Charcot-Marie-Tooth Disease, Dominant Intermediate E

A number sign (#) is used with this entry because dominant intermediate Charcot-Marie-Tooth disease E (CMTDIE) with focal segmental glomerulonephritis (FSGS) is caused by heterozygous mutation in the INF2 gene (610982) on chromosome 14q32.


Autosomal dominant intermediate Charcot-Marie-Tooth disease E with focal segmental glomerulonephritis is characterized by the neurologic features of CMT, including distal muscle weakness and atrophy and distal sensory loss, and the features of FSGS, including proteinuria, progression to end-stage renal disease, and a characteristic histologic pattern on renal biopsy (summary by Boyer et al., 2011).

Isolated focal segmental glomerulosclerosis-5 (FSGS5; 613237) is also caused by heterozygous mutation in the INF2 gene.

For a discussion of genetic heterogeneity of CMTDI, see 606482.

Clinical Features

Lemieux and Neemeh (1967) reported a French family in which several individuals had CMT disease, 1 of whom also had clear renal involvement. The 21-year-old proband developed walking difficulties at age 8 years, requiring orthopedic corrections, and showed hand weakness at age 14. At age 21 years, she had atrophy and weakness of the peroneal and anterior tibial muscles with steppage gait, atrophy of the distal muscles of the forearm, claw hands, and areflexia. At ages 19 and 21 years, she presented with fever associated with proteinuria and was found to have focal glomerulosclerosis and atrophic tubules on renal biopsy. However, renal function was normal. Her mother, a brother, and a sister had CMT, and the mother and 2 sisters had mild proteinuria, but no further renal studies were performed. Lemieux and Neemeh (1967) also reported 2 brothers with childhood-onset CMT, chronic nephritis, and deafness. However, mutations in the INF2 gene were not found in these brothers, suggesting that they may have had a different disorder (Boyer, 2012).

Hanson et al. (1970) reported a patient with distal muscle wasting, nephritis, and deafness, but with no family history of these features.

Boyer et al. (2011) reported 12 index cases of genetically confirmed CMTDIE. The median age of onset of proteinuria was 18 years (range, 10-21 years), with 11 patients developing end-stage renal disease at a median age of 21 years (range, 12-47 years). Renal biopsies showed typical FSGS. The median age at onset of neurologic dysfunction was 13 years (range, 5-28 years), and all had distal muscle atrophy and weakness affecting the lower limbs, although the severity was variable; older individuals had greater impairment. Four patients developed proteinuria before neurologic symptoms, 5 developed neurologic symptoms before proteinuria, and 3 developed both symptoms at the same time. The neurologic symptoms were progressive, and included difficulties walking, frequent falls, steppage gait, hypo- or areflexia, pes cavus, and distal sensory impairment. Seven patients also had significant upper limb involvement, some of whom had paresis of the hand muscles resulting in claw hands. Sural nerve biopsies showed axonal loss and onion bulb formation, and neurophysiologic studies were variable, most consistent with an intermediate form of CMT. Four patients also had mild to moderate sensorineural hearing loss.


In the families reported by Boyer et al. (2011), the transmission pattern of CMTDIE was consistent with autosomal dominant inheritance.

Molecular Genetics

In 12 (75%) of 16 index patients with CMTDIE with FSGS, Boyer et al. (2011) identified 9 novel heterozygous mutations in the INF2 gene (see, e.g., 610982.0006-610982.0011). One of the patients with a mutation had been reported by Lemieux and Neemeh (1967). The INF2 gene was selected for study because of its known role in FSGS5 (613237) and its known interaction with the myelin and lymphocyte protein (MAL; 188860); only exons 2, 3, and 4 were sequenced. All INF2 mutations in CMTDIE were located in exons 2 and 3, which encode the diaphanous inhibitory domain (DID), and most of them were between nucleotides 300 and 500 in the second and third armadillo repeats. These mutations were located in distinct areas from those associated with isolated FSGS5. Cells expressing mutant INF2 exhibited less cortical actin and a reduced number of long actin stress fibers compared to wildtype, suggesting a disorganized microtubule network. Boyer et al. (2011) concluded that mutant INF2 disrupts actin dynamics in peripheral Schwann cells, leading to disturbed myelin formation and maintenance and resulting in CMT.