“Pain serves to warn us so that we can protect our body,” explains Michaela Auer-Grumbach, a neurologist at the Medical University of Vienna. “A healthy individual will pull their hand back from a hot stove top or feel that there is a foreign object in their shoe.” This is not the case for people with an extremely rare hereditary disease that kills off certain nerve cells in the body. This disease is called hereditary sensory and autonomic neuropathy (HSAN). “It may well be that these patients keep walking a whole day with a broken leg or on a thumbtack they have stepped on, without realizing it,” notes Auer-Grumbach. Such injuries are fraught with a double danger. Apart from leaving the patient insensitive to pain, the condition also affects wound healing, which means that injuries take longer to heal and can become severely infected. Currently, there are about 50 patients in Austria, and in most cases several individuals within one family are affected. “This makes working together at the European level all the more important. Rare diseases often receive only marginal attention because of the low case numbers. That's why we don’t have medical services for them,” emphasizes Auer-Grumbach. European specialists are now working together to bring clarity to unsolved cases and investigate genetic mechanisms in the FWF-funded project “European Network for Inherited Sensory Neuropathies and Insensitivity to Pain (ENISNIP)”.
A daily challenge for those affected
There are several types of HSAN, categorized by their varying degrees of severity and age groups concerned. The risk of self-injury is particularly high in young children, because they are learning about their environment by touching things and putting objects in their mouths. “A healthy child suffers pain when they bite their own tongue or lips. But children with such rare neuropathies can suffer terrible injuries and even mutilations in their mouth and fingers,” says Auer-Grumbach. In addition, the disease affects nerve cells of the autonomic nervous system, which works in the background and regulates aspects such as digestion, heartbeat and sweating. Babies with certain genetic forms of HSAN may experience severe bouts of fever, because they do not sweat and are therefore unable to regulate their body temperature.
Set preventive measures
Other genetic subtypes of the disease start later in life and primarily affect the sensation of pain in the hands and feet. Auer-Grumbach tells us of patients who noticed it for the first time during military service. They only realized they had a wound after marching in coarse footwear for a long time. “The friction causes an injury that in healthy people will heal after a few days. But with these forms of neuropathy, such a wound can quickly become infected, penetrate to the bone and even lead to bone ulceration.” These examples illustrate the challenges sufferers are confronted with in everyday life. “It is important to teach patients preventive behavioral measures,” says Auer-Grumbach. They should never go barefoot, always check their shoes for foreign bodies, wear soft footwear and avoid even the smallest injuries. When the patients are children, such rules are a particular and daily challenge. “Because the disease is so rare, it is very difficult for parents to integrate their child in a social environment. Starting with nursery school, you would have to make sure that all educators receive specific training,” explains Auer-Grumbach.
Depending on the gene affected, the severity of the disease and the age of onset will vary. “For many of the families affected in Austria, we have been able to identify the genetic cause over the past two decades. We are thus at the cutting edge of global research into the disease,” notes neurologist Auer-Grumbach, who was instrumental in the discovery of several HSAN genes, including the best-researched triggers SPTLC1 and 2. If these genes exhibit mutations, the derivative proteins are formed incorrectly and end up in the nerve cells as toxic waste products. While the first therapeutic options for this particular genetic subtype are already available, others – despite progress made in understanding the disease – still lack therapies and the necessary care structures. Funded inter alia by the Austrian Science Fund FWF, the ENISNIP network at the European level should make it possible to pool knowledge and expertise found in several countries.
European specialists join forces
“The initial impetus came from German colleagues, but experts from Turkey, Switzerland and the Czech Republic are also involved in the project. There is also good cooperation with the UK, where there are many affected individuals,” notes Auer-Grumbach. Since 2020, the group has been dedicated to three main goals: firstly, patients who have not yet been diagnosed should receive a diagnosis based on genetic testing and the measurement of toxic metabolites. Secondly, cases that were previously unsolved in genetic terms should be resolved. For this purpose, the researchers collected national data on mutations and disease patterns in a joint analysis and examined it for overlaps. And thirdly, the project is intended to result in a registry of all known cases to allow experts to access the data in the future. “This will enable us to estimate how many patients are affected throughout Europe and by what mutations a particular case has been triggered. We hope that these aggregate numbers will motivate pharmaceutical companies to work on the development of therapies,” says Auer-Grumbach.
Auer-Grumbach has been entrusted with the clinical part of the project and she was put in charge of recruiting new patients. The genetic analyses were carried out mainly in Munich and Aachen, and the measurements of toxic metabolites in Zurich. Although initial outcomes of the aggregate analyses have not yet revealed any new genes, they have confirmed suspected genes that the researchers now need to investigate in greater detail. In addition, the team intends to continue the collaboration beyond the project's official end date –September 2023. “We will continue to compare and discuss cases,” confirms Auer-Grumbach. “It is important for all people who exhibit the corresponding symptoms to be tested for the genetic cause.” Auer-Grumbach has specialized in the late-onset types of HSAN, which appear after the age of about 50. “The initial symptoms of these forms show similarities to other diseases, such as hereditary amyloidosis. But we have recently been able to treat them in a targeted manner. That's why it is essential to know what you’re dealing with.”
Michaela Auer-Grumbach is a specialist in neurology and psychiatry. She is in charge of neurology at the University Clinic for Orthopedics and Trauma Surgery at the Medical University of Vienna. For 25 years, this specialist has been dealing with hereditary sensitive-autonomous neuropathies and she established special consultation hours for rare neuro-orthopedic diseases at both the Orthopedic Hospital Speising and the Vienna General Hospital. The transnational project “European Network for Inherited Sensory Neuropathies and Insensitivity to Pain (ENISNIP)” has been running since 2020 and was funded by the Austrian Science Fund FWF with EUR 103,671.
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