Charcot-Marie-Tooth Disease with Glaucoma

Clinical Characteristics
Ocular Features: 

Optic atrophy can be an ocular manifestation of CMT disease, especially in the X-linked forms, but this variant is the only one in which early-onset glaucoma is a feature.  It may begin at birth in some patients who have features of congenital glaucoma such as buphthalmos, while in other family members, including juveniles, only elevated intraocular pressures were reported.  Optic nerve damage seems to occur rapidly.

Systemic Features: 

This is a sensorineural disease of myelination that causes a polyneuropathy with muscular weakness and sensory deficits.  CMT4B2 is characterized by abnormal myelin sheath folding.  Symptoms of lower limb weakness and evidence of muscle atrophy commonly appear in the middle of the first decade with progression to upper limb involvement.  Areflexia follows with development of pes cavus and hammertoes.  Motor nerve conduction velocities may be severely reduced and muscle biopsies show severe loss of myelinated fibers and focal myelin sheath folding.

Genetics

This seems to be an autosomal recessive disorder although only a few families have been reported.  Homozygous mutations in the SBF2 gene (sometimes called MTMR13) (11p15.4) were found in these CMT families with early-onset glaucoma (604563).  This gene codes for SET binding factor 2 important to the normal development of the trabecular meshwork.  Not all SBF2 mutations cause glaucoma though.  Of course, it is possible that the occurrence of glaucoma is incidental and not part of CMT4B2 at all.

A clinically similar neurological condition without glaucoma, CMT4B1 (601382), has been reported to be caused by a mutation in MTMR2 located at 11q22 (601382). 

Treatment
Treatment Options: 

Little is known about the natural history of the glaucoma in this condition but it occurs early and severe visual loss seems to be common.  Early diagnosis and vigorous treatment are important.  The neurological disease requires a multidisciplinary approach with physical therapists, neurologists, orthopedic surgeons and the use of prostheses.

References
Article Title: 

Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease associated with early-onset glaucoma

Azzedine H, Bolino A, Taieb T, Birouk N, Di Duca M, Bouhouche A, Benamou S, Mrabet A, Hammadouche T, Chkili T, Gouider R, Ravazzolo R, Brice A, Laporte J, LeGuern E. Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease associated with early-onset glaucoma. Am J Hum Genet. 2003 May;72(5):1141-53.

PubMed ID: 
12687498

References

Hirano R, Takashima H, Umehara F, Arimura H, Michizono K, Okamoto Y, Nakagawa M, Boerkoel CF, Lupski JR, Osame M, Arimura K. SET binding factor 2 (SBF2) mutation causes CMT4B with juvenile onset glaucoma. Neurology. 2004 Aug 10;63(3):577-80.

PubMedID: 15304601

Azzedine H, Bolino A, Taieb T, Birouk N, Di Duca M, Bouhouche A, Benamou S, Mrabet A, Hammadouche T, Chkili T, Gouider R, Ravazzolo R, Brice A, Laporte J, LeGuern E. Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease associated with early-onset glaucoma. Am J Hum Genet. 2003 May;72(5):1141-53.

PubMedID: 12687498