Compound heterozygous deletions of PMP22 causing severe CMTof DSD phenotype

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Am J Med Genet A. 2008 Sep 15;146A(18):2412-6.

Compound heterozygous deletions of PMP22 causing severe Charcot-Marie-

Tooth disease of the Dejerine-Sottas disease phenotype.

Al-Thihli K, Rudkin T, Carson N, Poulin C, Melancon S, Der Kaloustian

VM.

F. e Fraser Clinical Genetics Unit, Division of Medical

Genetics, McGill University Health Centre/Montreal Children's

Hospital, Montreal, Quebec, Canada.

Dejerine-Sottas disease (DSD) is a particular phenotype of the

Charcot-Marie-Tooth (CMT) disease spectrum that is genetically

heterogeneous. It represents a severe form of hypertrophic axonal and

demyelinating neuropathy. Although it is predominantly inherited as

an autosomal recessive condition, autosomal dominant inheritance has

also been described.

To date, the autosomal recessive forms of DSD are classified into

several CMT type 4 (CMT4) subclasses based on allelic heterogeneity.

We present a 7-year-old boy with a severe form of CMT disease

consistent with the autosomal recessive phenotype of DSD. He was

found to be a compound heterozygote for mutations in the PMP22 gene

resulting in homozygous deletion of exons 2 and 3. The maternally

inherited allele was the typical 1.5 Mb deletion involving PMP22 seen

with hereditary neuropathy with liability to pressure palsy (HNPP).

The paternally inherited allele was a deletion of exons 2 and 3.

Both parents presented with a typical clinical picture of HNPP. To

our knowledge, this is the first patient reported with large

deletions involving both PMP22 alleles. Our patient has also

developed severe gastroesophageal reflux disease (GERD), a clinical

feature not previously reported with CMT or DSD. The correlation of

the phenotype and the molecular defects observed in this patient may

set a new subcategory in the classification of DSD.