Photo File/MLB Photos via Getty Images Lou Gehrig of the New York Yankees stands ready at the plate

Yankee great Lou Gehrig may not have had the motor-neuron disorder that was famously named after him.

That's the intriguing suggestion of a group of neurologists who describe a new type of degenerative nerve disease that bears a striking resemblance to Lou Gehrig's but is distinguished by the presence of two signature proteins that would not have been detectable in the Hall of Famer's time. (See the top 10 medical breakthroughs of 2009.)

Dr. Robert Stern, co-director of the Center for the Study of Traumatic Encephalopathy and co-author of a report appearing in the Journal of Neuropathology and Experimental Neurology, says Lou Gehrig's disease, technically known as amyotrophic lateral sclerosis (ALS), is just one of a range of motor disorders that are becoming better understood thanks to more sophisticated scientific techniques. Distinguishing them is not easy, he says  it's still possible only at autopsy, when pathologists can study brain tissue and look for telltale proteins or other molecular signatures of the different conditions. While the patient is alive, the signs and symptoms of these motor-neuron disorders look very similar  weakness or numbness in the limbs, uncontrollable twitching of the muscles and gradual loss of movement.

Stern and his team at the center made their surprising discovery in the course of studying brain tissue from athletes who had died of complications related to chronic traumatic encephalopathy, or CTE, in which repetitive concussions or other head injuries cause gradual deterioration of brain function. The team had reported previously that the brains and spinal cords of CTE patients had higher levels of a protein called tau. In the current study, they worked with samples of brain and spinal-cord tissue from 12 patients, all of whom had CTE and all of whom had the tau marker. But the researchers noticed that three of the donated tissues they had recently received had come from athletes who had also been diagnosed with ALS, so they decided to look for other protein signatures that such individuals might share.

ALS patients do not generally accumulate tau in their brains. It turned out that 10 of the 12 patients did have a second anomalous protein, known as TDP-43, which is responsible for helping the long fingers of nerve cells resume their function after being sheared or disturbed by a violent head trauma. But in only three of the patients had both proteins  not just the tau  invaded the brain and spinal cord and possibly caused the deterioration of the motor functions that led to their ALS diagnoses. (See "The Year in Health 2009: From A to Z.")

To make sure they had indeed found a condition that was truly different from both CTE and ALS, Stern and his team then compared the three patients' brains to those of other ALS patients who had not reported any traumatic head injuries and found that those brains did not contain the same proteins. In fact, no other brain studies have reported the presence of both tau and TDP-43, which led Stern's team to give the condition a new name: chronic traumatic encephalomyopathy, or CTEM. At the moment, Stern says, CTEM can be diagnosed only at autopsy, but the finding suggests that ALS and conditions like CTEM may look similar in the clinic but actually have very different biological causes. And that may be important for devising new therapies. "Our goal is to try to understand what a disease like ALS looks like while people are alive and to be able to develop biomarkers to diagnose and detect the disease while they are alive," says Stern. (See TIME's health and medicine covers.)

The new study is by no means concusive: the number of brains analyzed was small, and the finding needs to be replicated by other groups before doctors treating patients can even think about applying the results in clinics. But the report raises the intriguing possibility that ALS may be a catchall for several different but related motor-neuron disorders. "If you ask me how to distinguish between motor-neuron diseases and ALS, there is no clear distinction," says Dr. Hiroshi Mitsumoto, director of the Eleanor and Lou Gehrig MDA/ALS Multidisciplinary Care Center at Columbia University, describing the current lack of a definitive way to diagnosis ALS. "ALS is a disease of unknown cause, so we find the patient's [medical and family] history, examine the patient and exclude all possible diseases mimicking ALS."

Making such a conclusive diagnosis and distinguishing ALS from the other related diseases has not been critical until now, because there have been few effective treatments for ALS. But it may become more important in coming years. Treatments for CTEM, for example, may target the tau and TDP-43 proteins, while therapies for ALS may focus on entirely different proteins. "This is such a dreaded and enigmatic disease, for which we have no cure, and we don't know the cause, so anything with potential to understand the disease better should be studied, without a doubt," says Mitsumoto.

While the paper does not mention Lou Gehrig specifically, Stern says there is a possibility that the ballplayer may have suffered from CTEM rather than ALS; there were several accounts of his being hit in the head severely enough to knock him out. And he played in a then record 2,130 consecutive games from 1925 to 1939, during which he could have sustained any number of other, less severe blows to the head. But the possibility that Gehrig has been misdiagnosed all these years is still small, since even Stern acknowledges that CTEM is a very rare condition that requires a unique combination of environmental and biological factors. "In a way, it's more of an intellectual game to think whether he had what is referred to as Lou Gehrig's disease or some other type of motor-neuron disease," he says.

Gehrig has been the face of ALS ever since his diagnosis and emotional farewell from baseball in 1939, but he was cremated after his death in 1941, ensuring that his legacy as ALS's most famous patient will continue.

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