what ist hsp_Kleinsorge

HSP ( Hereditary Spastic Paraplegia) FSP, SSP, Strumpell-Lorrain Syndrome

By Rudolf Kleinsorge, Weil der Stadt/ Germany

The following is an attempt to describe our disease, HSP, in greater detail for the benefit of all concerned. The text does not claim to be 100% accurate from a medical point of view. It presents a radically simplified view of the disease with the aim of providing HSP sufferers with an initial insight into the disorder. The text only applies to the pure form of HSP which most of us have.

If you have any questions on the article or suggestions for amendments or improvements, please make contact with Rudolf Kleinsorge at e-mail

The following version was proof-read and checked for major mistakes by Herr PD Dr. Jan Kassubek (University Clinic Ulm) and Herr Dr. Sven Klimpe (University Clinic Mainz)

HSP has been diagnosed

What is that, in fact? Why can’t I walk properly? What triggered it off? So what can I do about it? These are some typical questions relating to HSP.

Some typical answers are: "I have an inherited disease which causes the leg muscles to deteriorate. The nerves in my legs have been destroyed. I have to try to build up my leg muscles. These answers are incorrect no matter how apparent they may seem.

The name of the disease explains what exactly it involves. The designation "hereditary spastic spinal paralysis" conveys four messages.

a) hereditary…. this is the cause.

b) spastic …. this is a symptom.

c) spinal …. this is where the disease is located.

d) paralysis…. this is the consequence of the disease.

The following is an attempt to explain HSP using these four terms. The terms will be dealt with in a different order, the explanations appearing in the following order:

1. Spinal

2. Hereditary

2.1 Where are our genes?

2.2 The task of our genes.

2.3 The result of incorrect information.

2.4 Hereditary paths.

3. Paralysis

4. Spasticity

Section 5 will involve a brief review of current therapeutic treatment for spasticity. In this regard, the limits of therapeutic treatment should be recognised in view of the facts presented in sections 1 to 4.

A footnote on section 2: the following discussion, under section 2, is, indeed, confined to the "H" in HSP i.e. the hereditary cause. However there are cases where there are no other family members affected with HSP. These cases are referred to as "sporadic" and are, strictly speaking, not hereditary as the disease has not been inherited.

For information on current therapeutic treatment, please refer to the website http://sp-foundation.org/treatment.htm which elucidates this subject so clearly that there is no need to repeat it here.

1. "Spinal" - where the disease is located

When "spinal" is translated , it means "concerning the backbone and (especially in connection with HSP) the spinal cord". And this is exactly where our disease is located.

There are numerous nerve cords running through the spinal cord. These nerve cords conduct information from the brain through the backbone to the legs, arms and the rest of the body. The nerve cord which among other things is responsible for movement, is the cortico-spinal tract (spinal cord) If we compare this nerve cord to an electric cable, then this cable emanates from a special part of the brain which is responsible for movement. It transmits its information (= electric impulses) to other nerves protruding from the backbone via multiway adapters, which are called synapses. These transmittent nerves are entirely healthy in the case of HSP. The defect with HSP is, therefore, exclusively in the spinal cord. .

The cortico-spinal tract is crucial to fine motor co-ordination. It facilitates random muscle spasms as well as controlled muscle movement. It terminates, with part of the nerve cords, in every indentation of the backbone and, in each of these, connects up to nerves which transmit further. As mentioned above, it is only the cortico-spinal tract (= primary motor neuron) which is damaged in the case of HSP. The nerve fibres which conduct the information from the cortico-spinal tract (= secondary motor neuron) and transmit it to the muscles are not damaged by HSP.

Let us bear in mind that HSP is located in a bundle of nerve fibres in the spine – thus the word "spinal" in the name of the disease. But how does the disease develop at this location? This brings us to the second point which we have designated "hereditary" above.

2. Hereditary: the Cause of it all

So the cause of our disease is hereditary. Many of those affected who are told by their doctors that they have a hereditary disease think immediately of genes and everything that has been said in the news about genetic research and gene therapy and resign themselves to their fate. They surrender and say that nothing can be done about it anyway, and, what’s more, it’s all just too complicated.

This section adopts a different approach in examining the cause of our disease. It comprises a brief description of where our genes are actually located. Then the task of our genes will be touched on briefly. Finally, we will explain what happens to the result of the genetic information. An explanation of the two most common ways of inheriting the disease will follow so that the risk of passing the genetic defect on to the next generation can be clarified.

2.1 Where are our genes located?

The illustration on the left depicts a cell. Of crucial importance for our purposes are the cell body and the axon (both in green) The cell body is characterised by extensions. These are the dendrites. They function like aerials and receive signals. Messages from the dendrites are processed in the cell body and further transmitted as messages through the axons. Many axons (each surrounded by a myelin sheath) comprise a tract. The cortico-spinal tract (cf. section 1) is very long. It extends from the brain to the end of the backbone. The cells that are bundled within it are the longest cells in the human body. A blue dot is depicted in the cell body. This is the nucleus of the cell. Our genes are located within it.

Every cell is organised like a town in which there are numerous streets with traffic going through them. There are houses and power stations there and a lot of traffic – just as in a real town. On the left, a cell is depicted (green in the picture above). In the middle, a nucleus can be distinguished shaded in red (blue in the picture above). This is the nucleus of the cell. We could also say that this is the town hall in our cell town. Our genes are located here in the town hall. This is where decisions are made concerning the town; here it is determined which genes are to be activated in order to perform particular tasks. The illustration depicted here can be found on the internet. The description of these components as well as their function can be called up by clicking on the "internal parts of the body of the cell" See www.angelfire.com/punk3/mp1/pfzelle.html

Human beings are known to have 25 000 different genes. This would amount to a terrible muddle in the nucleus of the cell. For this reason, the genes are organised into libraries. These libraries are called chromosomes. They are comparable to cookery books. Each nucleus contains two lots of 23 cookery books, in other words 46 chromosomes in which the genes are recorded like recipes. But what happens to the genes? What do they do exactly? What tasks do they have?

2.2 The Functions of the Genes

In 2.1 we, figuratively, compared genes to recipes. This is not so far off the mark. Genes are, in fact, only the transmitters of information on which "recipes" are based. We don’t need to explain here how exactly this process works. In the same way as we use a cookery recipe in order to bake a cake, for example, something is likewise produced with the aid of the genes, and these are the proteins. Genes contain instructions for combining specified amounts of particular amino acids in a given order just as we combine flour, sugar, milk etc in the right order according to the recipe we are following.

Natürlich ist ein Kuchen etwas anderes als e...

Of course, a cake is something quite different to a protein. Let’s simply compare a protein to a key. Our picture illustrated a key which is exactly the right shape for its lock at the front and which carries an information tag on the coloured part at the back. The shaft of the key is unique. It only fits one lock. And with the aid of this key, the door to one particular house in the cell town can be unlocked. When this door is unlocked, our protein delivers its information. Certain tasks can then be performed on the basis of this information. So a healthy gene produces a protein which performs its task.

2.3 The Result of the Inaccuracy

Now we will come to our genetic defect, in other words the error in the recipe. Chromosome 2 is depicted on the left hand side. At the top, a red bar can be distinguished. This is where the spastin gene is located which has mutated in the case of many HSP sufferers. If there is a mutation in the spastin gene, it means there is an error in the recipe. If our "mutated" recipe had listed salt instead of sugar, our cake would be a catastrophe.

The genetic recipe has produced a key with a fault located on the shaft. The key no longer fits the lock. What is the consequence?

It’s quite simple. In the core of the cell, in other words the town hall, they have decided to form a protein with a very specific function in one area of the "cell town". Following the gene recipe, the protein is to be formed so that it can unlock the door of a particular house in the cell town in order to perform its task there. However, as the key can no longer unlock the door, the function cannot be carried out.

In the case of HSP, just two possible fields of activity come into question for the protein key. One such key is, for example, supposed to be responsible for disposing of refuse from defunct stabilising elements in the cell. As the refuse is not disposed of, the cell clogs up. The consequence is similar to the case of a strike in the municipal refuse disposal services. Of course, the function of the cell is completely disrupted as a result. If we assume that the spastin protein (= SPG4) has this function, then it is apparent that in the case of a spastin defect, the function of the cell is disrupted. It degenerates and dies off.

To take a second example: a protein key is supposed to provide the power stations in the cell town with energy. As a result of the faulty construction of the key, the power station cannot be unlocked. No more energy can be produced. The cell town will soon run out of energy and the function of the cell is disrupted. Assuming that the protein paraplegin (=SPG7) has this function, it is apparent that in the case of a defect in the paraplegin, the cell’s function is disrupted. It degenerates and dies off.

In the case of HSP, these defects mainly occur in the axons and synapses (see section 1). The cell bodies are hardly affected in the pure form of HSP. The consequence of disruption in the axons is a "traffic jam." This leads to an ever more intensive degeneration in the axon. In consequence, messages are either not transmitted at all, or they arrive too late or are too faint when they reach the next nerve and, are, thus, distorted when they reach the muscle.

2.4 Hereditary Paths

Every human cell contains 46 chromosomes, or, rather, 23 pairs of chromosomes, to express it more adequately for our purposes. These chromosomes are made from the DNA of our parents – 23 from the mother and 23 from the father. The chromosomes are the storage area for the 25000 or so genes. With a disease pattern such as HSP presents, one gene is mutated, that is to say changed. In the case of HSP, the autosomal dominant and the autosomal recessive hereditary paths are the most frequently-occurring ones in the case of such genes, and it’s here that mutations trigger the disease

If there is a dominant hereditary path, a mutation in one gene on one chromosome in a pair will suffice to trigger off the disease. In the illustration on the left, gene A is mutated and gene a unaffected. It might be said that the single mutated gene has a position of dominance over the other gene from the other parent, and triggers the onset of the disease. So only one parent need be the carrier of the genetic defect. (Aa has a 50% risk of becoming affected)) (The parents on the left, and above are marked in grey.) If the hereditary path is recessive, a mutation in the gene on one chromosome only is not enough to trigger off the disease. In this case, the healthy gene, is strong enough to trump the defect in the mutated gene. The disease doesn't break out in such a case. The person affected is, however, a carrier of the genetic defect. If such a person conceives children with a partner who is also a carrier of this genetic defect, the disease can break out. The second gene can no longer compensate for the mutation as it is mutated itself. (AA has a 25% risk of contracting the disease. The disease doesn't actually break out in the case of children with the genetic make-up Aa but they become carriers of the mutation and can pass it on to their own children.

The X-chromosome hereditary path is not outlined here as it occurs extremely rarely with HSP. Should you have any questions about it, please get in touch with Rudolf Kleinsorge by e-mail

That was the explanation of the hereditary paths. In order to gain a deeper understanding, it is necessary to know that it is sections of chromosomes – not chromosome pairs – that are passed on genetically. It is only due to the forming of a simple chromosome from the chromosome pair in both the man and the woman respectively that the child produced also receives a pair of chromosomes i.e. one from each parent. This takes place in the germ cells – the ovules of women and the sperm cells of men. Thus, the germ cells can be distinguished from all other cells in the body. The latter contain genetic information from the father and the mother, whereas in the germ cells only the individual’s own genetic information, which will be passed on to the offspring, can be found. The genetic information in the germ cells is made up from a mixture of the genetic information from the father and the mother. The information is "mixed" again for every germ cell. This ensures that our children differ from one another. If it wasn’t for this process of "mixing" each child would simply be a copy of the next as the genetic information would be the same. From this it emerges that the risk of passing on our genetic defect, as described above, arises in our own germ cells. Here it is determined for each germ cell whether gene A (marked grey in the illustration above) or gene a is passed on in the process of procreation.

The following internet-link provides a graphic illustration of the hereditary path of our disease - both the dominant and the recessive path. Here we can clearly recognise that due to the double set of chromosomes from the parents, four possible combinations always come into question.

Animated pictures of the hereditary paths described here can be seen at: http://www.musjle.0catch.com/HSP/Genetics_HSP.swf . ( Flash Player required)

So let us note that the consequence of our genetic defect is the faulty production of a certain protein, the make-up of which is recorded in the gene. Let us further note that this protein which has been formed defectively – if at all – cannot perform its functions. This all leads to a degeneration (= slow wearing down) in the nerve. The nerve’s ability to function is then impaired or destroyed completely depending on the damage incurred. This all happens on the axon in the uncomplicated form of the disease, and it is the synapses which are affected. (see section 1). The diagram on the left is a simplified illustration of a healthy synapse. The axon comes from above. Beneath it is the subsequent nerve, which is unaffected in the case of HSP. The synapse is the term used to refer to the intersection of the upper and lower nerve.. In the case of our impaired nerve, this is located in the spinal cord where the transfer to the subsequent nerve (= 2^nd motor track – see point 1) takes place. The area marked in yellow which is called the "neuro-transmitter" is likewise of interest to us. This will be dealt with later. The mitochondria represented in the diagram are part of the cell’s interior. Mitochondria resemble "power-houses".

3. Paralysis – Consequence of the Disease

Paralysis or plegia denotes the complete paralysis of muscles and groups of muscles. Paralysis occurs when nerve cords leading to the muscles have been damaged. It is apparent from the choice of the term "paralysis" alone that it denotes an advanced stage of the disease. After all, not all those affected by HSP suffer from complete paralysis of the leg muscles and, when it does occur, it is usually several years after onset of the first symptoms. What HSP sufferers normally experience is palsy. We talk about palsy when there is only partial paralysis and some muscle power remains. Palsy caused by HSP is also attributable to an impairment of the nerve cords in the spinal cord as well as in the brain. After all, we know that, with our disease, such a nerve cord i.e. the cortico-spinal tract is impaired by a malfunctioning protein (cf. section 2.3). Even if medical research has identified some of these proteins, their function still remains largely obscure. An analogy will serve to elucidate the defect which occurs with HSP.

Let’s imagine that the protein spastin is responsible for disposing of refuse from our cell. We’ll simply say that spastin functions like a refuse disposal service in our town. If the refuse is not collected in the cell town, all the streets will soon become obstructed. But the main traffic runs through these streets in our cell town. So there will now be more congestion on account of the refuse not having been collected. The traffic could even come to a complete stand-still. This traffic normally includes goods which have to be delivered to the recipient very quickly. These goods consist of information, neural information to be precise, which is to be delivered to specific parts of the body, for example, the muscles. Due to the traffic congestion described, this information either fails to arrive on time or in the necessary intensity, or, even does not arrive at all. This simple analogy is really not so far-fetched at all. Most HSP sufferers carry a defect on the spastin gene. It is known that this gene, and the protein it produces, contributes to the break-down of the microtubules. The latter are stabilising elements in the cell which are constantly being formed and broken down. However, when they cannot be broken down due to the spastin defect, the result is the congestion described above; the cell is no longer viable and it begins to degenerate.

We said above that the paralysis is caused by damage to the nerve tract. As the muscle no longer receives the necessary information, it can no longer function properly. A limp paralysis sets in which becomes more acute as the disease progresses. This paralysis manifests itself in widely-varying groups of muscles. The muscles responsible for lifting the feet can be affected as can those which move the thighs. The bladder can also be affected so that urination no longer functions properly. The group of muscles responsible for the correct position of the pelvis can equally be affected. An incorrect positioning of the pelvis can result in the overall posture not being correct so that the entire sequence of movement is impeded.

It can be concluded that the function of the nerve tract is disrupted due to a defective protein manufactured by a mutated gene. It should further be noted that the information flow to the muscles is no longer functioning properly on account of this defect and that this manifests itself in varying degrees of paralysis in some muscles.

An animated illustration of the foregoing description can be found at: http://www.musjle.0catch.com/HSP/Genetics_HSP.swf . ( Flash Player required))

4. Spasticity: the Manifestation of the Disease
Spasticity is an increase in the tension within the muscle which is sometimes painful. It is caused by a defect in the central nervous system (brain or spine).
	So what triggers spasticity in the case of HSP? A nerve cell was illustrated. In section 2.1. It was noted that the nerve cord consists of numerous individual axones, each of which has its own cell body. We can see from the illustration on the left that a nerve consists of many such axones. If we want to make a movement, for example walk forward a pace, vast amounts of information have to be sent to various muscles. The necessary information is transmitted through numerous axones.
For example, we have to lift the front of the foot, put a knee forward, take the weight off the leg that we want to move, lift the thigh etc. Numerous individual impulses are necessary for each single step. Let us suppose, for the sake of simplicity, that 100 individual pieces of information are necessary for taking a step forward (even if far more are actually required for a complex movement). This large volume of information cannot, of course, be provided by one single nerve cell. This is why we have so many nerve cells along with their axones in the nerve cord. Taking a step forward is triggered by nerve impulses in many cells with their cell bodies and axones. In order to take just one step, our putative 100 single commands have to be made at the right level of intensity, in the correct order and at the right time. In section 3 we saw why our cells degenerate. Of course, not all our cells degenerate simultaneously. Some degenerate more slowly, others more rapidly. The process is slower in the case of some cells and more rapid in the case of others. This means that some cells can continue to transmit their commands without interruption. Other cells perform their function too late due to the incipient degeneration, and others cannot perform at all as they have completely degenerated. For the muscles which are supposed to be enabling us to take a step forward, this means that the necessary information may not be provided at the intensity required, or the sequence or timing may be incorrect. Now the muscles have a problem: they are rendered more or less incapable of producing a regular, stable step. So what happens? The procedure for taking a step begins but cannot be carried out completely satisfactorily. The consequence is that we fall. In fact, we would probably trip up like this with every step we take. However, our body is really quite ingenious and has thought up a stabilising mechanism as a "rescue function" for such cases. All the muscles which are necessary for this stabilisation are tensed, thus preventing the fall. The simultaneous tensing of these muscles prevents the movement which has been started from being carried out further. The step can only be continued when we release this tension in the muscles and let go. This stabilising mechanism within the body really is a superb rescue function. The stabilising mechanism is, in fact the spasticity itself. This rescue function only kicks in very rarely in the case of healthy people. After all, their movements are normally co-ordinated and harmonious. With HSP sufferers, however, the movement process is permanently impaired as the neural impulses are defective. The body thus makes permanent use of its rescue function: spasticity. Spasticity typically effects the anti-gravity muscles which means those responsible for stretching in the leg and for bending in the arm. All HSP-sufferers are, of course, aware of what an impediment spasticity is, but without the spasticity, they would trip up all the time and fall flat on their faces. An attempt can be made to limit the negative effects of spasticity medicinally. However, such treatment involves side-effects which affect movement. This will be elaborated on in section 5. To conclude: spasticity is not the cause of HSP but, rather, the body’s permanent reaction to the impaired information-flow from the nerves. The body attempts to stabilise itself with this reaction. Spasticity is, therefore, a symptom which is extremely acute on account of the permanently impaired information flow.
5. Treatment using Medicines which reduce Spasticity
As a medical solution has not yet been found for HSP, efforts are directed at minimising the spastic reactions of the body. For this purpose, medicines such as Lioresal are being prescribed. However, many HSP sufferers do not get on so well with these medicines and report that their ability to walk continues to deteriorate,
	We are already familiar with the diagram on the left from section 2. It was mentioned above that we would be returning to the area marked in yellow on the illustration. This is what we are now addressing. To summarise briefly: the diagram illustrates the structure of a synapse, that is to say, the point at which a nerve (the spinal tract in the case of HSP) transmits its information to the next nerve. The yellow area is designated "neurotransmitter". It is these neurotransmitters which transmit information from one nerve to the next. Neurotransmitters are small chemical molecules which can penetrate the wall of the cell. There are two categories of neurotransmitter: excitatory (those which help the initiation of a nerve impulse in the receiving neuron) and inhibitory (those which discourage such an impulse.) Quick, sudden body movements are transmitted by the excitatory (quick) neurotransmitters. Spastic reactions are quick reactions, which should, thus, be influenced by inhibitory neurotransmitters. The medicines discussed above are, in fact, nothing but inhibitory neurotransmitters. The active ingredient in these medicines is "gamma-aminobutyric acid " (abbr.: GABA) which causes the impulses to be transmitted more slowly. Stupidly enough, this does not only apply to the spastic action but to every nerve impulse. All instructions to the nerves which are necessary for walking are delayed. If large doses are taken, HSP sufferers have the feeling that they are walking on sticky, rough ground, which makes it almost impossible for them to lift their legs. Other muscles, too, such as the arm muscles or the bladder muscles can also be impeded by too high a dose of this substance. The positive effect of such medicines is that spasticity is reduced. The negative effect is that all movements are, likewise, slower because other impulses are also transmitted more slowly. This is the reason why many HSP sufferers complain that while spasticity is, in fact, reduced by the medication, they actually walk even worse than they did before. With this category of medicines it is all down to a question of dosage. Some HSP sufferers don't have any problems at all with dosages of over 50 milligrams per day, Others have problems with just 5 milligrams. Some sufferers have 1mg tablets specially made up for them in the chemist's which are based on the weakest potency available (5mg in the case of Lioresal.) They take just 2 to 3 milligrams per day. These do not radically reduce spasticity, but have a parallel effect of increasing ability to move. There is no dosage here which is generally applicable. But the motto "as little as necessary" can be applied. Some publications indicate that in the case of sufferers who experienced onset of HSP during childhood, spasticity is more predominant while palsy predominates more with other sufferers. From this, it can apparently be deduced that, in the case of the former, spasticity-reducing medication should be prescribed in stronger dosages while lower dosages would appear to be expedient in the case of the latter. Unfortunately there is still no absolute clarity on this issue. This concludes section 5 "spasticity-reducing medication". To sum up: the use of inhibitory neurotransmitters reduces the rate of transmission at the synapses. Put very simply, this means that the intensity of spasticity is reduced but movement dynamics are likewise retarded.
6. _Final Conclusion
The aim of the article was to shed some light on the development of "hereditary spastic paraplegia". This was done by means of extreme simplification. Specialised medical explanations were not included as a more general level of comprehension was aimed at. It can be concluded that HSP is caused by a genetic defect which causes a protein to be produced incorrectly. This defective protein causes the degeneration of nerves in the spine which are, thus, unable to continue to transmit their impulses properly. This results in spastic paralysis of particular muscles. The body resorts to spasticity to prevent itself from stumbling. We did not elaborate on the genes so far identified as containing defects which result in HSP, whose proteins have also been partially identified. Details can be found at http://www.fsp-info.de/patienten.htm In the table illustrated here, the protein manufactured with the aid of the genes is designated as a "genetic product." Detailed information on therapies currently available can be found at http://sp-foundation.org/treatment.htm

TWS is indebted to Herr Kleinsorge, who is also a member of our committee (http://www.fsp-info.de/foerderprojekte/beirat.htm) for this excellent account of the disease which is clearly comprehensible for all readers and serves as a further step towards our goal of providing information. particulary we appreciate the excellent work of Mrs. Anna Bennett- Long who did the translation of this very complicated text.