NOVEL COMPOUND HETEROZYGOUS ALS2 MUTATIONS CAUSE JUVENILE AMYOTROPHIC LATERAL SCLEROSIS IN JAPAN

Abstract

Dickson DW. The relationship between histopathological features of progressive supranuclear palsy and disease duration. Parkinsonism Relat Disord 2006;12:109 -112. 7. Demer JL. Pivotal role of orbital connective tissues in binocular alignment and strabismus: the Friedenwald lecture. Invest Ophthalmol Vis Sci 2004;45:729 -738. NOVEL COMPOUND HETEROZYGOUS ALS2 MUTATIONS CAUSE JUVENILE AMYOTROPHIC LATERAL SCLEROSIS IN JAPANHomozygous mutations in ALS2 on chromosome 2q33 are responsible for autosomal recessive, early-onset forms of upper motor neuron diseases such as infantile ascending hereditary spastic paraplegia (IAHSP) and juvenile primary lateral sclerosis (JPLS). 1 These mutations are rarely associated with lower motor neuron involvement in juvenile amyotrophic lateral sclerosis (JALS). 2 Seventeen mutations from 16 families have been reported, but the phenotype-genotype correlation remains unclear. 3-5 We searched for ALS2 mutations in 2 Japanese siblings presenting with infantile-onset ascending spastic paraplegia, pseudobulbar palsy, and amyotrophy of the extremities.Case reports. The older sibling was a 32-year-old Japanese man who started walking on tiptoes at 13 months of age and had never run. He developed dysarthria at 11 years of age and lost the ability to speak at 14. He displayed spasticity predominantly in the lower limbs, bilateral extensor plantar responses, and complete paralysis of the tongue without atrophy or fasciculation at 32 years of age. He also had discrete signs of lower motor neuron involvement manifesting as muscular atrophy of the distal upper and lower limbs. However, he was ambulatory with support and there was no evi-dence of cognitive dysfunction. Brain and spinal MRI showed no abnormalities. The peripheral nerve conduction velocities and latencies were within normal limits, but electromyography showed chronic denervation in the tongue and leg muscles. A 23-year-old brother showed progressive symptoms similar to his older brother; however, his symptoms were relatively mild. He started walking on tiptoes at 3 years of age, but he was able to participate in gymnastics in elementary school. He experienced slight muscular atrophy in the extremities. His speech was unintelligible, but his cognitive function was normal. Their nonconsanguineous parents had no neuromuscular disorders.An analysis of the ALS2. After obtaining informed consent, genomic DNA and RNA were extracted from the patients' blood. We directly sequenced all of the 34 exons and flanking intronic regions of the ALS2 and cDNA was synthesized by reversed transcription methods. Novel compound heterozygous mutations were detected in the ALS2 in each patient. These mutations comprised a 1-bp deletion at position 3565 leading to the creation of a premature stop codon and a transition of guanine to cytosine 5 nucleotides downstream from the normal exon 22 5Ј splice site

Clinical and genetic basis of familial amyotrophic lateral sclerosis

“…ALS2 (MIM #205100) represents a rare autosomal recessive slowly progressive UMN-dominant juvenile ALS as a consequence of homozigosity mutations in ALS2 gene (2q33.1), coding alsin, involved in the membrane and endosomal intracellular trafficking as guanine nucleotide exchange factor for Rac1 and Rab5 GTPases, in neurite outgrowth in hippocampus mediated by Rac1 activation and in prevention of glutamartegic excitoxicity mediated by Glur2 subunit of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors 15,21 . It begins in preschool child until the young adult ages (up to third decade) and has been described in japanese, turkish, tunisian, kuwaitian, saudi arabian, cypriot and Amish population.…”

“…ALS2 starts with lower limb and facial spasticity, moderate muscular atrophy, pseudobulbar signs, spastic dysathrophonia and bladder dysfunction evolving statically after two decades. Important clinical overlap with allelic forms of Juvenile primary lateral sclerosis and infantile ascending hereditary spastic paralysis occurs 13,15,21 .…”

Alsin Related Disorders: Literature Review and Case Study with Novel Mutations

“…They comprise a clinical continuum from infantile ascending hereditary spastic paraplegia (IAHSP) (OMIM number 607225), to juvenile forms without lower motor neuron involvement, namely, juvenile primary lateral sclerosis (JJPLS) (OMIM number 606353), and to forms with lower motor neuron involvement, namely, autosomal recessive juvenile amyotrophic lateral sclerosis (JALS) (OMIM number 205100) [1, 2]. There is no available data on the prevalence of ALS2 related disorders.…”

Genetic analysis and SOD1 mutation screening in Iranian amyotrophic lateral sclerosis patients

“…Nonneuronal neighboring cells, particularly the microglia, might also contribute to pathogenesis in ALS (Ilieva et al, 2009). Age at onset of symptoms is quite variable and onset in individuals as young as 1 (Shirakawa et al, 2009) and as old as 94 (Andersen et al, 1996) years old have been reported. In addition to age at onset, rate of disease progression and duration until death are variant clinical features.…”