Rare Disease Report

Physician Perspective on LBSL

APRIL 20, 2018
Krista Rossi
Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a rare genetic disorder.

It is slowly progressive and primarily pertains to the brain and spinal cord, affecting gait and motor symptoms. Patients with LBSL are typically cognitively intact, but between ages 2 years and 6 years of age, they develop balance issues and difficulty with their gait.

Unofficially, pediatric patient Ellie McGinn has renamed it the “Awesome Disease.”

Dr Ali Fatemi, MD, Director of the Moser Center of Leukodystrophies, and associate professor of neurology and pediatrics at Kennedy Krieger Institute and John Hopkins University, described this “Awesome Disease,” and the young girl now inspires his research. 

In an interview with Rare Disease Report, Dr Fatemi summarized his reasoning for working so heavily in the LBSL space. “One [reason] is that we have a lucrative program here [Kennedy Krieger Institute]; this is what we do for a living. We’re interested in diseases that affect the brain’s white matter."

"Second was Ellie herself and her mom. She wasn’t even my patient, but one of our team members asked me, 'Have you met this girl and her mom?' She was just hoping to meet me as the director of the clinic, and I met them on the staircase. She's one of the main reasons, I think.”

“I think, given that [Ellie] has improved on an antioxidant ‘mitochondrial cocktail,’ there is some hope that this is a treatable disorder, and that there is an opportunity here. I think that makes a big difference when you have a disease. There is some rational for a therapeutic. It’s [LBSL] not a low-hanging fruit, but it’s a lower-hanging fruit than many other rare diseases. This is something that certainly made sense for us to explore.”

It’s a slowly progressive disorder, explained Dr Fatemi. For example, when a patient is examined after 10 years of follow-up, approximatrely half of them will require assistance walking. At present, there isn’t enough data to evaluate how these individuals will thrive (or not) as they age.

Fortunately, after years of research, a mutation in the DARS2 gene has been linked to the condition and the symptoms that could result in a lack of mobility. “This proves part of the problem—a lack of detailed knowledge about this disorder,” said Dr Fatemi. “There’s really no comprehensive natural history study that has been done on this disorder yet.”

Some individuals experience a later onset of the disease than others; however, which only increases the difficulty in diagnosing it and treating it both properly and efficiently. “We saw someone from Russia who didn’t have any symptoms until her early 20s, and some kids similar to that are reported in the literature [on the disorder],” Dr Fatemi said. On the other extreme, however, he also explained how some individuals experience an extremely early onset of the disease.

“We’ve also seen a very severe form of this disease that is essentially neonatal in onset, and, presumably, is prenatal in onset. The babies are born and have half the symptoms right at birth [such as] severe, low muscle tones, head lag (hypotonia), respiratory issues, seizures, and very small heads (microephaly).”

“Those individuals, in the very neonatal form of this disease or early infantile form of this disease, are severely affected. They have mobile delays, cognitive impairment, and bad epilepsy. There’s a handful of them that have been reported at autopsy (meaning they died). We really are just learning about these infantile forms. The first cases reported was in 2011, so this is quite a new disorder.”

While it is broadly understood that LSBL is an autosomal receptive disorder caused by mutations in the DARS2 gene, there has been much deliberation over whether the disease is a mitochondrial disorder or something more than that.

“There’s been a discrepancy over the last 2 years, and there have been 2 camps of people: one camp claims this is not a mitochondrial disease, even though the gene is responsible for mitochondrial protein synthesis; the other says this is a mitochondrial disease.

“I think the bottom line is we need to do some more experiments to figure this out exactly.”
  
Conflicting takes aside, Fatemi stressed how complicated LBSL really is: “[When] we knock out this [DARS2] gene in specific cells and look at those cells, we do see decreased mitochondrial activity. But so far, in the patients, when they studied their skin or muscle cells, they have not seen abnormal mitochondrial activity. It’s not entirely clear why that’s the case. The thought is that 90% of the patients have mutations on one specific site of this gene, which is a so called “splice site.”

The lack of research on LBSL only emphasizes the need for enhanced research. Currently, Dr Fatemi and his colleagues at the Kennedy Krieger Institute are working on obtaining more data.

“One of the things we are doing right now is that we have generated animal models in which we have selectively knocked out the gene in the brain. We are also looking at patients views of stem cells and are looking at mitochondrial activity there. In the mice, we see that affected cells actually have more mitochondria. So, we do have some suggestions from the animals that this is a mitochondrial problem, but it may be specific to the brain cells.”

To prove the benefit being provided by the work being done in the LBSL space, Fatemi says to look no further than the remarkable case McGinns. “There have been attempts to treat this disease even though we don’t know a whole lot about it. People have been tried on an antioxidant ‘mitochondrial cocktail,’ which is what Ellie McGinn, the girl from the McGinns family from the Cure for Ellie foundation, is on. Some of these individuals, by reports from the parents, are said to have improved with their gait, wobbliness, and hand tremors.”

“I think there are only 5 or 6 individuals who are on this [antioxidant combination], and there really hasn’t been any systematic studies. We also don’t know the exact cause of the disease. I am hopeful that the [medicine] is doing something. Certainly in Ellie, we have seen that her gait and hand tremors improved, and she is doing quite well. She’s not normal—she has seizures, she has a wobbly gait, she has hand tremors—but she is pretty high functioning.”

An ongoing study is currently being conducted by Dr Fatemi and his colleagues to learn more about LBSL. “One of the things we don’t know though is if she would have been the same way if we hadn’t treated her. This [Ellie’s treatment, a combination of vitamins and antioxidants targeted to the dysfunction in LBSL mitochondria] was not done at a clinical trial, and it’s very difficult to do a clinical trial with supplements you can get over the counter. We have an aim here as part of our research program to understand this disease and come up with therapeutics.”

This past week, the Kennedy Krieger Institute and “A Cure for Ellie” presented a conference on LBSL in Baltimore, Maryland to help further spread awareness on the rare disease and its need for more research.

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