Charcot-Marie-Tooth Disease, Type 4b2

A number sign (#) is used with this entry because Charcot-Marie-Tooth disease type 4B2 is caused by mutation in the SBF2 gene (607697).

Description

Autosomal recessive Charcot-Marie-Tooth disease type 4B is a demyelinating hereditary motor and sensory neuropathy characterized by abnormal folding of myelin sheaths. CMT4B1 (601382) is a clinically similar disorder caused by mutation in the MTMR2 gene (603557) on 11q22.

For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive demyelinating CMT, see CMT4A (214400).

Clinical Features

Gambardella et al. (1998) reported 2 sibs in a family from a small village in southern Italy who had early-onset CMT with focally folded myelin sheaths. The patients developed symptoms at 2 and 10 years of age, respectively. Both had progressive distal lower limb weakness and atrophy, followed by involvement of the upper limbs. There was distal sensory loss, areflexia, and bilateral pes equinovarus. Both patients also had unilateral sensorineural hearing loss, suggesting cranial nerve involvement. Sural nerve biopsy showed segmental demyelination and redundant loops and folds of the myelin sheath. Gambardella et al. (1998) suggested autosomal recessive inheritance. Linkage analysis excluded the CMT4B1 locus on chromosome 11q23.

Senderek et al. (2003) reported a consanguineous Turkish family in which 4 patients were affected with a severe sensorimotor neuropathy characterized by focally folded myelin sheaths on nerve biopsy. Disease onset was around age 5 years and was characterized by distal muscle weakness and atrophy, foot deformities such as pes cavus and hammertoes, steppage gait, and areflexia in the lower limbs. Motor nerve conduction velocities (NCVs) were severely reduced (e.g., 16.5 m/s, 18.5 m/s). Sural nerve biopsies showed severe loss of myelinated fibers with focally folded myelin protrusions.

CMT4B2 With Early-Onset Glaucoma

Kiwaki et al. (2000) reported a consanguineous family from southern Japan in which 3 members had hereditary motor and sensory neuropathy with myelin folding accompanied by juvenile-onset open-angle glaucoma. All 3 patients had early childhood onset of neuropathy, markedly slowed NCVs of less than 20 m/s, aberrantly excessive myelin folding complexes with segmental de- and remyelination on nerve biopsy, increased CSF protein, and juvenile-onset glaucoma.

Azzedine et al. (2003) reported 2 consanguineous families from Tunisia and Morocco with a demyelinating sensorimotor neuropathy and early-onset glaucoma. Mean age at onset was 8 years. Motor nerve conduction velocities were severely reduced, and nerve biopsies showed myelin outfoldings. In the index patient of each family, visual impairment was precocious and severe, leading to a loss of vision. Ophthalmologic examination showed congenital glaucoma with a buphthalmos, a megalocornea, and increased intraocular pressure. Other affected members of both families had increased intraocular pressure.

Mapping

In 2 Tunisian families with a CMT4B phenotype, Ben Othmane et al. (1999) excluded linkage to the CMT4B1 locus, thus demonstrating genetic heterogeneity. Using homozygosity mapping and linkage analysis in the largest Tunisian pedigree, they mapped the disorder to chromosome 11p15. A maximum 2-point lod score of 6.05 was obtained with marker D11S1329. Recombination events refined the CMT4B2 locus region to a 5.6-cM interval between markers D11S1331 and D11S4194. The second Tunisian CMT4B family was also excluded from linkage to the 11p15 locus, demonstrating the existence of at least a third locus for the CMT4B phenotype.

Linkage analysis of both families affected with CMT4B2 with early-onset glaucoma reported by Azzedine et al. (2003) yielded a maximum lod score of 6.25 at D11S4149. Haplotype reconstruction in both families placed the candidate interval in a 4.6-cM region flanked by markers D11S1760 and D11S4194.

Molecular Genetics

In all 4 affected individuals of a Turkish family with CMT4B2, Senderek et al. (2003) identified a homozygous in-frame deletion of exons 11 and 12 of the SBF2 gene (607697.0001).

In 2 Italian sibs with CMT4B2 reported by Gambardella et al. (1998), Conforti et al. (2004) identified a homozygous splice site mutation in the SBF2 gene (607697.0005).

CMT4B2 With Early-Onset Glaucoma

In 2 families with CMT4B2 with early-onset glaucoma, Azzedine et al. (2003) identified 2 homozygous nonsense mutations in the SBF2 gene (607697.0002-607697.0003). The mutations segregated with the disease in both pedigrees.

Hirano et al. (2004) identified a homozygous nonsense mutation in the SBF2 gene (607697.0004) in 3 affected members of a family with CMT4B2 with early-onset glaucoma reported by Kiwaki et al. (2000). Hirano et al. (2004) noted that CMT4B2 patients with truncating mutations in the SBF2 gene developed early-onset glaucoma.

Animal Model

Tersar et al. (2007) generated Sbf2-null mice as a mouse model of CMT4B2 and found that Sbf2-null mice progressively developed myelin outfoldings and infoldings in motor and sensory peripheral nerves concomitant with decreased motor performance. The number and complexity of myelin misfoldings increased with age, associated with axonal degeneration, and decreased compound motor action potential amplitude. There was mild impairment of nerve conduction velocities. There was not a significant alteration in myelin thickness or axon diameter. Loss of Sbf2 did not affect the levels of its binding partner Mtmr2 in peripheral nerves.

Robinson et al. (2008) found that mice with targeted disruption of the Sbf2 gene developed a peripheral neuropathy characterized by reduced nerve conduction velocity, myelin outfoldings and infoldings, and progressive dysmyelination, similar to that observed in CMT4B2. Although myelin infoldings and outfoldings were most prominent at the paranode, morphologic analysis indicated that the ultrastructure of the node of Ranvier and paranode was intact in Sbf2-deficient nerve fibers. Mtmr2 levels were decreased by approximately 50% in Sbf2-deficient sciatic nerves, suggesting a regulatory relationship between the 2 proteins.