The data expands the available information on clinical manifestations of the disease, which is extremely scarce, and calls attention to the fact that not all patients with CMT4B2 are affected by glaucoma. Genetic testing should be used for a diagnosis, even in the absence of signs of glaucoma, researchers note.
The study, “Novel SBF2 mutations and clinical spectrum of Charcot‐Marie‐Tooth neuropathy type 4B2,” was published in the journal Clinical Genetics.
Charcot-Marie-Tooth (CMT) disease is a group of inherited disorders of the peripheral nerves that can be caused by mutations in more than 80 different genes.
Mutations in the SBF2 gene (also called MTMR13) cause a subtype known as CMT4B, characterized by so-called out-foldings of myelin sheaths, the protective layer surrounding the nerve cells that are essential for the transmission of nerve impulses.
SBF2 encodes a protein called SET binding factor 2, of unknown function. At least five SBF2 mutations have been identified in CMT4B2 patients.
However, very few cases of CMT4B are known and have been studied. The small number of reported patients has limited an understanding of the link between SBF2 mutations and disease manifestations, knowledge important for medical care and genetic counseling.
Researchers in Europe identified nine novel SBF2 mutations found in 10 members of seven different families (Turkish, German, Czech, Indian, and Kurdish). The patients, ages 3 to 35 years old, had been referred for genetic testing due to suspected CMT.
Neurological signs were evident in all of them, including slow nerve conduction velocity, foot deformities, muscle weakness, or gait problems.
Nerve biopsies revealed loss of myelin-surrounded nerve cells, regions of de- and remyelination and irregular myelin folding, the hallmark of the disease.
In five patients, glaucoma — the buildup of fluid pressure inside the eye that can lead to vision loss — was diagnosed in the first year of life, while four remained without vision problems. One developed slightly increased pressure within the eye (intraocular pressure) in adulthood.
Disease progression, though, was slow and all patients were able to walk independently, some helped by assistive devices.
To create an up-to-date overview of the signs and symptoms of CMT4B2, researchers combined the information gathered from the patients with data collected from the literature, covering 25 additional patients with SBF2 mutations.
Several signs were shared: all had onset of peripheral nerve disorders in the first or early second decade of life, involvement of lower limb extremities, independent walking, absent or diminished reflexes, and myelin misfolding in nerve biopsies.
The study extended the spectrum of CMT4B2-causing SBF2 mutations to 22, and increased the reported clinical manifestations to 35 patients.
Based on this data, the researchers made key recommendations.
“Glaucoma is not a constant feature and genetic testing for demyelinating CMT should include SBF2, irrespective of presence or absence of glaucoma,” they stressed.
“[P]atients without ocular involvement appear at risk for developing glaucoma later in life and should be monitored for increased IOP [intraocular pressure].”
In addition, glaucoma does not seem related with certain types of SBF2 mutations termed truncations, as suggested by others. This and other studies report individuals with other mutations who also develop glaucoma.