Krabbe's disease - a genetic metabolic disease

Krabbe's disease (globoid leukodystrophy) is a little known, very rare genetic disease that mainly affects the peripheral and central nervous system. Classically, Krabbe disease affects newborns, but it can also happen later in life. In most cases, Krabbe disease leads to death around 2 years of age. What are the causes and symptoms of Krabbe Disease? What is the treatment?

Contents:

1. Krabbe's disease - causes
2. Krabbe disease - symptoms
3. Krabbe disease - diagnosis
4. Krabbe's disease - treatment
5. Krabbe's disease - Charles's story

Krabbe's disease(globoid leukodystrophy) belongs to the group of so-called storage diseases and consists in the deficiency or lack of an enzyme that is necessary for the proper structure of myelin, i.e. the substance surrounding nerve fibers.

The consequence of this defect is an excess of galactocerebroside, which disrupts the functioning of the central (central) and peripheral nervous system, and as a result, progressive dysfunction of muscles and nerves is said - says Assoc. dr hab. n. med. Jolanta Sykut-Cegielska, Head of the Department of Metabolic Diseases, Endocrinology and Diabetology, Institute "Children's Memorial He alth Center" in Warsaw, coordinator of Orphanet Poland

Krabbe disease is an example of a disease that is rare, although the total number of patients in the EU is estimated at over 240,000. Most of them are genetic and their clinical course is severe; they often pose a threat to life or cause chronic disability - adds the expert.

Krabbe disease - causes

The cause of Krabbe's disease is a mutation in the GALC gene (14q31), which encodes the lysosomal enzyme galactocerebrosidase, which catalyzes the hydrolysis of galactose from galactocerebroside and galactosylsphingosine (psychosine).

Globoid leukodystrophy is called Krabbe's disease after the Danish neurologist Knud Haraldsen Krabbe, who first described the disease.

A build-up of psychosin leads to demyelination of the central and peripheral nervous systems.

The disease is inherited in an autosomal recessive manner. This means that a person must inherit two altered copies of the same gene (one altered copy fromeach parent) so that the disease occurs.

If a person inherits one altered copy and one correct copy, then in most cases that person will be a he althy carrier because the presence of the correct copy compensates for the presence of the altered copy.

Being a carrier means that you are not affected by the disease, but are carrying an altered copy of one gene in a pair and can pass it on to your offspring.

Krabbe disease - symptoms

There are four types of the disease: ¹

• infant form (also called "classic") - the most common - onset in the first 6 months of life
• child character - beginning between 6 months and 3 years of age
• adolescent figure - beginning between years 3 and 10
• adult figure (rarest) - beginning over 10 years old

In Polish literature there are no reports of the presence of adolescence, and in the English-language one they are found sporadically. There are also few scientists interested in this subject, which is probably due to the small scale of the problem from the point of view of society and the related lack of funding for this type of research .¹

Infant symptoms appear between 2 and 6 months of age, and the course of the disease can be divided into 3 stages:

The patient quickly develops swallowing, breathing, blindness and deafness. The baby usually dies up to the age of 2 - says Assoc. dr hab. n. med. Jolanta Sykut-Cegielska.

• Stage I - irritability, stiffness, poor head control, feeding difficulties, intermittent thumb tightening, episodes of increased body temperature, developmental delay
• II stage - seizures of increased muscle tension with opisthotonus, myoclonic convulsions, regression in development, clenching of hands and visual impairment
• III stage - there is a reduction in muscle tone, blindness and deafness

Patients go vegetative and die before the age of 2-3 years, generally from respiratory infections.

In the late infant / adolescent (age 1-8) and adult (>8), symptoms are variable at first and disease progression is variable (generally slower in older adults). patients).

The symptoms in patients with the infant form / adolescence form are similar to those seen in the infant form, but often the initial symptoms in the adult form are:

• weakness
• gait disturbance (spastic paraparesis or ataxia)
• strong paraesthesia
• hemiplegia and / or lossvision, with or without peripheral neuropathy

Cognitive regression varies and is often not seen in adulthood.

Krabbe disease - diagnosis

Diagnosis is made by symptoms, neurological testing, and enzyme and genetic testing.

Krabbe's disease - treatment

Treatment is limited to haematopoietic stem cell transplantation in presymptomatic infant patients and late onset in mild cases. This treatment regimen has been shown to slow disease progression.

Other treatment options (i.e. chaperone protein therapy, enzyme replacement therapy, gene therapy) are currently under investigation in animal models.

According to an expertDoc. dr hab. n. med. Jolanta Sykut-Cegielska, head of the Department of Metabolic Diseases, Endocrinology and Diabetology, CZD Institute, coordinator of Orphanet Poland

Tame orphan diseases

In Poland, the problem is the low awareness of the existence of such rare diseases, called orphans due to the feeling of isolation of patients and their families, associated with a common misunderstanding in the environment (also among doctors).

That is why the initiative of the European Commission, which launched public consultations on these diseases in the EU countries, is so important. The aim of the consultation is to disseminate knowledge about them, improve diagnosis, access to treatment and care for patients.

Patients with rare diseases should have the right to the same prevention, diagnosis and treatment as other patients. I encourage all interested parties to use the internet information service http://www.orpha.net/

Krabbe's disease - Charles's story

Karol was born on June 19, 1995. He was our first, longed-for child. Everything was going according to the plans: first the wedding, then my own apartment and the child.Pregnancyand the delivery was uneventful. Karolek ate well, grew up and started to raise his head at the age of three months.

When he was less than six months old, we were visited by friends with a child of the same age. It was the first time that we noticed that Karolek was behaving differently than that boy. He was very lethargic, much less mobile. We started watching him.

Soon I went with him to the doctor at the clinic. The doctor said that the little one was … malnourished and recommended a consultation at a lactation clinic. I breastfed Karol and ate quite a lot, and he certainly wasn't emaciated.

It was only after a month and completely by accident - thanks to a private acquaintance - we found ourselvesat the Children's He alth Center. Karolek stayed in the hospital for tests. We found out about their results quite quickly. I will never forget this visit.

A doctor from the metabolic department said that Karol suffers fromKrabbe's disease- a raremetabolic diseasegenetic deficiency or no enzyme at all. There is no chance of a cure.

We learned that our son's condition will gradually deteriorate, and that such children usually die before the age of 2. We got a leaflet from the hospice for leaving. It was a shock for us. The husband could not stand the tension, he shouted something to the doctor …

Children with Krabbe's disease usually die before the age of two

So far, I don't know how I survived it all. In order to think as little as possible, I tried to focus on specific matters - everyday activities related to caring for my sick son. And it was getting more and more difficult.

Neurological disorders progressed - Karolek was losing his eyesight, had more and more problems with swallowing, he was choking. I had to feed him and drink him through the probe. Nowhere, even for a walk, did I move without an electric suction device to suck up secretions from the respiratory tract.

It was very hard. Sometimes we were visited by hospice workers - a psychologist and two young people. I am very grateful to them. They were the only people who were involved in what was happening, they accompanied me in my suffering.

People tend to avoid families with such sick children because they don't know how to deal with misfortune. Additionally, the feeling of alienation and misunderstanding was intensified by the fact that it is a very rare disease.

Karolek died at night, while sleeping, 10 days after his first birthday. Our son was born without the enzyme necessary for the proper functioning of the nervous system. This is a rare genetic disease where both parents have one gene that is abnormal.

This is called recessive gene - it has no effect on my and my husband's he alth, but when two people with such genes meet, there is a high risk (25%) that the child will inherit both recessive genes and will be sick.

The probability that both partners have such a gene is very small, but unfortunately it was our case. It can be bitterly said that we are "chosen by fate."

Worth knowing

Where did Krabbe's disease come from in Poland?

Krabbe's disease in Poland is probably related to the Swedish Deluge¹ It may have initiated the spread of the mutant allele originating in the country where it is now foundthe highest incidence of Krabbe disease in Europe. For the time being, these assumptions remain a working hypothesis that can only be verified by genetic testing .¹

A clinic in Rotterdam that deals with Krabbe's disease

We had tests done right after the diagnosis of Karolek's disease and we heard that if we decide to have another child, we do it at our own risk. It's hard to give up dreams of a family, but we were afraid to try.

However, after some time, we were called to say that a clinic in the Netherlands, in Rotterdam, that was dealing with Krabbe's disease had been found and that it would be able to determine from prenatal tests whether the child would be sick. Then we made an attempt. I got pregnant for the second time quite quickly and without any problems.

I had amniocentesis in week 21 and the amniotic fluid sample taken was sent to the Netherlands. We waited about a month for the test results. They came to CZD by fax. And they were like a sentence - a death sentence on our second child.

We found out that he is a boy again and that he is afflicted with this damned disease again. I had to terminate my pregnancy. It would be cruel to bear a child only to suffer, to condemn it to a slow, inevitable death. We already knew what it meant.

However, there were people who had the courage to remind me of "termination of pregnancy". How much does one have to be heartless and devoid of imagination to have women bear a child in this situation? But I'm not that easy to touch.

I knew I had to be strong, I have to cope, I absolutely can't break down. And I was strong. After two unsuccessful attempts, even my husband - a born optimist - broke down a bit. We were reluctant to talk about it. But we did not move away from each other, although in such crisis situations it sometimes happens.

Third pregnancy - prenatal tests have shown that the child will not be burdened with a genetic disease

At the end of 1997, I got pregnant for the third time. Amniocentesis again and a month of waiting for test results. The closer I was to meet them, the more I was afraid. I remember it was Friday afternoon and I was at work. The phone rang after 3 p.m.

I thought: who the hell is calling at this time? It's almost weekend now. It was a lady from the Children's Memorial He alth Institute who said that the results from the Netherlands have just come and that our child is he althy. I felt a shiver. So it's possible! I will give birth to a normal, he althy child, a son. What a relief, what a joy! After living in constant fear for two years.

Thanks to the prenatal examinations, we also knew that the baby did not have any other serious defects, especially the spinenervous, and such knowledge is priceless. But, of course, the fear did not completely abandon me. After what I'd been through, each stronger contraction, each additional examination made me uneasy. Fortunately, the pregnancy went smoothly and Jakub was born on July 23, 1998.

Big, he althy, beautiful boy. When he was little, I trembled about everything - when he got hiccups at night, I wanted to go to the doctor with him! It took a long time to realize that Jakub could be treated like any other, he althy child. For example, I was mixing all his meals for a very long time, because I remembered those terrible moments when Karolek was choking and choking.

I will probably be an overprotective mother forever … Jakub, however, grew wonderfully: he grew fast, he rarely got sick, he started talking quite early, and when it comes to walking, then … phew, I feel tired from the very memory.

This little guy didn't actually walk at all, he just ran! He was the busiest child I know - as if he had a built-in motor in his legs. It lasted for a good few years. Movement has always been his element - already at the age of seven he was a great swimmer and skiing enthusiast, and today, at the age of nine, he trains hockey at Legia and is also doing very well.

Unexpected pregnancy - stress and fear that the child may be at risk of a genetic disease

We never wanted an only child, but we planned a second child when Jakub goes to school. Meanwhile, just after his third birthday, it turned out that I was pregnant.

I wasn't thrilled. It was only after my parental leave that I returned to work, and I wanted to continue my studies and write my doctorate. My life was stable, happy - we built a house, my husband's business prospered.

And here everything is back, fear is back. I was afraid. I didn't want to go through all this research again and wait for the results. It was a very difficult period for me. It must be remembered that the material for the research is collected in the 21st week, and the results are known a month later - that's almost half a year of constant anxiety!

Robert tried to cheer me up and reassure me, convincing me that everything would be fine … And it was so. The results of the research turned out to be successful. Ludwik was born on March 23, 2002. Since he appeared in the world, I had no doubts if it was a good time for another child and I cannot imagine today that he might not be there.

He is completely different from his big brother - calmer, more reflective. When he was tiny, he often surprised us with some age-wise insight. At the age of 5, he started playing the piano. He touched us very much when he played his first during the last ChristmasChristmas carols.

I lost two children, I had the worst moments a mother could have. Today I have two wonderful sons. Life doesn't always turn out the way we want it to. But the most important thing is not to lose hope. You have to believe that fate will change and that after worse times better will come. We made it.

Bibliography:

1. Jastrzębski K., Klimek A., Krabbe's globoid leukodystrophy - a disease with many faces ?, "News Neurologiczne" 2008, No. 8

The text uses excerpts from Agnieszka Roszkowska's article from the "M jak mama" monthly.