When was muscular dystrophy first recognized as a genetic disorder?

Answer 1

Alkaptonuria was the first identified Genetic disorder noted as following Mendelian Inheritance (by Sir Archibald Garrod in 1902). It is a rare disease: less than one in 250,000 people are affected. Many physicians will never see a patient with Alkaptonuria in their career. It is a recessive disorder, caused by a single gene defect, mapped to Chromosome 3, between regions 3q21-q23. The site of the homogentisate 1,2-dioxygenase (HGD) gene.

Alkaptonuria is a genetic disease, meaning that it is passed on by the sufferer's parents. For this to happen both parents must be a carrier of the gene that can cause Alkaptonuria. Because the gene does not always cause Alkaptonuria, people can be carriers without themselves suffering from the disease.

If both parents are carriers, the child has a one in four chance of having Alkaptonuria. This happens when the child receives the gene with the disease-causing change from both parents.

So even if both parents are carriers, there is still a 75 per cent chance that the child will not have Alkaptonuria. This would be the case if the child receives the gene that doesn't have a disease-causing change from one or both parents.

This explains the low incidence of the disease: both parents must be carriers, and both parents must pass on the gene with the disease-causing change. It also explains why one child in a family may have Alkaptonuria but their siblings may not.

What Alkaptonuria does

People with Alkaptonuria do not have enough of an enzyme called homogentisic acid oxidase. The body uses this enzyme to break down a substance called homogentisic acid. Because normal amounts of this enzyme are missing,homogentisic acid is not used and builds up in the body. Some is eliminated in the urine, but the rest is deposited in body tissues, where it accumulates at 2,000 times the normal rate.

This accumulation of homogentisic acid causes ochronosis, a blue-black discoloration of connective tissue including bone, cartilage, and skin caused by deposits of ochre-colored pigment. And because homogentisic acid is toxic, this build-up in the body tissues eventually leads to multiple and chronic health problems for Alkaptonuria sufferers.

Diagnosis and symptoms

Babies born with Alkaptonuria do not suffer any immediate ill effects. However, because of the presence in their urine of homogentisic acid, which turns a dark colour after several hours' exposure to air, parents may notice dark staining of the baby's nappies or diapers. If proper tests are then carried out, this can lead to diagnosis of the disease.

Many sufferers, however, are not diagnosed with Alkaptonuria until symptoms appear later in life, after years of accumulation of homogentisic acid in their body tissues. The onset of clinical joint disease may differ from an age of six years to an age of 60 years. Generally, there is increasing joint pain and limited and painful use of the large weight-bearing joints: knees, hips, spine and shoulders.

The main symptoms and some of the health problems caused by Alkaptonuria and ochronosis are described below.

Skeletal (bones and cartilage)

The knees, shoulders, and hips are most affected. Deposits of pigment cause cartilage to become brittle and eventually to fragment (break apart). Arthropathy (diseased joints characterised by swelling and enlarged bones) is common.

Patients suffer intense joint pain and decreased mobility. Many will have surgery to replace affected joints. Sometimes patients end up wheelchair-bound.

In general, people start complaining of Back pain in their 20s and 30s, and knee pain in their 40s. However, the onset of symptoms depends on the individual and can vary greatly. Hip and shoulder pain often occurs later, but usually by the age of 50. Many people have at least one joint replaced by age 55.

Cardiovascular (heart and blood vessels)

Heart problems often start after age 50. These include calcification of the coronary arteries (the vessels that feed the heart). The aortic and mitral heart valves -- which separate chambers of the heart -- are most affected. The build-up of homogentisic acid can cause valves to calcify or harden, leading to narrowing of the valve causing problems with blood flow. Pigment deposits also can lead to the formation of atherosclerotic plaques (hard spots in arteries) containing cholesterol and fat.

Genitourinary (genital and urinary systems and organs)

In men, the prostate is most commonly affected. Pigment deposits can form stones in the prostate.

Respiratory (organs and structures involved in breathing)

Heavy pigment deposits are common in the cartilage of the larynx (voice box), the trachea (windpipe), and the bronchi (air passages to the lungs).

Ocular (eyes)

Vision is not usually affected, but pigmentation in the white part of the eye is evident in most patients by their early 40s.

Cutaneous (skin)

Again, the age at which this becomes noticeable varies according to the individual. Effects are most noticeable in areas where the body is exposed to the sun and where sweat glands are located. Skin takes on a blue-black speckled discoloration. Sweat can actually stain clothes brown.

Pigmentation of the skin is more visible in some patients than others. It is often first seen in the ear lobe. It can also be seen in the bridge of the nose, cheeks, hands, and skin overlying tendons.

Other body systems

The teeth, central nervous system (brain and spinal cord), and endocrine organs (which make hormones) also may be affected.

Description taken from The Alkaptonuria website -

http://www.alkaptonuria.info/380158