Gene mutation may be culprit in kidney disease in CMT patients


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Medscape Medical News
Gene Mutation Links Kidney Disease to Common Nerve Disorder
Fran Lowry

December 21, 2011 — Mutations in the INF2 gene appear to be the culprit in the development of kidney disease among patients with Charcot-Marie-Tooth neuropathy.

A team of researchers led by Olivia Boyer, MD, PhD, from INSERM Unité 983 and Université Paris Descartes, Sorbonne, France, have identified 9 new INF2 mutations in a high percentage of patients with Charcot-Marie-Tooth neuropathy and focal segmental glomerulosclerosis (FSGS).

The results were published in the December 22 issue of the New England Journal of Medicine.

Although the finding may not be applicable to most patients with this common inherited neuropathy, and may not translate into immediate new treatments, it may lead eventually to a better understanding of Charcot-Marie-Tooth neuropathy, Amanda Peltier, MD, from Vanderbilt University, Nashville, Tennessee, told Medscape Medical News.

"Mutations in INF2 were recently identified in patients with autosomal dominant FSGS," Dr. Boyer and colleagues write. "INF2 encodes a formin protein that interacts with the Rho-GTPase CDC42 and myelin and lymphocyte protein (MAL) that are implicated in essential steps of myelination and myelin maintenance."

This observation led the researchers to hypothesize that INF2 may be the cause of cases of Charcot-Marie-Tooth neuropathy associated with FSGS.

INF2 Mutation Implicated

The study investigators performed direct genotyping of INF2 in 16 index patients with Charcot-Marie-Tooth neuropathy and FSGS. None of the patients had mutations in PMP22 or MPZ.

They found 9 new heterozygous mutations in 12 (75%) of the 16 index patients, all located in exons 2 and 3, encoding the diaphanous-inhibitory domain of INF2.

These 12 patients with INF2 mutations presented with an intermediate form of Charcot-Marie-Tooth neuropathy plus glomerulopathy with FSGS on kidney biopsy.

They also showed proteinuria at a median age of 18 years (range, 10 - 21 years), and end-stage renal disease developed in 11 patients at a median age of 21 years (range, 12 - 47 years).

Peripheral nerve dysfunction began in these patients at a median age of 13 years (range, 5 - 28 years). At diagnosis, 10 of the 12 patients had moderate to severe symptoms, including walking difficulties, limited hand function, muscle wasting, and abolition of deep tendon reflexes in the lower and upper limbs.

Four patients also had mild or moderate hearing loss, and magnetic resonance imaging of the brain in 2 patients showed white matter hyperintensity and ventricular dilation.

New Insights

Median nerve conduction velocities ranged from 23 to 45 m/second, and 6 sural-nerve biopsy specimens showed axonal and demyelinating changes, characterized by a marked decrease in myelinated fibers compared with that in age-matched control patients, as well as numerous multilayered "onion bulbs."

"Together, these data suggest an intermediate Charcot-Marie-Tooth phenotype in patients with INF2 mutations," the authors note.

The researchers also detected "robust" INF2 staining in Schwann cells and podocytes. In addition, they demonstrated that INF2 colocalizes and interacts with MAL in Schwann cells.

The mutations in INF2 disrupted the INF2-MAL-CDC42 pathway, which resulted in cytoskeleton disorganization, enhanced INF2 binding to CDC42, and mislocalization of INF2, MAL, and CDC42, the authors report.

They conclude: "INF2 mutations appear to cause many cases of FSGS-associated Charcot-Marie-Tooth neuropathy, showing that INF2 is involved in a disease affecting both the kidney glomerulus and the peripheral nervous system," adding that the findings "provide new insights into the pathophysiological mechanisms linking formin proteins to podocyte and Schwann-cell function."

Conclusion Overblown?

For Dr. Peltier, the study was very interesting, but the conclusion was somewhat overblown.

"They made it sound like this mutation accounted for 75% of cases of Charcot-Marie-Tooth but that's not truly accurate because they are really talking about patients who don't have any known mutations," she said.

"It is interesting because it's another genetic cause that might lead to more effective treatments, but unfortunately, you are only talking about a small subset of Charcot-Marie-Tooth patients," Dr. Peltier added.

In any case, it will be a while before this new finding can be used at the bedside, Dr. Peltier said.

"For example, we've known about the PMP22 mutation for a good 20 years now, but we still haven't come much closer to figuring out how to treat these patients," she pointed out.

Discovering genetic mutations will be most helpful for allowing scientists to determine how nerves work, Dr. Peltier added.

"The finding may not necessarily help Charcot-Marie-Tooth patients, but it may improve our understanding of how the neuropathy occurs, and which proteins are important, and may end up giving us information that we would not have gotten otherwise."

The study was funded by the Agence Nationale de la Recherche among others. Dr. Boyer and Dr. Peltier have disclosed no relevant financial relationships.

N Engl J Med. 2011;365:2377-2388.