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A Dietary Change Found to Help Patients with Rare Familial Neuropathy

Talan, Jamie

doi: 10.1097/01.NT.0000408563.73345.e4
HEREDITARY SENSORY AUTONOMIC NEUROPATHY — shown here in a young girl —is characterized by a sensory deficit in the distal portion of the lower extremities, chronic perforating ulcerations of the feet, and progressive destruction of underlying bones

HEREDITARY SENSORY AUTONOMIC NEUROPATHY — shown here in a young girl —is characterized by a sensory deficit in the distal portion of the lower extremities, chronic perforating ulcerations of the feet, and progressive destruction of underlying bones

Adding a single amino acid – L-serine – to the diet of patients with a rare familial neuropathy reduced levels of a potentially toxic lipid, and could potentially improve sensory and peripheral disability, according to a pilot study of 14 people with hereditary sensory autonomic neuropathy type 1 (HSAN1).

The clinical trial, conducted at Harvard Medical School, was initiated after the scientists found that HSAN1 transgenic animals fed a diet rich in L-serine showed significantly lower levels of deoxysphingolipids (dSLs) that are believed to be toxic for sensory neurons. The animals on the L-serine-enriched diet also exhibited improvements on sensory and motor tasks, the investigators reported in the Nov. 1 online edition of The Journal of Clinical Investigation.

HSAN1 is caused by several missense mutations in the genes encoding two of the subunits of the enzyme serine palmitoyltransferase (SPT). The mutation — documented in 120 patients worldwide — alters the activity of the enzyme SPT, which normally uses L-serine as a substrate. In the mutated form, the enzyme swaps out L-serine for L-alanine or glycine. The reduced affinity for L-serine leads to the generation of toxic dSLs that are five- to 10-fold higher in HSAN1 patients.

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In the first set of experiments, Florian Eichler, MD, assistant professor of neurology at Harvard, and his colleagues set out to test whether a buildup of this toxic substance leads to peripheral neuropathy. The Harvard team fed transgenic animals a 10 percent L-serine-enriched diet and found that it reduced dSL levels and led to significant improvements on a number of peripheral and sensory measures. But when they fed another group of transgenic mice a 10 percent L-alanine-enriched diet, the dSL levels climbed and the neuropathy got worse.

Designing the perfect study proved challenging. The mice that carry the transgene do not show symptoms of neuropathy until 15-months old. But Dr. Eichler said that luck was on their side. When they fed the animals the 10 percent L-alanine diet they developed severe neuropathy by two months. Histopathology revealed that they were losing their large myelinated and unmyelinated axons in the sciatic nerve. They also had ulcerations and hair loss, similar to patients with the mutation.

By contrast, the animals on the L-serine-enriched diet showed preserved sensory and motor performance well beyond the 15-month period when symptoms would normally arise. Histopathology revealed healthy axons.

“We just did not expect this,” said Dr. Eichler. “This is a real indication that it was impacting the peripheral nerves in a big way.” Unlike patients, the HSAN1 transgenic mice also had infertility and low sperm count. These problems were also corrected with the L-serine diet, he added. “Dietary intake can have an impact and we were able to show it.”

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On the heels of the animal work, the Harvard scientists began designing a pilot study in HSAN1 patients, which is also reported in the current paper. Dr. Eichler and his colleagues had been following a large family with a known HSAN1 mutation and in 2009 the family invited some of the scientists to their annual reunion in a small town outside Scranton, PA.



Dr. Eichler said that he packed several bottles of the supplement in his bags and drew blood from dozens of family members before and after a meal; dSL levels were slightly higher after eating. Attempts at altering dSL levels by diet alone do not work, he explained, because all foods that are rich in the beneficial amino acid, L-serine, are also high in the detrimental amino acid, L-alanine.

The researchers enrolled 14 family members with neuropathy. They were given enough L-serine supplements — at 200 or 400 mg/kg —for 10 weeks. Blood tests taken every two weeks measured dSL levels. The dSL levels in their study dropped up to ten-fold into the range found in healthy people.

By six weeks, dSL levels dropped to normal levels. The higher dose of L-serine in the diet produced quicker results but overall the study subjects were all within the normal range, Dr. Eichler said. When they stopped the treatment, dSL levels started to rise again, according to results from the pilot study.

The short duration of the study made it impossible to assess a change in symptoms. But Dr. Eichler said that a few patients reported increased menstrual cramps and tingling in the hands.

Dr. Eichler and his colleagues will start a double-blind placebo trial of L-serine in 20 patients with the HSAN1 mutation. They will look for improvements in nerve conduction, epidermal nerve fiber density and see whether it reduces the symptoms of neuropathy.

They are also following six patients from the initial pilot study who are taking L-serine supplements for a year. Routine blood tests to assess levels of the neurotoxic lipid, diaries tracking symptoms, and changes in sensory and peripheral measures will help determine whether the levels of dSLs correlate with the symptoms and if the added amino acid makes a difference in the natural history of the disease, said Dr. Eichler.

“It is hard to imagine that this treatment will reverse neuropathy but we are aiming to arrest the disease process,” Dr. Eichler added. Ultimately, he thinks that the real benefit will come for the children who carry the rare mutation but have yet to develop symptoms, which can start in the early 20s with tingling and shooting pain in the hands and feet and progress to a loss of sensation. Patients also lose hair on their distal limbs.



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Christopher Klein, MD, a neurologist at the Mayo Clinic in Rochester, MN, said that an additional reason for optimism arises from earlier experience in other neurologic metabolic disorders where inborn errors of metabolism have been treated by amino acid supplementation. Specifically, children with other serine-metabolism defects (serine-deficiency syndromes) who have low serine levels and associated congenital microcephaly and seizures benefited from oral serine supplementation.

In those patients, the L-serine supplementation has allowed for normalization of serine levels, improved seizures and possibly returns of normal head size with early treatment and was generally tolerated at doses comparable but also at higher doses (600 mg/kg/day).

“Although different disorders this experience supports the potential safety issues,” said Dr. Klein. supplementation. Specifically, children with other serine-metabolism defects (serine-deficiency syndromes) who have low serine levels and associated congenital microcephaly and seizures benefited from oral serine supplementation.

Peter J. Dyck, MD, director of the Peripheral Nerve Research Laboratory at the Mayo Clinic in Rochester, MN, called the work “highly meritorious,” but said that “results in the murine model may not be replicable in the human disease and it may take considerable effort and time to assess whether this treatment will be as effective” in patients.

“These data suggest a rational candidate therapy for this devastating condition,” said Steven S. Scherer, MD, PhD, professor of neurology at University of Pennsylvania, who wrote an editorial for the study. “It is a noteworthy step forward.”

This possible treatment, he added, “does not have implications for any other neuropathy. L-serine is unlikely to help patients who have other forms of neuropathy, including other forms of Charcot-Marie-Tooth (CMT),” for example, he said.

In anticipation of the phone calls from patients, Dr. Scherer said, clinicians might considering offering these take-home messages: “L-serine has not yet been proven to help patients who have HSAN1. It will be difficult to perform such a clinical trial – the number of HSAN1 patients is small, the natural history of HSAN1 is incompletely known, there are no validated outcome measures for HSAN1, and it is unlikely that any therapy can reverse the ravages of a chronic neuropathy.”

Michael Shy, MD, professor of neurology at Wayne State University School of Medicine, said that scientists may find recruitment for such studies difficult since patients can now go out and obtain L-serine on their own. “However, if diet supplementation does not significantly reverse the neuropathy, which is doubtful in a chronic condition with chronic axonal loss, it will be very important to conduct such a trial to measure not only the extent of improvement but to [also] determine when it occurs in the disease,” Dr. Shy said.

He added that an important issue for other inherited and acquired axonal neuropathies will be to determine what happens to patients who have had the disorder for years. It is commonly thought that axonal degeneration in chronic neuropathies will ultimately make them much more difficult to treat because axons will need to regenerate and contact their appropriate targets, chronically denervated Schwann cells may no longer function adequately to provide trophic support, and chronically denervated neuromuscular junctions (for motor axons) may be become refractory to re-innervation

“If patients with long-term cases of HSAN1 show better than expected improvement with L-serine,” said Dr. Shy, “then this would make investigators and patients with other forms of chronic neuropathy more excited about ultimate therapies for their forms of neuropathy.”

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Garofalo K, Penno A, Eichler FS, et al. Oral l-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1. J Clin Invest 2011; E-pub 2011 Nov 1
    Scherer SS. The debut of a rational treatment for an inherited neuropathy? J Clin Invest 2011; E-pub 2011 Nov 1.
      ©2011 American Academy of Neurology