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Neurogenetics
Published in John W. Scadding, Nicholas A. Losseff, Clinical Neurology, 2011
Sonia Gandhi, Sarah Tabrizi, Nicholas Wood
The protein TDP-43 has been identified to be the major aggregating protein in inclusions seen in both sporadic and familial ALS (and also a group of FTLD cases). The gene encoding this protein is TARDP and dominant mutations in TARDP have been identified in a minority (1–3 per cent) of ALS cases. Mutations in the FUS gene have also been discovered to cause autosomal dominant ALS. The FUS protein and the TDP-43 protein have the common characteristics of being an RNA/DNA-binding protein that is mainly nuclear. The other ALS genes are very rare, but include the ALS2 gene encoding alsin, mutations (recessive) in which cause a juvenile primary lateral sclerosis or infantile ascending spastic paralysis phenotype. Mutations in the senataxin gene cause a dominantly inherited juvenile onset ALS (while recessive mutations in the same gene cause AOA2). Mutations in the VAPB gene, angiogenin gene and the dynactin gene have also been implicated in adult onset familial ALS.
A novel mutation in the ALS2 gene in an iranian kurdish family with juvenile amyotrophic lateral sclerosis
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2023
Yousef Daneshmandpour, Zahra Bahmanpour, Somayeh Kazeminasab, Ehsan Aghaei Moghadam, Elham Alehabib, Marjan Chapi, Abbas Tafakhori, Negar Aghaei, Hossein Darvish, Babak Emamalizadeh
In the current study, a novel mutation in the ALS2 in an Iranian Kurdish family with ALS was detected. The symptoms of the patient are correlated with the juvenile form of ALS. As reviewed by Flor-de-Lima et al., the main symptoms of JALS are both lower and upper motor neuron system involvement resulting in loss of walking and speech problems (1). The study of Topp et al. showed ALSIN is mainly a cytosolic protein, but it is also observed in membrane transport events. Also, they found that the VPS9 domain has Rab5 guanine nucleotide exchange activity, and the ALSIN acts as a guanine nucleotide exchange factor for Rac1 (3). ALS2 is correlated with three different neurologic disorders including infantile ascending hereditary spastic paraplegia (IAHSP), juvenile primary lateral sclerosis (JPLS), and juvenile amyotrophic lateral sclerosis (JALS). The exact etiology behind the correlation between ALS2 mutations and three specific conditions is still ambiguous. Also, no genotype-phenotype correlation has been concluded yet (1,4).
Genetics of primary lateral sclerosis
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2020
Vincenzo Silani, Philippe Corcia, Matthew B. Harms, Guy Rouleau, Teepu Siddique, Nicola Ticozzi
Primary lateral sclerosis (PLS) is an adult-onset, neurodegenerative disorder primarily affecting the upper motor neurons (UMN) that originate the corticospinal and corticobulbar tracts, thus leading to widespread spasticity and bulbar involvement. Although previous diagnostic criteria required the absence of family history (1), mainly to differentiate PLS from the partially overlapping hereditary spastic paraparesis (HSP), rare pedigrees with multiple individuals affected with PLS have been described (2–6). This observation, together with the shared clinical and pathological features with other motor neuron disorders with high genetic component, mainly amyotrophic lateral sclerosis (ALS), raises the question whether there are genetic factors associated to PLS susceptibility as well. We will first examine the contribution of ALS-associated genes in PLS, then we will evaluate the genetic overlap between PLS and other diseases characterized by corticospinal tract degeneration such as HSP, and lastly we will describe the genetics of juvenile PLS-like syndromes (JPLS) (Table 1). To account for the possibility that any observed genetic overlap between PLS, UMN-predominant ALS and HSP may in fact be due to misdiagnosis of these three conditions, whenever feasible we applied the novel consensus criteria for the diagnosis of PLS to critically review available literature (7).
The expanding clinical and genetic spectrum of alsin-related disorders: the first cohort of Brazilian patients
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2022
Alzira Alves De Siqueira Carvalho, Marco Antônio Troccoli Chieia, Igor Braga Farias, Acary Souza Bulle Oliveira, Wladimir Bocca Vieira De Rezende Pinto, Paulo Victor Sgobbi De Souza
Since the discovery of the ALS2 gene (OMIM*606352) (ENST00000264276/NM_020919) by Hadano and Yang (1,2) almost concurrently 20 years ago, pathogenic variants in this gene have been shown to result in one of three clinically recognizable motor neuron diseases: 1. infantile-onset ascending spastic paralysis associated with a clinical infantile-onset ascending hereditary spastic paralysis (IAHSP, OMIM#607225), 2. autosomal-recessive juvenile amyotrophic lateral sclerosis and juvenile forms with LMN involvement (ALS2, OMIM#205100), and 3. juvenile primary lateral sclerosis without lower motor neuron involvement (JPLS; OMIM#606353). Nonetheless, only a few reports have been published about these disorders, mainly from Mediterranean countries and Asia (1–5) Figure 1.