other than those which determine the sex of the child. “Dominant” means the effects of the Marfan gene dominate or override the effects of the normal gene in the pair. Therefore, if one parent contributes the Marfan gene and one parent contributes a normal gene, the child will inherit the Marfan disorder. There is a 50% chance during each pregnancy that the affected parent will pass on the Marfan gene and the child will get the Marfan syndrome. There is, of course, also a 50% chance that the affected parent will pass on his or her normal gene, in which case the child will not get the disorder.

Symptoms of the Marfan syndrome may include one or more of the following:

  • Excessive height
  • Particularly long arms and legs, with long slender fingers and toes.
  • Nearsightedness (myopia)
  • Indented or protruding breast bone
  • Curvature of the spine (scoliosis)
  • Mild to severe heart problems
  • Excessive Height

 Eye Problems

Nearsightedness (myopia) is a common condition. It can be corrected with prescription glasses or contact lenses. Many children experience problems with the lens of the eye (the focusing structure located just behind the pupil of the eye and held in place by ligaments). The lens can become torn from its supports and become “dislocated.” This can cause vision problems that are mild or severe enough to interfere with progress in school. In rare instances, the lens may need to be removed surgically.

On rare occasions, a child may suffer a detachment of the retina (the light sensitive tissue located at the back of the eye). This causes a sudden loss of vision and requires emergency surgery.

Problems with the Spine

A child with the Marfan syndrome tend to develop defective spine. Defect in the curvature of the spine (scoliosis) is common. Removable brace to stabilize the spine may be helpful. In some cases, if the curve worsens, in spite of bracing, surgery may be recommended.

Problems with The Breast Bone

Surgery is occasionally recommended to correct an indented chest if it presses severely on the heart or lungs.

Heart Problems

Heart problems can occur because the Marfan syndrome may cause leakage of the mitral or aortic heart valves. These valves control the flow of blood through the heart. Defects of the mitral valve may cause shortness of breath, an irregular pulse, and undue tiredness. Defects of the aortic valve can lead to serious heart failure. In addition, the main artery in the body, the aorta, can become dangerously weakened and rupture.

Marfan syndrome does not affect intelligence, but that visual problems often interfere with progress in school and that may affect the child’s social and psychological adjustment

Thalassaemia

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Thalassaemia

Thalassaemia is inherent impairment of haemoglobin production due to partial or complete failure to synthesize a specific type of globin chain.

Hereditary disorders that result in a structurally abnormal hemoglobin or an insufficient quantity of hemoglobin are the most common genetic diseases of humans.

The production of hemoglobin requires a supply of iron, synthesis of heme, and synthesis of globin. Hemoglobin is essential for normal oxygen delivery by red blood cells.

When the condition is Heterozygous, the production of hemoglobin is mildly affected and the condition causes little disability. The synthesis is grossly affected when the patient is Homozygous.

In thalassaemias there is decrease in the quantity of normal globin chains in the hemoglobin. Thalassaemias are divided into the alpha thalassaemias, in which it is the production of alpha globin is deficient, and the beta thalassaemias, in which beta globin production is defective. The thalassaemias are divided clinically into Thalassaemia Minor and Thalassaemia Major, based on disease severity.

Beta-Thalassaemia

In this there is failure to synthesize beta globin chains. It is the most common type and is seen in highest frequency in the Mediterranean area. Those who are heterozygous, are thalassaemia minor, the condition is mild with mild anaemia and usually no disability. The homozygous are thalassaemia major, have profound anaemia after first 4 months of life.

Beta Thalassaemia major
Causes profound anaemia which has crippling effect on the health of the child. The child needs blood transfusion and chances for survival without transfusion for few years are low. Changes in the bone marrow (hyperplasia), results in head bossing and prominent malar eminences, which gives typical appearance of these diseases.

Development and growth of the child is retarded.
Folic acid deficiency develops.
Spleenomegaly (enlargement of spleen) is an early feature.
Cardiac enlargement with heart failure is common.

Repeated transfusions give rise to haemosiderosis (excessive deposition of iron ).

Beta Thalassaemia minor
Is detected often after treatment for mild anaemia with iron therapy fails. The condition is mild and often without any symptom.

Management of Beta Thalassaemia

  • Blood transfusion to maintain haemoglobin.
  • Bone marrow transplantation – Allogeneic bone marrow transplantation from HLA complatible sibling.
  • Folic acid 5 mg daily.
  • In case of iron overload – Desferrioxamine therapy.
  • Splenectomy performed as late as possible.

Prevention
During early in pregnancy, DNA analysis of chorionic villus material can be done to identify a fetus with homozygous beta thalassaemia. Such pregnancy can be terminated. This examination can be done if both the parents are known to be carriers (thalassaemia minor).

Alpah Thalassaemia

It is due to reduction or absence of alpha chain synthesis. This type is common in the South East Asia. There are 2 alpha gene loci on chromosome 16 are therefore four alpha genes. If one is deleted there is no clinical effect. If two are deleted there may be a mild hypochromic anaemia. If three are deleted the patient has Hemoglobin H disease. If all four are deleted the baby is still born. Treatment of Hemoglobin H is similar to beta thalassaemia of intermediate severity.

Genetic Disorders