Charcot-Marie-Tooth (CMT) disease is the most common form of inherited motor and sensory neuropathy. CMT is a genetically heterogeneous disorder of the peripheral nervous system; thus, many genes have been identified as CMTcausative genes. Traditionally, subclassification of CMT has been divided into autosomal dominant inherited demyelinating (CMT1) and axonal (CMT2) neuropathies, X-linked neuropathy (CMTX), and autosomal recessive inherited neuropathy (CMT4). Recently, intermediate type (CMT-Int) with NCVs between CMT1 and CMT2 is considered as a CMT type. There are several related peripheral neuropathies, such as Dejerine- Sottas neuropathy (DSN), congenital hypomyelination (CH), hereditary neuropathy with pressure palsies (HNPP), and giant axonal neuropathy (GAN). Great advances have been made in understanding the molecular basis of CMT, and 17 distinct genetic causes of CMT have been identified. The number of newly discovered mutations and identified genetic loci is rapidly increasing, and this expanding list has proved challenging for physicians trying to keep up with the field. In addition, the encouraging studies have been published on rational potential therapies for the CMT1A.
Axons ; Charcot-Marie-Tooth Disease* ; Genetic Loci ; Giant Axonal Neuropathy ; Paralysis ; Peripheral Nervous System ; Peripheral Nervous System Diseases

Hereditary motor and sensory neuropathy (HMSN), or Charcot-Marie-Tooth (CMT) disease, was described by Charcot and Marie in France and, independently, by Tooth in England in 1886. CMT is the most common form of inherited motor and sensory neuropathy, and is a genetically heterogeneous group of disorders in the peripheral nervous system. Traditionally, CMT has been subclassified into autosomal dominant inherited demyelinating (CMT1) and axonal (CMT2) neuropathies, X-linked neuropathy (CMTX), and autosomal recessive inherited neuropathy (CMT4). There are several related peripheral neuropathies, such as Dejerine-Sottas neuropathy (DSN), congenital hypomyelination neuropathy (CHN), hereditary neuropathy with liability to pressure palsies (HNPP), and giant axonal neuropathy (GAN). A large amount of new information on the genetic causes of CMT has become available, and mutations causing the disease have been associated with more than 20 different genes and 40 chromosomal loci. Advances in our understanding of the molecular basis of CMT have revealed an enormous diversity in genetic mechanisms, despite the clinical entity that is relatively uniform at presentation. Recent studies have shown therapeutic effects of certain chemicals in animal models of CMT1A, which suggests potential therapies for the most common form of CMT, CMT1A. This review focuses on the subgroups of inherited motor and sensory neuropathy on which there has been an explosion of new molecular genetic information over the past decade.
Axons ; Charcot-Marie-Tooth Disease* ; England ; Explosions ; France ; Giant Axonal Neuropathy ; Hereditary Sensory and Motor Neuropathy ; Models, Animal ; Molecular Biology ; Paralysis ; Peripheral Nervous System ; Peripheral Nervous System Diseases ; Tooth

OBJECTIVETo explore the disease-causing mutations in a patient suspected for giant axonal neuropathy(GAN).

METHODSTarget sequence capture sequencing was used to screen potential mutations in genomic DNA extracted from peripheral blood sample of the patient. Sanger sequencing was applied to confirm the detected mutation. The mutation was verified among 400 GAN alleles from 200 healthy individuals by Sanger sequencing. The function of the mutations was predicted by bioinformatics analysis.

RESULTSThe patient was identified as a compound heterozygote carrying two novel pathogenic GAN mutations, i.e., c.778G>T (p.Glu260Ter) and c.277G>A (p.Gly93Arg). Sanger sequencing confirmed that the c.778G>T (p.Glu260Ter) mutation was inherited from his father, while c.277G>A (p.Gly93Arg) was inherited from his mother. The same mutations was not found in the 200 healthy individuals. Bioinformatics analysis predicted that the two mutations probably caused functional abnormality of gigaxonin.

CONCLUSIONTwo novel GAN mutations were detected in a patient with GAN. Both mutations are pathogenic and can cause abnormalities of gigaxonin structure and function, leading to pathogenesis of GAN. The results may also offer valuable information for similar diseases.

Amino Acid Sequence ; Child ; Computational Biology ; Cytoskeletal Proteins ; genetics ; Giant Axonal Neuropathy ; genetics ; Humans ; Male ; Molecular Sequence Data ; Mutation ; Sequence Analysis, DNA