Medical Breakthrough Uncovers Rare Syndrome Linked to Neuron Failure and Severe Muscle Weakness

Understanding why some cells weaken while others resist remains one of the greatest challenges in modern biology. When an organism goes wrong for no apparent reason, the response is sometimes hidden well upstream of the symptoms, in the molecular architecture of life. It was by following this trail that researchers shed light on a previously unknown metabolic disorder, the cause of profound muscle failures in two children. This dysfunction, now referred to as MINA syndrome, reveals the unsuspected role of the cellular energy machinery in certain rare neurological pathologies.

When motor neurons fail

Two patients, brother and sister, from Eastern Europe, had presented since childhood a combination of neurological symptoms that medicine was unable to classify: poor coordination, muscular atrophy, malformations of the feet and hands, speech disorders, visual disturbances and generalized weakness. Nothing in the classic examinations explained the origin of this slow degradation. The brain appeared intact, standard scans revealed no obvious abnormalities. However, by adolescence, both children had lost the ability to walk.

An in-depth genetic analysis revealed an anomaly common to both children. Both had a homozygous mutation in the NAMPT gene, essential for the production of NAD⁺. This cofactor plays a key role in the energy metabolism of cells. The mutation, identified as p.P158A, acts like a grain of sand in a fundamental engine. However, this gene has never been associated with a human neurological disease. This discovery therefore represents a first. It allowed researchers to designate this disorder under the name MINA syndrome, for Mutation in NAMPT Axonopathy.

What MINA syndrome reveals about cellular energy

NAD⁺ plays a central role in almost all energy circuits in the cell. It is involved in particular in glycolysis, mitochondrial respiration and the Krebs cycle. However, in both patients, a mutation called p.P158A strongly deactivates the NAMPT enzyme. From then on, ATP production falls, while the redox balance becomes disorganized. As a result, the cells no longer use glucose correctly. They no longer react to metabolic stress and accumulate toxic compounds, including acylcarnitines and free radicals. This failure was confirmed by multiomic analyzes carried out on their fibroblasts.

This energy imbalance is particularly observed in motor neurons, among the longest and most demanding cells in the body. Their operation is based on a continuous distribution of energy throughout the axon, sometimes over more than a meter. Starved of fuel, these neurons degenerate, causing a progressive disconnection between the brain and muscles. Although the NAMPT mutation is present in all cells in the body, only those that carry an extreme energy load, such as motor neurons, appear vulnerable.

The study led by Zhang et al., published in Science Advances, confirms that this energy dysfunction not only causes a drop in NAD⁺ and ATP levels, but also an alteration of mitochondria, lipid metabolism and synaptic signaling, reinforcing the hypothesis of a hereditary metabolic disease not yet recorded.

Why this cellular breakdown escapes animal models

To better understand the mechanisms of MINA syndrome, researchers created a mouse model carrying the same genetic mutation. To their surprise, the mice did not develop any of the symptoms observed in the patients. They maintained a normal weight, intact motor skills and little altered biological markers. However, inside their cells, the same biochemical abnormalities were present, such as the drop in ATP, the NAD⁺ deficiency and the weakening of synapses.

This gap between humans and animals therefore raises a fundamental question. Why do certain cellular defects cause disease in humans, but not in mice? Several avenues are emerging. First, human motor neurons, much longer than those of rodents, require greater energy stability. Second, humans seem less able to compensate for the loss of NAD⁺ through alternative pathways. Finally, sensitivity to oxidative stress varies greatly between species. In humans, this stress accumulates until the cellular balance is disrupted.

This observation calls into question the ability of animal models to faithfully reflect certain rare pathologies. It encourages researchers to develop approaches closer to the human field, such as cerebral organoids derived from patient cells. With this in mind, the first attempts to restore NAD⁺ levels using molecules like NMN or P7C3 are proving promising. These compounds made it possible to restore energy to diseased cells in the laboratory, reviving the hope of a targeted treatment against this until recently unnamed disease.