For some children with rare diseases, being in the right place at the right time can lead to a treatment. That’s what happened to 8-year-old Ellie McGinn.
FROM GYMBOREE TO GENETIC DISEASE
“The first hint that something was wrong with Ellie’s balance, coordination, and muscle strength was when she was almost 3. At a gymboree birthday party, she couldn’t do what the other kids were doing,” recalled mom Beth Frigola McGinn. “Then she began saying ‘my feet hurt’. It was a sensation that we now know is due to the lack of feeling from the brain to the spinal cord to the feet that was sending a shock, a spasm. She was so little, she didn’t know how to describe it.”
An initial visit to the pediatrician in January 2011, about balance, led to “let’s just see how it goes” when Ellie flopped down the hallway. Beth and her husband Michael mentioned it again at a check-up on Ellie’s third birthday, in May 2011. This time Ellie’s painful feet were x-rayed, but they looked normal. “Let’s just keep an eye on it,” said the pediatrician, but by the end of the summer, Ellie was falling, her knees buckling after only 10 steps.
At the next visit to the pediatrician’s office, they saw a different doctor who recognized the abnormal gait. When Lyme disease and lead poisoning were ruled out, by late August 2011, Ellie was referred to a pediatric neurologist.
Scary possibilities loomed. A tethered spine? Cancer? Ellie had a second MRI as well as an MRS (magnetic resonance spectroscopy) at Children’s National Medical Center to image the soft tissues of her central nervous system. And that’s where luck entered the picture.
That day, they saw Dr. Adeline Vanderver, who had trained with Dr. Marjo van der Knaap
, a pediatric neurologist at the Center for Children with White Matter Disorders at VU University Medical Center, the Netherlands, who in 2003 had identified “leukoencephalopathy with brainstem and spinal cord involvement and increased lactate” (LBSL
So Dr. Vanderver had been specifically trained to recognize that Ellie’s scans revealed the telltale abnormal white matter nerve tracts in the brain and spinal cord that appeared damaged and had an increased lactate level. This was a sign of mitochondrial activity shifting from aerobic to anaerobic, like when lactic acid causes leg cramps after a sprint depletes oxygen from skeletal muscles.
THE DIAGNOSTIC ODYSSEY
LBSL is a leukodystrophy (abnormal white matter) with symptoms arising from abnormal mitochondria. But as Dr. van der Knaap and her team identified more patients, they realized that LBSL is autosomal recessive, inherited from two carrier parents, rather than due to a mutation in one of the 37 genes in the mitochondrial genome. But anything that disrupts mitochondria will lead to fatigue, weakness, and poor coordination -- exactly the problems that Ellie was developing.
The gene that is mutated in LBSL, DARS2
, encodes a mitochondrial tRNA synthetase, which is an enzyme that attaches one of the 20 types of amino acids (aspartic acid for DARS2
) to transfer RNAs. The enzyme acts only in mitochondria, and when abnormal or deficient, dampens protein synthesis there.
Fewer than 100 cases have been reported, 20 in the US. Dr. van der Knaap’s team described great variability
among 78 patients, ranging from early infantile onset and early death, to adult onset with gradual weakening until a wheelchair becomes necessary. Ellie has the most common presentation – childhood onset with gradual decline.
has many distinct mutations – the 78 patients had 60 mutations, and nearly all patients have two different missense mutations (compound heterozygotes), which substitute single amino acids. Deletion of the gene in animal models is lethal. A splice site mutation specific to neural cell types may lie behind LBSL.
Beth and Michael dove into the medical literature, and soon papers by Dr. van der Knaap led to her collaborator Dr. SakkuBai Naidu at the Kennedy Krieger Institute (KKI) of Johns Hopkins University in Baltimore.
“Dr. Naidu said, ‘I’ve heard about your case, and I’m not sure if I can help, but come today to Baltimore. We’ll need blood and urine and she can’t eat for 3 hours.’ So we took the goldfish out of Ellie’s mouth, packed up, and drove an hour and a half north. Then we didn’t hear for awhile,” Beth said.
Meanwhile, Ellie was being considered as a candidate for a treatment used on some patients with mitochondrial diseases – nutrient “cocktails” tailored to a patient’s biochemistry.
When the family returned to KKI a few weeks later, they met with Dr. Naidu, Dr. Richard Kelley, an expert in metabolic diseases and biochemistry, and a geneticist. “They came into the room and asked to see Ellie walk. Ellie got off the table and she started down the hallway, and within 10 feet she grabbed onto the wall because her knees buckled,” Beth recalled.
INTO THE MITOCHONDRIA
Dr. Kelley picks up the narrative. “Ellie’s biochemical abnormalities were similar to what we find in many childhood mitochondrial diseases, especially those with deficiencies of mitochondrial complex I.” A carefully calibrated mix of co-enzymes, vitamins, antioxidants and amino acids might restore enough mitochondrial function to improve Ellie’s walking. Most importantly, it couldn’t hurt (see “A Modern Approach to the Treatment of Mitochondrial Disease
“Complex I” is a large, organized group of mitochondrial proteins that transfer electrons from NADH to ubiquinone (aka coenzyme Q10). The transfer sets up a cascade of positive charges, which provides the energy that ultimately produces ATP, the body’s energy currency. But complex I, especially when impaired, is also the source of oxygen free radicals, which are atoms with unpaired electrons that damage delicate cell parts. Such oxidative, free radical damage is why we need to eat foods rich in antioxidants, such as fruits and vegetables.
Dr. Kelley described Ellie’s treatment. “I design a specific ‘cocktail’ for each patient based more on the individual’s metabolic abnormalities than on the genetic defect. The cocktails prevent oxidative damage, increase the activity of impaired mitochondrial pathways, and replace secondary amino acid and vitamin deficiencies.”
Ellie’s formula is similar to what Dr. Kelley uses to treat children with autism associated with mitochondrial dysfunction
. The mother of one of his autism patients helped a company, MitoMedical
, develop MitoSpectra, which is $104 for 180 capsules, with 1 to 8 suggested per day, based on a physician’s recommendation. Pharmaceutical compounding would cost much more.
The cocktail components make biochemical sense (see the 2009 paper linked to above). However, the United Mitochondrial Disease Foundation cautions
that a physician familiar with metabolic disorders be consulted before attempting a dietary intervention, which may be inappropriate or even harmful for some of the hundreds of types of mitochondrial diseases.
Dr. Kelley was concerned only with Ellie. “I simply worked to enhance the natural system in the mitochondrial inner membrane for dealing with free radicals, which is vitamins C and E and CoQ10. Any one of these alone rarely works. It’s the combination that does the trick.” Ellie also takes carnitine and pantothenic acid (vitamin B5), which can increase complex I activity, and amino acids that provide alternate metabolic routes for mitochondria to extract energy from nutrients.
Ellie especially needed the amino acid methionine; some patients require threonine, isoleucine, and/or tyrosine. The situation is subtler than a simple blood test that assays levels of a single amino acid type, Dr. Kelley maintained, because being at the low end of the normal range for a few key amino acids can impair mitochondria. She also takes vitamins that can increase mitochondrial function (B1, 2, and 3 and biotin) and alpha lipoic acid, consuming a ½-teaspoon mixture thrice daily in an orange-flavored drink.
ANECDOTAL EVIDENCE, BUT NO CLINICAL TRIAL -- YET
Ellie has done very well since starting on the cocktail. “We began to see the results very quickly. Within a week, her energy level and appetite did a complete 180. That was October 2011. By January we noticed ability to walk longer without falling. Within 18 months on the cocktail, her leg spasms and falling completely disappeared. She wasn’t the fastest kid in her class, and she still can’t run very far, but that summer she hiked for a mile. More recently, in the 5k race for acureforellie.org, she ran about a quarter mile, but then she was winded, her muscles cramping. So she’s not cured, but this was a child who when she first visited KKI couldn’t walk down the hall without falling,” Beth said.
Ellie’s turnaround began exactly five years ago. “She has just started third grade, and takes tennis lessons and swims and does a lot of things healthy kids do, but that can take longer. She’s an animal lover to the core, wants to be a veterinarian, and is working on us to get a dog,” Beth said.
A few other children with Ellie’s disease have responded to the formula with improved gait – a boy in Brazil, others in Germany and New Zealand, a young woman in Italy. Some of them see Dr. Hilary Vernon in the metabolism clinic at KKI. But dietary intervention is not the main focus at the institute.
The KKI team is developing an animal model to ultimately test a novel, small molecule antioxidant delivered using nanoparticles, which would enable the researchers to directly track its effects. “Nanoparticles enhance the ability to achieve more targeted delivery into the CNS, rather than the small fraction of a nutritional compound that is taken up,” explained Dr. Ali Fatemi, Director, Division of Neurogenetics and the Moser Center for Leukodystrophies at KKI.
The group is also planning a natural history study as part of the Global Leukodystrophy Initiative
, a consortium that is using standardized forms to collect data across different sites to measure degree of ataxia and perhaps correlate it clinically, “We’ll be looking for numbers to get a sense of the rate of progression” of the disease Dr. Fatemi said, information that is crucial to assessing whether clinical improvement is due to an experimental treatment or lies within the range of the natural history.
Until preclinical and clinical trial results can show a sustained effect with appropriate controls for the nutritional approach, some health care providers (and insurers) remain skeptical. Dr. van der Knaap said in an email that “there is no scientific evidence that supplements work, and I do not give any for the patients with LBSL I know.” Although Dr. Fatemi agreed with Dr. Kelley that ataxia in some children has improved, he added that effects on the dementia that typically appears in adolescence aren’t known.
Starting a clinical trial will face the common hurdles of assembling a cohort for a very rare disease and implementing controls, complicated by the tailored, multiple-component nature of the cocktail. And the wide availability of nutritional supplements may foster a potentially harmful DIY attitude while countering financial incentive for a pharmaceutical company.
A clinical trial is clearly the best way to demonstrate whether any treatment, nutrient cocktail or nanoparticle-loaded small molecule, can help. Summed up Dr. Fatemi, “Rather than promoting any remedy at this point, we are hoping to raise awareness about this disease.”
Beth McGinn can connect parents with Dr. Kelley through acureforellie.org
Kennedy Krieger Institute