(mentions CMT) Chapter 15 Juvenile amyotrophic lateral sclerosis

[Guest guest]

Handb Clin Neurol. 2007;82:301-12.

Chapter 15 Juvenile amyotrophic lateral sclerosis.

Orban P, Devon RS, Hayden MR, Leavitt BR.

Centre for Molecular Medicine and Therapeutics, Department of Medical

Genetics and British Columbia Research Institute for Women and

Children's Health, University of British Columbia, Vancouver, BC,

Canada.

Several forms of genetically defined juvenile amy-otrophic lateral

sclerosis (ALS) have now been charac-terized and discussion of these

conditions will form the basis for this chapter. ALS2 is an autosomal

recessive form of ALS with a juvenile onset and very slow progression

that mapped to chromosome 2q33.

Nine different mutations have been identified in the ALS2 gene that

result in premature stop codons, suggesting a loss of function in the

gene product, alsin. The alsin protein is thought to function as a

guanine-nucleotide exchange factor for GTPases and may play a role in

vesicle transport or membrane trafficking processes.

ALS4 is an autosomal dominant form of juvenile onset ALS associated

with slow progression, severe muscle weakness and pyramidal signs, in

the absence of bulbar and sensory abnormalities.

Mutations in the SETX gene cause ALS4, and the SETX gene product

senataxin may have DNA and RNA helicase activity and play a role in

the regulation of RNA and/or DNA in the cell.

A third form of juvenile-onset ALS (ALS5) is associated with slowly

progressing lower motor neuron signs (weak-ness and atrophy)

initially of the hands and feet, with eventual bulbar involvement.

Progressive upper motor neuron disease becomes more obvious with

time. ALS5 has been linked to a 6 cM region of chromosome 15q15.1-

q21.1, but the causative gene mutation for ALS5 has yet to be

identified.

The high degree of clin-ical and genetic heterogeneity in the various

forms of juvenile ALS can make differential diagnosis difficult,

other genetic disorders that must be considered include: spinal

muscular atrophy, hereditary spastic paraplegia, SBMA, GM2

gangliosidosis and the hereditary motor neuronopathies/motor forms of

Charcot-Marie-Tooth disease.

Acquired disorders that must also be consid-ered include heavy metal

intoxications (especially lead), multifocal motor neuropathy,

paraneoplastic syndromes, vitamin deficiencies (B12) and infections

(HTLV-II, HIV and poliomyelitis).