Researchers from the National Institute of Health (NIH) have pioneered the discovery of a novel gene mutation that leads to a rare form of pediatric neuropathy. The culprit in this case is a gene that encodes for protein KCC3. Backed by similar results found in the mouse model, the study is a promising development towards the treatment of pediatric neuropathy.

The study was jointly ventured by scientists from NIH’s National Institute of Neurological Disorders, Strikes (NINDS), Nashville, Vanderbilt University and Yale School of Medicine, New Haven, Connecticut.

Funded by the National Institute of Health, the study was also recently published in the journal Science Signaling.

To our surprise, the fault arises when this protein, acting as a potassium chloride co-transporter, deviates from the normal functioning. Responsible for the movement of potassium (K) and Chlorine (Cl) ions across the cell membrane, the role of this protein is crucial for the development and maintenance of nerve tissues. In addition, the protein responds to swelling and helps drain fluid out of shrunken cells to ensure normal cellular function.

Previously known to contribute towards the symptoms of Andermann Syndrome (AS) – which also causes damage to motor and sensory cells – the protein also effects the working mechanisms of other proteins which are sensitive to cell ion-concentration. Now that the role of this faulty protein has been observed in children, targeted therapeutics are likely to be formulated.

Researchers are hopeful that children with this problem will be able to lead a better life in the near future. In this regard,  NINDs Director Walter J. Koroshetz MD said; “This case superbly illustrates how the intensive study of children with very rare neurological disorders can lead quickly to a deep knowledge of a specific genetic condition, as well as uncover mysteries of the nervous system relevant to a wide spectrum of disorders.”

In this rare form of neuropathy, the nervous system is progressively damaged and the severity of the damage varies from one person to the other. In children, the problem often occurs in the peripheral nervous system and in the coordination of central nervous system with the body. It hinders the normal functioning of motor and sensory neurons, and leads to numbness, muscle weakness and pain sensation.

Combining the symptoms of both motor neuropathy and sensory neuropathy in children, in this rare form of neuropathy, children are likely to experience problems while talking, with their hand movements, walking, tying their shoe laces, and sensitivity to touch or pain, along witha burning sensation.

Although the condition can present itself as a result of other conditions, including diabetes, alcohol abuse, exposure to toxic substance, autoimmune disorders or viral diseases, it often shows an underlying hereditary pattern in children.

In this study, researchers were able to reach a significant finding when a 10-year old child with an early on-set of progressive nerve damage was examined. The child experienced difficulty in walking and performing fine motor skills. The complete genetic analysis of the child showed a mutation in the protein KCC3 coding gene known as SLC12A6 gene. Upon further investigation, it was found that the gene was over expressed and the protein continued to perform the co-transporter function even when it was not required. The phosphorylation-mediated regulation of the transporter was disrupted, which leads towards the activation of the transporter to continue without a regulated inhibitor of the activity.

Resulting in ion and water molecule imbalance across the cell membrane, the neurons were shrunk and coordination between neighboring neurons was severely hampered. Known as gain-of-function mutation, the protein actively contributed to neural cell damage and to the manifestation of neuropathy symptoms. According to researchers, the KCC3 protein has been previously linked to other forms of neuropathy but what makes this study unique is the discovery of the “gain-of-function” mutation leading towards neuropathy.

In earlier evidence, mutations leading to nerve damage were caused by repressed KCC3 protein expression, which had a detrimental impact on the patient’s cognitive ability, in addition to restricted motor functions.  On the other hand, the neuropathy in the subject of this research only exhibited motor neuron problems, but no behavioral or cognitive problems were found.

To validate the understanding further, the manipulated gene was introduced in a mouse model and similar symptoms were observed. Dr Bonnemann, senior author of the paper said; “When we tested this mouse, we saw many of the same physical deficits, including problems with movement and coordination, and a decrease in the ability of neurons to send signals to the muscles”.

This helped pinpoint the mutation as the primary cause of neuropathy in the child. With a strong established linked between the genetic aberration and disease symptoms, avenues have been opened to formulate drugs to target KCC3 in neuropathy patients.

How Can This Discovery Open the Realms of Treatment for Neuropathies?

Previously, a drug by the commercial name of Lasix (Generic: Furosemide) has been used to treat water retention in the heart kidneys and liver, by regulating the co-transporter function. But no such drugs are present to help children. Scientists are hopeful that they will be able to work towards formulating a similar drug to treat neuropathy. Alongside this, the genetic testing for diagnosing neuropathy in children will also find the right dimension, whereby they can be helped before symptom manifestation.