Metachromatic Leukodystrophy (MLD) is a genetic disease where the lysosomes1 of the cell don't store materials correctly, resulting in an abnormal accumulation of lipids2, which causes progressive deterioration of motor control and neurological functioning.
To further classify MLD, it is both autosomal3 and recessive4.
Cause and Effect
The cause of MLD is well known: the gene that tells the body how to make an important enzyme, arylsulphatase A (ASA), is defective in some manner. ASA is the enzyme that is responsible for the breakdown of sulphatides5. ASA is normally stored in the lysosome inside the cell, which is why MLD is a lysosomal disease.
The process by which ASA breaks down sulphatides is called hydrolysis6. During hydrolysis, cerebroside sulphatide is normally transformed to form a chemical known as galactocerebroside (GalC)7. GalC, under normal circumstances, is then broken down further by other enzymes or reused in other areas of the body. If the GalC is not properly broken down, it begins to build up, and the brain experiences very severe problems8. Two other sulphatides also begin to build up in the body (Galactosyl sulphatide and lactosyl sulphatide). When these sulphatides build up, a problematic process begins, called demyelination. The symptoms of MLD are the effects of demyelination
Perhaps the best way to understand demyelination is using an electrical analogy.
There are thousands of 'wires' in the brain called axons. These axons carry the electrical impulses we call 'thoughts' from one end of the brain to the other. Also, like normal wires, the axons have insulation. As in electrical wires, this insulation, called a 'myelin sheath' protects the electrical charge inside of the axon from escaping, and protects the areas around the axons from being shocked. Unfortunately for people with MLD, sulphatides break down both the myelin sheath and the cells that make myelin. This is called 'demyelination', and because the sulphatides which cause this condition are not broken down by the ASA enzyme, they are free to affect all the myelin they want. That is a bad thing.
As soon as the axons lose their myelin coating, they begin to short circuit. This hurts some areas of the brain that are not used, due to the extra voltage, and it also stops messages from getting where they're supposed to go. This is what causes all of the symptoms of MLD.
How Do You Know If You Have It?
The only way to tell if someone has MLD (other than gene therapy), is to look for symptoms. MLD occurs in three forms: Late Infantile, Juvenile, and Adult. These types are known as Type I, Type II, and Type III, respectively. The most debilitating type of MLD is Type I, Late Infantile Form.
Type I MLD
In Type I MLD, normal development of the child usually occurs until 12 to 18 months. In some rare cases, developmental delays can occur before 12 months, however it is not a common occurrence. After 12 to 18 months, serious developmental delays begin to take place. By the end of the second year, or 24 months, the regression becomes progressively more rapid.
The first growth delays occur in gross motor control, which is the control of major muscle groups. This is usually characterized by weakness in the major muscle groups, along with hypotonia. Hypotonia is a condition in which muscle cells lose their osmotic9 pressure, and essentially become useless, as muscle tone is lost. Hypotonia also affects the eye muscles, and can cause severe eye conditions to develop. Common conditions include nystagmus, or eye spasms, discoloration of the macula in the eye, and even blindness. Symptoms of hypotonia include a stagger while walking, if walking is possible for the child, and hyperextensions of the knee. Along with hypotonia, severe speech problems also appear. Many speech skills are lost, or never gained.
Two conditions, aphasia and dysarthria, are very common in these cases. Aphasia, the inability to express oneself verbally, can stem from either sensory or motor areas. If both sensory and motor areas are involved, the condition is then called 'complete' aphasia. Dysarthria is the lack of sufficient control over the tongue. This problem comes from a breakdown in communication between the brain and the tongue, and can easily happen if the myelin coating on the brain's axons is removed. Both of these conditions result in an inability to speak, or even to make noises in some cases. Many other symptoms also manifest themselves in a child, such as an inability to swallow, muscle spasms, and irritability. The final, and possibly the least obvious of the symptoms of MLD in infants is a mental regression. Because of the limited number of mental achievements apparent in an infant, it is hard to gauge exactly when a child goes into mental regression. Infants, in the first place, do not have the communication skills necessary to show a parent that they are experiencing mental frustrations, and these severe mental retardations are often hard to differentiate from slow development in a child. Eventually, however, the symptoms become more apparent as the child regresses into a total loss of all meaningful contact with the world around it. The prognosis of these cases is not good; death normally occurs within the first decade, typically two to four years after the original diagnosis.
Type II MLD
The second type of MLD, Type II, is the juvenile form of the disease. Type II MLD becomes apparent anywhere from the age of four to the age of twelve. There are many more obvious signs of MLD in Type II than in Type I, making it a much easier disease to diagnose. The most obvious of these manifestations of the disease is a loss of developmental milestones at the end of the child's first ten years. These are apparent to the child in question, although the parents may not realise the implication of these symptoms simply through a lack of communication. Also, a child may not even realise that this is happening because the child would not know what to look for.
There are many other symptoms of MLD, though, that may make the condition more obvious to both the parent and the child. Again, a stagger may develop in the child's gait. Many cognitive problems begin to occur as well, including daydreaming, abnormal behaviour, emotional difficulties, and eventual mental deterioration. These things, however, could be rationalised to be an abnormal growth pattern common in teenagers and developing children, rather than actual medical conditions, as children do not generally realise the implications of these symptoms until they have progressed to a more advanced stage and have become more noticeable to their parents. There are, however, other symptoms which are more easily recognisable.
Losses in the muscle tone and degradations of the general condition of the major muscle groups will become noticeable, along with eye problems related to hypertonic muscle conditions, as in Type I MLD. Thus, the child could experience spasms of the major muscle groups and in the eyes, with the possibility of the onset of blindness. Seizures also may become common, along with urinary incontinence and possible pseudobulbar palsy, which is a type of paralysis resulting from lesions10 in the cortical centres11 of the brain. The prognosis for this type of MLD is better than Type I, but not by much. Death in Type II cases normally occurs in the second decade, typically four to six years after the original diagnosis.
Type III MLD
Type III MLD is the adult form of the disease. Unlike Type II, all of the normal events of puberty occur without incident. Development is normal throughout most of the first two decades of life.
After puberty, though, changes may begin to occur. Behavioural patterns start to deteriorate, involving personality and work attitude changes. The sufferer may become apathetic, anxious, or constantly frightened. Emotional instability may occur, resulting in abrupt mood swings, and the sufferer may also be affected by psychosis, which is the total loss of connection with reality and self. Work or school performance may recess rapidly, as mental alertness decreases and cognitive abilities diminish. Thinking may become disorganised, hand-eye coordination may suffer, and all visual-spatial discrimination may be thrown off. The most noticeable loss in cognitive abilities is a decreased memory span, and a generally poor memory, causing absent-mindedness.
Some other very serious effects can also occur in Type III MLD that would not take place in the other forms of MLD. Due to the adult atmosphere of the world of a Type III MLD victim, inappropriate manners may be seen when dealing with a superior, causing a degradation of lifestyle through loss of a job, or demotion to a worse job. Also, alcoholism may manifest itself in a Type III patient. This is especially dangerous, as thought processes and spatial analysis are already poor in such a person, and these conditions are only inflamed by the MLD.
Many physical symptoms also take effect in Type III MLD. Loss of gross motor control is seen, as in the other two types of MLD. However, loss of gross motor control is much more obvious in an adult than in an infant who cannot walk or a teenager who is dealing with a growing body. The same decreased muscle tone and possible loss of sight is evident here as in the other types of MLD, along with a possible paralysis due to loss of all muscle control. In Type III more than in the other types, general seizures are apparent, and come along with generalised dysfunctions in peripheral nerves. In some cases, loss of control over the eye muscles also occurs, along with atrophy of the eye, which can result in blindness in the individual.
Is It Curable?
It is obvious that Metachromatic Leukodystrophy is a very severe and deadly disease. As such, scientists and doctors are now working to find a cure for the symptoms of MLD. Since MLD is a genetic disease, it cannot be cured at the root. Instead, the symptoms of this disease must be corrected in order for the victim to overcome the debilitating effects it causes.
Stem Cell Transplants
One possible method of treatment being examined is stem cell transplantation. A study has been done in which people under 17 with MLD, along with other similar types of genetic diseases, receive stem cell transplants. The stem cells are transplanted into the bone marrow with the hope that they will reproduce and replace the defective or nonexistent gene in MLD thus telling the body to produce ASA. As of this time, the results of this testing have not been released - so its effects on the symptoms of MLD are widely unknown. Also, it is unknown whether or not this type of treatment would even be possible under new laws passed by the US government that forbid most stem cell research. Because of its status as a stem cell treatment plan, there is great opposition to this method from groups who support 'higher' ethics and morality in the medical field, and so we may never see stem cell transplantation become a common way of treating MLD.
Bone Marrow Transplant
Another method of treatment being explored for MLD symptoms is using bone marrow transplant. This is very similar to stem cell replacement, except that the material being replaced is bone marrow instead of stem cells. Bone marrow transplant is the only reliable method of treating the symptoms of MLD in actual use today. Bone marrow transplants, or BMTs, replace existing bone marrow that does not have the gene that produces ASA with marrow that does have this gene. This does not even come close to stopping the onset of MLD, however. BMTs only serve to delay the onset of some advanced conditions in MLD, and do not reverse any of the damage that has already been done to the brain, liver, kidneys, or nerves.
BMTs are also very dangerous in themselves. The chance of death while undergoing BMT therapy is relatively high, but not certain - as it is with untreated MLD. Since BMT therapy has this high rate of mortality, it is still classified as experimental by many doctors and practitioners in the medical field, as well as in the insurance field. The problems with MLD in the insurance field make BMT therapy even more difficult to undergo, as financial problems are involved along with the already arduous physical problems. Because of its experimental status, many insurance companies will not reimburse those sufferers of MLD who wish to receive BMT therapy. This makes BMT therapy inaccessible for people who are not very wealthy, (the cost of BMT therapy is well over £150,000 (approx US$250,000) at present). At this time, BMT therapy is in phase 2 of its clinical human trials. With luck and continued research, BMT therapy will continue to progress along the path to becoming a real and effective method of treatment, thus losing its experimental status. If this happens, it will make the suffering of MLD much easier to bear.
Hope for the future
Although Metachromatic Leukodystrophy is a very rare genetic disease, it is obvious that it is nevertheless a very dangerous and deadly disease for those who have it. Currently, victims of MLD must suffer throughout their short life with the few treatments that are available. The same was true of victims of smallpox, sufferers of the plague, and even those who had influenza in earlier years. Now, however, these diseases are treatable; smallpox and the plague have even been wiped out from the world, excepting some few isolated areas.
There is little doubt that as research into MLD goes on, new treatments and cures will be found; some for MLD alone, but also others that may affect all genetic diseases. This gives people who suffer from MLD and other genetic diseases some degree of hope - one day, they too may be able to be cured.
1 A lysosome is, simply put, a tiny stomach inside of every cell. The lysosome digests bacteria that the cell engulfs (especially in the case of white blood cells) and disintegrates the cell after it dies. These lysosomes have a very delicate balance of enzymes inside them for digestion.
2 Lipids are fatty substances which need to be broken down by the body. In this case, sulphatides are the lipids which need to be broken down.
3 The mutation does not reside in the sex chromosome, meaning that males and females have the exact same chance of inheriting it. For those of you who are particularly interested in the medical field, you should note that the chromosome which MLD occurs in is #22q13.31-qter.
4 In order to get the disease, both of the parent genes must be the recessive (MLD) version of that gene.
5 Sulphatides are simply materials which are composed largely of the element sulphur, which occur naturally in the human body. The 3-O links of cerebroside sulphatide are the specific sulphatides which cause MLD.
6 Hydrolysis is a chemical process by which materials are broken down by water.
7 Galactocerebroside is a primary component of the myelin sheath, which surrounds axons in the brain. Studies have shown that the absence of this does not eliminate the myelin sheath, but it does cause severe problems with the sheath. See this report.
8 Accumulation of GalC occurs in a related condition called Krabbe's disease (globoid cell leukodystrophy), but is not a feature of MLD.
9 Osmotic pressure refers to the pressure which affects the absorbtion of water by cells.
10 Well-defined injuries.
11 Referring to the cortex, which is the outer layer of grey matter in the cerebellum.