CMT and Deafness

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CHARCOT-MARIE-TOOTH DISEASE AND DEAFNESS

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=118300

CHARCOT-MARIE-TOOTH NEUROPATHY AND DEAFNESS, AUTOSOMAL DOMINANT

CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 1E; CMT1E

Gene map locus 17p11.2

TEXT

A number sign (#) is used with this entry because this syndrome, at

least in some cases, is caused by mutation in the peripheral myelin

protein-22 gene (PMP22; 601097). In these cases, inheritance is

autosomal dominant.

Mild deafness is sometimes coupled with the X-linked form of CMT

(302800). See 214370 for a possibly autosomal recessive form of CMT-

deafness syndrome and 311070 for an X-linked disorder that includes

optic atrophy also.

For a phenotypic description and a discussion of genetic

heterogeneity of autosomal dominant demyelinating CMT, see CMT1B

(118200).

CLINICAL FEATURES

Lemieux and Neemeh (1967) described 2 families, each with multiple

cases of CMT disease. In 2 members of one family and 1 member of the

other, chronic nephritis was also present. Foam cells were seen in

the interstitium in 1, and 2 of the 3 had nerve deafness. These

patients did not have the nonspecific polyneuropathy, due possibly to

chronic uremia, occasionally associated with Alport syndrome

(104200). Amyloidosis (see 176300), a cause of nephritis and a

condition misdiagnosed as CMT disease, was apparently excluded.

Hanson et al. (1970) reported a sporadic case.

Pyeritz (1979) examined 3 affected members of 2 generations of a

western land kindred, and Gummerson (1981) examined several

members of a southern Pennsylvania kindred. In both pedigrees,

classic CMT was always associated with sensorineural deafness. No

instance of renal disease occurred in either pedigree. A common

surname suggested that the kindreds were distantly related.

Kousseff et al. (1982) and Kousseff (1982) described a family in

which 82 persons in 7 generations appeared to have had this disorder.

Male-to-male transmission was observed 13 times. Onset occurred in

childhood with weakness of peroneal muscles, followed by atrophy, pes

calcaneovarus, steppage gait, poor balance, and diminished sensation

in the legs. Other distal muscles of the arms and legs became

involved, resulting in claw hands, pes cavus, hammertoes, and absent

deep tendon reflexes. Neuropathy was demonstrated by

electromyography. Sensorineural hearing loss, which became apparent

in the second decade, was severe to profound in most affected persons

after the third decade.

Hamiel et al. (1993) described as a 'new variant' a 3-generation

family in which hereditary motor-sensory neuropathy with

sensorineural deafness became apparent in early childhood and

infancy. Linkage to Duffy blood group on chromosome 1, where CMT1B

maps, was excluded. Duplication of the PMP22 gene (601097) found in

CMT1A (118220) was also excluded. Male-to-male transmission was

observed.

MOLECULAR GENETICS

In the family originally reported by Kousseff et al. (1982), Kovach

et al. (1999) identified an ala67-to-pro mutation in the PMP22 gene

(601097.0010).

Deafness appears to be a rare association with CMT in those cases in

which mutation in the PMP22 gene is responsible. Boerkoel et al.

(2002) noted that only 2 mutations in the PMP22 gene had been

identified as the cause of CMT and deafness: A67P (601097.0010) and

W28R (601097.0014).

In 3 affected members of a family with autosomal dominant CMT with

deafness, Sambuughin et al. (2003) identified a 12-bp deletion in

exon 4 of the PMP22 gene (601097.0015).

NOMENCLATURE

In keeping with the most common designations used in the medical

community, 'CMT1' referring to autosomal dominant demyelinating CMT

and 'CMT2' referring to axonal CMT, we have chosen to designate this

form of demyelinating CMT with hearing loss as 'CMT1E.'

REFERENCES

1. Boerkoel, C. F.; Takashima, H.; , C. A.; Olney, R. K.;

, J.; Berry, K.; Russo, P.; Kennedy, S.; Teebi, A. S.;

Scavina, M.; , L. L.; Mancias, P.; , I. J.; Krajewski,

K.; Shy, M.; Lupski, J. R. :

Charcot-Marie-Tooth disease and related neuropathies: mutation

distribution and genotype-phenotype correlation. Ann. Neurol. 51: 190-

201, 2002.

PubMed ID : 11835375

2. Gummerson, K. S. :

Personal Communication. Baltimore, Md., 1981.

3. Hamiel, O. P.; Raas-Rothschild, A.; Upadhyaya, M.; Frydman, M.;

Sarova-Pinhas, I.; Brand, N.; Passwell, J. H. :

Hereditary motor-sensory neuropathy (Charcot-Marie-Tooth disease)

with nerve deafness: a new variant. J. Pediat. 123: 431-434, 1993.

PubMed ID : 8355122

4. Hanson, P. A.; Farber, R. E.; Armstrong, R. A. :

Distal muscle wasting, nephritis, and deafness. Neurology 20: 426-

434, 1970.

PubMed ID : 5462235

5. Kousseff, B. G. :

Inheritance of Charcot-Marie-Tooth disease with sensorineural hearing

loss. (Abstract) Clin. Res. 30: 292A, 1982.

6. Kousseff, B. G.; Hadro, T. A.; Treiber, D. L.; Wollner, T.;

, C. :

Charcot-Marie-Tooth disease with sensorineural hearing loss--an

autosomal dominant trait. Birth Defects Orig. Art. Ser. 18: 223-228,

1982.

7. Kovach, M. J.; Lin, J.-P.; Boyadjiev, S.; , K.; Mazzeo,

L.; Herman, K.; Rimer, L. A.; , W.; Llewellyn, B.; Jabs, E. W.;

Gelber, D.; Kimonis, V. E. :

A unique point mutation in the PMP22 gene is associated with Charcot-

Marie-Tooth disease and deafness. Am. J. Hum. Genet. 64: 1580-1593,

1999.

PubMed ID : 10330345

8. Lemieux, G.; Neemeh, J. A. :

Charcot-Marie-Tooth disease and nephritis. Canad. Med. Assoc. J. 97:

1193-1198, 1967.

PubMed ID : 6054293

9. Pyeritz, R. E. :

Personal Communication. Baltimore, Md., 1979.

10. Sambuughin, N.; de Bantel, A.; Mc, S.; Sivakumar, K. :

Deafness and CMT disease associated with a novel four amino acid

deletion in the PMP22 gene. Neurology 60: 506-508, 2003.

PubMed ID : 12578939