Genetic cause of severe nerve damage in older adults with inability to walk deciphered

September 2, 2016, Medical University Vienna

Congenital gene mutations lead to afflicted persons of advanced age developing severe nerve damage (polyneuropathy) with paralysis, loss of sensation and pain. The illness can advance rapidly and lead up to the inability to walk with wheelchair dependency. The affected gene was now identified by an international team of researcher under the guidance of the Medical University Vienna and the University Munich.

"The gene mutation leads to an enzyme deficiency which probably triggers . In future, the balance of the reduced enzyme activity could represent a novel therapy approach which could cause the disease to be stopped," says Michaela Auer-Grumbach of the University Clinic for Orthopaedics of the MedUni Vienna. Polyneuropathy occurs in 2-3 percent of the population and in 7 percent of those over the age of 65; currently, the cause is still unclear in up to 50 percent of the affected people and a causal therapy is not yet available for this group of patients.

The origin of this discovery was three unrelated Austrian families, where several family members between the age of 55 and 80 initially noticed a loss of sensation and discomfort in the toes, which spread to the knees within just a few months. This was often accompanied by pain as well as a relatively quickly advancing muscle weakness when lifting toes and feet. Auer-Grumbach: "After a few years, walking freely was often no longer possible." Despite extensive research, the cause could initially not be clarified.

"Due to the rapid deterioration of the symptoms, some patients were initially treated with unsuitable medication, which showed no improvement, but often caused considerable side effects. Based on the poor response to anti-inflammatory medication, but also due to the familial accumulation of polyneuropathy, we ultimately assumed a genetic cause, even though the late start of the disease seemed rather atypical for inherited polyneuropathy. An analysis of the entire exome of the patients, i.e. the sections of the genetic makeup which encrypt proteins, subsequently resulted in a serious genetic deviation in the MME gene, which is responsible for the formation of the Neprilysin enzyme," explains the researcher from MedUni Vienna, who is also the lead author and manager of the study.

Together with Jan Senderek of the Friedrich-Baur-Institute of the Neurological Clinic and Polyclinic of the University Munich, who is also aware of similar patients in Germany, the MME gene was tested in other patients. Following the incorporation of further European and American work groups, mutations could be identified in 28 patients from 19 families. A further confirmation of these research results were subsequently provided by the results of the measurements of the enzyme Neprilysin in the blood and fatty tissue, which was significantly lower than in control persons. An additional study from Japan, which also describes sever polyneuropathy at a complete lack of the Neprilysin enzyme, confirms the study results of the work groups from Vienna and Munich, which has now been published in the current edition of the magazine American Journal of Human Genetics.

Lack of enzyme leads to the development of severe Polyneuropathy

"The discovery of the cause of this disease allows the specific genetic diagnostic and consultancy of afflicted patients and their families and shall avoid ineffective therapies, which are stressful due to undesirable side effects in the future," summarises Michaela Auer-Grumbach. "If further studies confirm that the deficiency of Neprilysin leads to the formation of polyneuropathy, there is justified hope that an effective therapy can be developed in the near future, either by enzyme replacement or with active ingredients, which are already known for raising the Neprilysin level.

The authors of the study (which was made possible due to a FWF project) are now planning further epidemiological examinations of with unclear polyneuropathy to discover whether mutations in the MME gene are also of significance in the sporadic (not family-cumulative) appearance of polyneuropathy. "Polyneuropathy from the age of 50 is frequent, but the cause can currently only be clarified and a therapy initiated in approx. 50 %. We hope that an MME/Neprilysin quick-test can lead to a quick diagnosis in the future and that this also accelerates the development of a therapy," so Michaela Auer-Grumbach.

Explore further: Prediabetes may not explain diabetic polyneuropathies

More information: "Rare variants in MME, encoding metalloprotease neprilysin, are linked to late-onset autosomal dominant axonal polyneuropathies." American Journal of Human Genetics. dx.doi.org/10.1016/j.ajhg.2016.07.008.

Related Stories

Prediabetes may not explain diabetic polyneuropathies

February 22, 2012
In a reversal of two decades of medical reports, a Mayo Clinic study finds the frequency of nerve damage called diabetic polyneuropathy is similar in prediabetic patients and healthy people. Physicians should seek explanations ...

Acute Zika virus infection associated with sensory polyneuropathy

August 26, 2016
A group of researchers from Honduras, Venezuela and the USA has described the first case of sensory polyneuropathy associated with acute Zika virus infection. The scientific paper was published in the Journal of the Neurological ...

Diabetic polyneuropathy not up with impaired glycemia

March 3, 2012
(HealthDay) -- Although significantly increased in subjects with new diabetes, the rates of typical diabetic polyneuropathy (DPN), retinopathy, and nephropathy are not significantly different between subjects with and without ...

Discovery of a novel gene for hereditary colon cancer

July 28, 2016
The formation of large numbers of polyps in the colon has a high probability of developing into colon cancer, if left untreated. The large-scale appearance of polyps is often due to a hereditary cause; in this case the disease ...

Gene therapy for metabolic liver diseases shows promise in pigs

July 27, 2016
With a shortage of donor organs, Mayo Clinic is exploring therapeutic strategies for patients with debilitating liver diseases. Researchers are testing a new approach to correct metabolic disorders without a whole organ transplant. ...

New cause of immune neuropathy discovered

August 3, 2016
Patients suffering from so-called immune-mediated neuropathies frequently have a long medical record. As there are no diagnostic tests available to reliably diagnose the disease, the diagnosis is frequently made belatedly ...

Recommended for you

RNA thought to spread cancer shows ability to suppress breast cancer metastasis

October 22, 2018
Researchers at The University of Texas MD Anderson Cancer Center have discovered that a form of RNA called metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) appears to suppress breast cancer metastasis in mice, ...

New tool gives deeper understanding of glioblastoma

October 22, 2018
Researchers in the lab of Charles Danko at the Baker Institute for Animal Health have developed a new tool to study genetic "switches" active in glioblastoma tumors that drive growth of the cancer. In a new paper in Nature ...

Researchers find common genetic link in lung ailments

October 22, 2018
An international research team led by members of the University of Colorado School of Medicine faculty has identified a genetic connection between rheumatoid arthritis-associated interstitial lung disease and idiopathic pulmonary ...

Scientists identify critical cancer immunity genes using new genetic barcoding technology

October 20, 2018
Scientists at Mount Sinai have developed a novel technology for simultaneously analyzing the functions of hundreds of genes with resolution reaching the single cell level. The technology relies on a barcoding approach using ...

A single missing gene leads to miscarriage

October 19, 2018
A single gene from the mother plays such a crucial role in the development of the placenta that its dysfunction leads to miscarriages. Researchers from the Medical Faculty of Ruhr-Universität Bochum (RUB) have observed this ...

Making gene therapy delivery safer and more efficient

October 18, 2018
Viral vectors used to deliver gene therapies undergo spontaneous changes during manufacturing which affects their structure and function, found researchers from the Perelman School of Medicine at the University of Pennsylvania ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.