Muscular Dystrophy

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

Duchenne muscular dystrophy (DMD) is a severe recessive X-linked form of muscular dystrophy characterized by rapid progression of muscle degeneration, eventually leading to loss of ambulation and death. This affliction affects one in 3500 males, making it the most prevalent of muscular dystrophies.

Duchenne Muscular Dystrophy is an X chromosome-linked, inherited, progressive, muscle wasting disease, which affects approximately one out of 3,500 male children.

For explaining the nature of Duchenne Muscular Dystrophy (DMD), we might start with the chromosomes.

Chromosomes are specifically folded DNA molecules. We speak of chromosomes rather than DNA, because in this form the DNA molecules are visible under the microscope, therefore, distinguishable from each other.

In normal circumstances we have 46 nuclear chromosomes. In certain conditions, such as cancer (for example in cancerous 'HeLa cells'), the number of chromosomes could be different. The 46 chromosomes include 2 sex chromosomes as well. We inherit 23 nuclear chromosomes (22 plus 1 sex chromosome) from each of our parent.

Females have two X chromosomes (XX), males have one X and one Y (XY). They each contribute one to their child. Since the mother has two X-es, she passes down one X, therefore the father's chromosomes decides the child's sex.

Duchenne muscular dystrophy arises from the mother's defective sex chromosome. The disease is a recessive trait, meaning only one of the mothers' two XX sex chromosomes is defective and the other X chromosome is able to compensate.

For this reason, if she passes the disease-carrying chromosome to her daughter, the daughter's disease-free paternal X chromosome would compensate. The girl will carry, and potentially be able to pass, the faulty chromosome to her child/children, but, she, herself, will not be at all, or just mildly, affected.

If, however, her son gets the disease-carrying chromosome, he will not have that opportunity; due to his Y chromosome from his father, he cannot compensate. Unfortunately, he will get the full-blown disease.

While the majority of the disease are inherited from the mother, as detailed above, 'spontaneous mutations', when the damage to the gene happens in the male child, is also possible.

So, what is the role of the X chromosome in that disease?

The long DNA molecules, therefore their tightly packed forms, the chromosomes, have specific areas, called 'genes'. Every chromosome has its 'own' specific genes on their 'own' specific areas. Those genes have the 'blueprints', the instructions, for the body to build proteins. Proteins are compounds, specific substances, which are essential to life; they are vital for every function, feature, and aspects of the body.

If a gene is faulty, inherited from either or both parents, (Duchenne muscular dystrophy is inherited only from the mother), or damaged/changed by environmental factors (like radiation, chemicals, or others), also by life style (smoking for example), then it cannot provide a correct instruction to assemble a properly working protein.

The fault arise from mistakes in the instruction; some parts are missing, others are repeated, and some are changed. It is like someone is building a cupboard. If the instruction gives the wrong dimensions for some parts or even omit some others parts, then it would be impossible to build a proper cupboard.

Neither can the body assemble the protein, called 'dystrophin', from the improper instruction given by the defective Dystrophin gene of the X-chromosome.

Dystrophin is a muscle protein with mechanical and protective functions. It might involve in cell to cell communications, as well. Due to the lack of dystrophin protein the muscles became weaker, damage easily, and gradually break down, waste away.

Symptoms (difficulty in sitting unaided, delayed start for walking, frequent stumbling and falling, difficulty in getting up, for example), could start to appear as early as one year of age, and the disease quickly progresses to the stage when the child needs a wheelchair (around 8-12 years of age).

Since the disease weakens not only the skeletal muscles, but all muscles, heart rhythm and the pumping ability of the heart are also affected. Likewise, breathing becomes difficult and needs assistance as the disease progresses to those involved muscles.

Lifespan, unfortunately, is not expected to extend beyond 30 years. Cure is not possible at the present.

Treatments are aimed to delay the wastage, steroid medication (with Vitamin D and calcium supplement to counteract its possible bone weakening side-effect), physiotherapy, and water exercises, possibility of low frequency electrical muscle stimulation, among others.

Improving the quality of the patients' life includes corrective bone surgery (bone deformities occurs frequently) to improve posture and comfort, braces, use of wheelchair (manual then electric), heart medications/treatments, assistance with breathing (ventilator, masks, others), - education/information/help to parents and carers, for example.

Research is ongoing, internationally, on several possible aspects; a few examples are:

· 'Gene bandage', specifically designed for the protein assembling process to 'skip over' the faulty segment of the gene, enabling the production of dystrophin,

· Implantation of stem cells,

· 'utrophin-based therapy', Utrophin is another muscle protein with similar function. Research going on to use it for compensate for the lack of dystrophin,

· Researching a drug (recently trialled in Diabetes Type 2 research, as well), which, also, could increase the level of HSP72 (a specific protein). HSP72 expected to improve muscle function, decrease muscle break down, and increase lifespan by 20 %,

· and an older research into low frequency electrical muscle stimulation.

There is no known cure for muscular dystrophy, although Eastern philosophies believe that humans can heal many illnesses and conditions by "balancing" the body.

In Muscular Dystrophy, prolonged inactivity (such as bed rest and even sitting for long periods) can worsen the disease. Physical therapy, occupational therapy, orthotic intervention (e.g., ankle-foot orthosis), speech therapy and orthopedic instruments (e.g., wheelchairs and standing frames) may be helpful.

Occupational therapy assists the individual with MD in engaging in his/her activities of daily living (self-feeding, self-care activities, etc.) and leisure activities at the most independent level possible