autosomal recessive CMT research - from Austria

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Abstract from Brain 2003 Mar;126(Pt 3):642-649

Mutations in the ganglioside-induced differentiation-associated

protein-1 (GDAP1) gene in intermediate type autosomal recessive

Charcot-Marie-Tooth neuropathy.

Senderek J, Bergmann C, Ramaekers VT, Nelis E, Bernert G, Makowski A,

Zuchner S, De Jonghe P, Rudnik-Schoneborn S, Zerres K, Schroder JM.

Departments of. Human Genetics, Neuropediatrics and Neuropathology,

Aachen University of Technology, Aachen, Germany, Department of

Biochemistry, Flanders Interuniversity Institute for Biotechnology,

Born-Bunge Foundation, University of Antwerp, Belgium and Department of

Pediatrics, University of Vienna, Austria.

Mutations in the gene for the ganglioside-induced

differentiation-associated protein-1 (GDAP1) on 8q21 recently were

reported to cause autosomal recessive Charcot-Marie-Tooth (CMT)

sensorimotor neuropathy. Neurophysiology and nerve pathology were

heterogeneous in these cases: a subset of GDAP1 mutations was associated

with peripheral nerve demyelination, whereas others resulted in axonal

degeneration.

In this study, we identified two novel mutations disrupting the GDAP1

reading frame. Homozygosity for a single base pair insertion in exon 3

(c.349_350insT) was observed in affected children from a Turkish inbred

pedigree. The other novel allele detected in a German patient was a

homozygous mutation of the intron 4 donor splice site (c.579 + 1G>A).

Patients with GDAP1 mutations displayed severe, early childhood-onset

CMT neuropathy with prominent pes equinovarus deformity and impairment

of hand muscles. Nerve conduction velocities were between 25 and 35 m/s

and peripheral nerve pathology showed

axonal as well as demyelinating changes. These findings fitted the

definition of intermediate type CMT and further support the view that

GDAP1 is vital for both, axonal integrity and Schwann cell properties.