<i>ALS2</i>
            mutations

Sheerin, Una‐Marie; Schneider, Susanne A.; Carr, Lucinda; Deuschl, Günther; Hopfner, Franziska; Stamelou, María; Wood, Nicholas W.; Bhatia, Kailash P.

doi:10.1212/wnl.0000000000000254

Cited by 29 publications

(25 citation statements)

References 7 publications

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“…The novel phenotype of JALS/ALS2 associated with generalized dystonia has previously been reported in two unrelated consanguineous families of Bangladeshi and Turkish descent, with homozygous loss of function variants in ALS2 [26]. Shortly thereafter, the same phenotype was described in a large consanguineous Pakistani family with a homozygous splice site variant in ALS2 [27].…”

Section: Discussionmentioning

confidence: 63%

“…Shortly thereafter, the same phenotype was described in a large consanguineous Pakistani family with a homozygous splice site variant in ALS2 [27]. Other novel clinical findings in the Bangladeshi family described in the first paper [26] include microcephaly and cerebellar signs, but the authors noted that it is unclear whether these features are caused by the ALS2 pathogenic variant.…”

Section: Discussionmentioning

confidence: 77%

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Clinical presentation and natural history of infantile-onset ascending spastic paralysis from three families with an ALS2 founder variant

et al. 2018

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Biallelic mutations of the alsin Rho guanine nucleotide exchange factor (ALS2) gene cause a group of overlapping autosomal recessive neurodegenerative disorders including infantile-onset ascending hereditary spastic paralysis (IAHSP), juvenile primary lateral sclerosis (JPLS), and juvenile amyotrophic lateral sclerosis (JALS/ALS2), caused by retrograde degeneration of the upper motor neurons of the pyramidal tracts. Here, we describe 11 individuals with IAHSP, aged 2-48 years, with IAHSP from three unrelated consanguineous Iranian families carrying the homozygous c.1640+1G>A founder mutation in ALS2. Three affected siblings from one family exhibit generalized dystonia which has not been previously described in families with IAHSP and has only been reported in three unrelated consanguineous families with JALS/ALS2. We report the oldest individuals with IAHSP to date and provide evidence that these patients survive well into their late 40s with preserved cognition and normal eye movements. Our study delineates the phenotypic spectrum of IAHSP and ALS2-related disorders and provides valuable insights into the natural disease course.

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Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 77%

Clinical presentation and natural history of infantile-onset ascending spastic paralysis from three families with an ALS2 founder variant

et al. 2018

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“…Although juvenile ALS may be suspected based on the clinical symptoms alone, it requires a large number of clinical tests to draw the conclusion, since the presentation of ALS2 mutation carriers is known to be heterogeneous and several other forms of familial spastic paraplegia or hereditary motor neuropathy may lead to similar presentations [11] , [17] , [18] . Recently, Sheerin and colleagues reported nonsense and frameshift mutations in ALS2 in individuals presenting with generalized dystonia and cerebellar signs [17] . ALS2 mutations are also known to cause complicated, infantile-onset forms of hereditary spastic paraplegia [11] .…”

Section: Discussionmentioning

confidence: 99%

A Novel Splice-Site Mutation in ALS2 Establishes the Diagnosis of Juvenile Amyotrophic Lateral Sclerosis in a Family with Early Onset Anarthria and Generalized Dystonias

Siddiqi

Foo

et al. 2014

PLoS ONE

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The diagnosis of childhood neurological disorders remains challenging given the overlapping clinical presentation across subgroups and heterogeneous presentation within subgroups. To determine the underlying genetic cause of a severe neurological disorder in a large consanguineous Pakistani family presenting with severe scoliosis, anarthria and progressive neuromuscular degeneration, we performed genome-wide homozygosity mapping accompanied by whole-exome sequencing in two affected first cousins and their unaffected parents to find the causative mutation. We identified a novel homozygous splice-site mutation (c.3512+1G>A) in the ALS2 gene (NM_020919.3) encoding alsin that segregated with the disease in this family. Homozygous loss-of-function mutations in ALS2 are known to cause juvenile-onset amyotrophic lateral sclerosis (ALS), one of the many neurological conditions having overlapping symptoms with many neurological phenotypes. RT-PCR validation revealed that the mutation resulted in exon-skipping as well as the use of an alternative donor splice, both of which are predicted to cause loss-of-function of the resulting proteins. By examining 216 known neurological disease genes in our exome sequencing data, we also identified 9 other rare nonsynonymous mutations in these genes, some of which lie in highly conserved regions. Sequencing of a single proband might have led to mis-identification of some of these as the causative variant. Our findings established a firm diagnosis of juvenile ALS in this family, thus demonstrating the use of whole exome sequencing combined with linkage analysis in families as a powerful tool for establishing a quick and precise genetic diagnosis of complex neurological phenotypes.

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“…For example, mutations in the Rab5 GEF ALS2 are associated with amyotrophic lateral sclerosis, 69 missense mutations in Rab7 cause the Charcot-Marie-Tooth type 2B disease, 70,71 whereas Rab8 has been linked to Huntington's disease through its effector optineurin. Here, mutant huntingtin disrupts the Rab8-optineurin complex resulting in an overall deficit in post-Golgi trafficking.…”

Section: Rab Proteins Regulating Ampar Trafficking Under Ltdmentioning

confidence: 99%

Coordination of AMPA receptor trafficking by Rab GTPases

Haußer

Schlett

2017

Small GTPases

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Synaptic connections in the brain are continuously weakened or strengthened in response to changes in neuronal activity. This process, known as synaptic plasticity, is the cellular basis for learning and memory, and is thought to be altered in several neuronal disorders. An important aspect of synaptic plasticity is the tightly controlled trafficking and synaptic targeting of the AMPAtype glutamate receptors, which are the major mediators of fast excitatory transmission in the brain. This review addresses the role of Rab GTPases in AMPA receptor trafficking in neurons under basal conditions and during activity-induced synaptic plasticity, especially during long-term potentiation (LTP) and long-term depression (LTD). We highlight the importance of the tight spatio-temporal control of Rab activity and suggest that this is critical for proper neuronal functions. We also discuss how abnormal AMPA receptor trafficking and malfunctioning of Rabs can lead to neurologic disorders or memory problems.

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ALS2 mutations

Cited by 29 publications

References 7 publications

Clinical presentation and natural history of infantile-onset ascending spastic paralysis from three families with an ALS2 founder variant

Clinical presentation and natural history of infantile-onset ascending spastic paralysis from three families with an ALS2 founder variant

A Novel Splice-Site Mutation in ALS2 Establishes the Diagnosis of Juvenile Amyotrophic Lateral Sclerosis in a Family with Early Onset Anarthria and Generalized Dystonias

Coordination of AMPA receptor trafficking by Rab GTPases

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