Unraveling the genetics of distal hereditary motor neuronopathies

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Neuromolecular Med. 2006;8(1-2):131-46.

Unraveling the genetics of distal hereditary motor neuronopathies.

Irobi J, Dierick I, Jordanova A, Claeys KG, De Jonghe P, Timmerman V.

Peripheral Neuropathy Group, Department of Molecular Genetics,

Flanders Interuniversity Institute for Biotechnology, University of

Antwerp, Antwerpen, Belgium; and Laboratory of Molecular Pathology,

Sofia Medical University, Sofia, Bulgaria.

The hereditary motor neuronopathies (HMN [MIM 158590]) are a

heterogeneous group of disorders characterized by an exclusive

involvement of the motor part of the peripheral nervous system.

They are usually subdivided in proximal HMN, i.e., the classical

spinal muscular atrophy syndromes and distal hereditary motor

neuronopathies (distal HMN) that clinically resemble Charcot-Marie-

Tooth syndromes.

In this review, we concentrate on distal HMN. The distal HMN are

clinically and genetically heterogeneous and were initially

subdivided in seven subtypes according to mode of inheritance, age at

onset, and clinical evolution.

Recent studies have shown that these subtypes are still heterogeneous

at the molecular genetic level and novel clinical and genetic

entities have been delineated.

Since the introduction of positional cloning, 13 chromosomal loci and

seven disease-associated genes have been identified for autosomal-

dominant, autosomal-recessive, and X-linked recessive distal HMN.

Most of the genes involved encode protein with housekeeping

functions, such as RNA processing, translation synthesis, stress

response, apoptosis, and others code for proteins involved in

retrograde survival.

Motor neurons of the anterior horn of the spinal cord seems to be

vulnerable to defects in these housekeeping proteins, likely because

their large axons have higher metabolic requirements for maintenance,

transport over long distances and precise connectivity.

Understanding the molecular pathomechanisms for mutations in these

genes that are ubiquitous expressed will help unravel the neuronal

mechanisms that underlie motor neuropathies leading to denervation of

distal limb muscles, and might generate new insights for future

therapeutic strategies.