Beyond Blood: Exploring Paraproteins in the Peripheral Nervous System

By Mayra Aldocoa, MD, Neurologist and Clinical Fellow from McGill University, Canada

Imagine experiencing unexplained numbness or pain in your limbs. A couple of weeks later, you trip and fall because your coordination is impaired. You then find out you have a type of white blood cell producing an abnormal amount of protein called a ‘paraprotein’. This is the reality for patients affected with Monoclonal Gammopathies of Neurological Significance (or MGNS), explained Professor Chiara Briani, Head of the Peripheral Neuropathy Centre of Padova in Italy, as she gives the Arthur K Asbury lecture at PNS2024.

Paraproteins are a type of antibody, called ‘immunoglobulin’, or fragment of it, which normally help defend us against microorganisms from the outside world. They are produced by plasma B-cells, or lymphoplasmacytic lymphoma cells, and come in one of three main categories: IgG and IgA, and IgM.  Having high amounts of these proteins in the blood (known as a ‘gammopathy’) is actually quite common: about 3% of people over the age of 50 have paraprotein and most will develop no further symptoms. However, they are also found in 10% of unexplained peripheral neuropathies.

One example of an IgM paraprotein disorder are anti-MAG antibodies, which attack part of the myelin sheath surrounding the nerves. Anti-MAG neuropathy is a slow and progressive disease affecting mainly sensory nerve cells. Electrical conduction within the nerves is impaired leading to loss of balance and coordination. An immunotherapy that kills the lymphoplasmocytes B-cells – called Rituximab – remains the primary treatment for IgM gammopathies. However, recent advances in our genetic understanding have improved treatment options. Mutations in the gene MYD88, which controls crucial pathways, are common in people with these disorders. New drugs targeting these pathways may offer effective treatment with fewer adverse effects, as well as may help patients who may not benefit from standard therapy. Fortunately, Dr. Briani tells us, “Controlled studies are underway…”.

IgG and IgA gammopathies are more varied and less frequently associated with neuropathy than IgM but should be suspected when presented with a rapidly progressing neuropathy with features of axonal damage, demyelination, pain, or autonomic dysfunction, explained Dr. Briani. Examples are Light chain (AL) amyloidosis and POEMS syndrome, the latter standing for the bodily systems affected: Poly-neuropathy (i.e., many nerves involved); Organ enlargement (typically liver or spleen); Endocrinological disorder; ‘M-protein’; and Skin changes. This complexity means diagnosis of POEMS is challenging and relies on specific criteria.

Besides polyneuropathy, Dr. Briani’s research has found that the majority of POEMS patients had a thickening of the meninges – the membrane that covers the brain and spine. Meticulous analysis showed that meningeal thickening (known as pachymeningeal involvement) is very common at diagnosis and was reduced in 62.5% of patients after treatment, particularly those with a complete or very good partial response. Dr. Briani’s team believe that brain pachymeningeal involvement could be a potentially useful addition to the diagnostic criteria in POEMS patients.

The range of signs and symptoms of gammopathies, from slow progressive anti-MAG neuropathies, to complex and rapidly progressive POEMS syndrome, mean that delays in diagnosis are still unfortunately common. Dr. Briani emphasised the need for collaboration between neurologists and blood specialists. Timely treatment is crucial because patient outcomes depend on it.

The PNS Science Journalist programme was facilitated Dr. Alexander Davies, Communications & Website Committee member & scientific article mentor.

One arrow for two targets? How genetic disorders could affect muscle and nerve at the same time

By Mayra Aldocoa, MD, Neurologist and Clinical Fellow from McGill University, Canada

This year’s PK Thomas lecture at PNS2024 was given by Dr. Tanya Stojkovic, Head of the Reference Center for Neuromuscular diseases at Pitié-Salpêtrière Hospital in Paris and past president of the French Peripheral Nerve Society. Through the practice of neurophysiology, she has developed an interest in myopathies, neuromuscular junction and peripheral nerve diseases. In her talk, titled “Hereditary Motor Neuropathies: from the Motor Neuron to the Muscle”, Dr. Stojkovic illustrated how the same genetic variants can lead to defects in both the muscle and nerve.

Traditionally, neuro-muscular conditions were treated as separate entities, with distinct treatments depending on the tissue affected. However, recent research has unveiled a complex interplay where different variants in the same genes can lead to both muscle diseases (myopathies) and nerve diseases (neuropathies). Imagine what could happen if instead of treating nerve and muscle disorders separately, we could develop treatments that address both specific inherited neuropathies and myopathies simultaneously?

So, what is a genetic variant? Doesn’t all our DNA differ from one another? ‘Variant’ in this case is used to refer to a specific change in the DNA or resulting protein sequence. A pathogenic variant, also known as a ‘mutation’, refers to a change in sequence that is associated with disease. Think of DNA as the instructions given to construction workers and the proteins as the building materials. Changing the instructions (DNA), jumbles the construction materials (proteins), disrupting the structure or function of the cells and tissues, leading to a disease.

Many of the pathogenic variants discussed by Dr. Stojkovic are related to the extracellular matrix: A network of proteins that provides structural and biochemical support to cells within tissues; a bit like the concrete that gives the structural integrity to a construction site. One standout example highlighted by Dr. Stojkovic was Laminin α2. This protein is critical in the extracellular matrix, acting like the main component in the cement mix and crucial for muscle and nerve function. The instructions for how to make it are found in the LAMA2 gene. A mutation in this gene can result in Merosin Deficient Congenital Muscular Dystrophy Type 1A (MDC1A). In MDC1A patients, along with the muscle dystrophy, abnormal nerve myelination with thinner myelin sheaths and reduced nerve conduction velocities occurs, causing significant weakness in all the body.

But proteins aren’t just passive components; they may also be specialized tools, such as enzymes, crucial for cell function. Some pathogenic variants affecting enzymes can lead to dual neuropathies and myopathies. For example, Valosin-containing protein (VCP) is one of the ‘quality control inspectors’ of the cell, responsible for the degradation of misfolded proteins – in other words, disposing of faulty building materials.

When the same materials are used in the construction of more than one building, variation in quality or a miscommunication between workers could have different impacts depending on where they are.

“This means we’ll have to use our eyes and our minds, because the same gene can cause several types of diseases, depending on the type of mutation, its location and the genetic background.”

Dr. Stojkovic’s work on the genetic overlap of these diseases has shown a real need for integrated approaches to study and treating these conditions. Clinical, imaging and histological testing will all be crucial to effectively diagnose and manage complex neuromuscular disorders.

The PNS Science Journalist programme was facilitated Dr. Alexander Davies, Communications & Website Committee member & scientific article mentor.

To be or not to be myelinated: The Axonal Dilemma and its relationship to genetic neuropathies

By Mayra Aldocoa, MD, Neurologist and Clinical Fellow from McGill University, Canada

The closing Keynote Lecture 2024 annual meeting of the Peripheral Nerve Society was given by Dr. Stefano Carlo Previtali, Head of the Clinical Centre for Neuromuscular Diseases and the Neuromuscular Research Unit at the San Raffaele Scientific Institute in Milan, Italy. In his lecture, “Peripheral Nerve Development and the Pathogenesis of Genetic Neuropathies”, Dr. Previtali explored the complex cell interactions involved in nerve development, what happens when it fails and offered some possible solutions.

During nerve development, signals between cells help make a crucial decision: to determine which nerve fibers, or ‘axons’, will be covered by an insulating myelin sheath. Schwann cells are responsible for forming the myelin sheath around axons, ensuring rapid electrical signal transmission. Schwann cells must also ‘sort’ which axons will be myelinated. This important decision is called ‘radial sorting of axons’ and involves Schwann cells separating and individually wrapping certain axons (larger than 1 micron in diameter) to ensure that nerves function correctly and transmit signals efficiently. However, radial sorting can go wrong in certain disorders of the peripheral nervous system, making this process the cause of some peripheral neuropathies and a potential target for regenerative medicine.

Impaired radial sorting of axons results in inadequate myelination of nerve fibers, known as a ‘dysmyelinating neuropathy’.  One example given by Dr. Previtali was LAMA2 disease, a genetic disorder affecting multiple organs in children. Gene carriers have severe muscular dystrophy, dysmyelinating neuropathy and respiratory failure early in life. LAMA2 mutations result in a loss of support of the extracellular matrix – the gel-like substance around Schwann cell-axon units of the nerve. In mice with LAMA2 mutations, this loss of matrix support disrupts the proper interactions between Schwann cells and their environment during radial sorting, affecting nerve development, and ultimately causing a peripheral neuropathy.

Numerous genes associated with nerve disorders encode molecules known to be involved in radial sorting. Many of them involve molecular pathways linking extracellular matrix and Schwann cells.  Little is known instead about molecules mediating direct interactions between Schwann cells and axons. These molecules may operate like tiny magnets, involving both repulsion and attraction mechanisms. Slit2, a repulsive molecule produced by Schwann cells, helps directs axon organization. The presence of too much Slit2 results in unsorted axons, while Slit2 elimination results in bundle sorting but random placement.

Dr. Previtali showed that defective radial sorting of axons is also observed in other genetic diseases such as the neuropathy Charcot-Marie-Tooth (CMT), as well as spinal muscular atrophy (SMA), where the neurons involved in voluntary movement of muscles are affected.

Hopes of treating axonal sorting defects could lie with small molecules called ‘linker proteins’. These ‘linkers’ help to reconnect orphan receptors on Schwann cells (or muscles) to the extracellular matrix. When added to muscle and nerves in mice, these proteins improved muscular strength and prevented paralysis, suggesting they could be used to rescue or even repair the neuropathy.

To translate these findings to patients it will be important to understand the best time of life for treatment, as well as the possible side-effects on brain development. However, Dr. Previtali was optimistic that the success of linker proteins in correcting nerve defects and improving muscle strength in mice demonstrates the potential for treating or even reversing LAMA2-disease in people.

The PNS Science Journalist programme was facilitated Dr. Alexander Davies, Communications & Website Committee member & scientific article mentor.