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From animal models to human disease: a genetic approach for personalized medicine in ALS.

Picher-Martel V, Valdmanis PN, Gould PV, Julien JP, Dupré N - Acta Neuropathol Commun (2016)

Bottom Line: Numerous different gene mutations have been found in familial cases of ALS, such as mutations in superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43), fused in sarcoma (FUS), C9ORF72, ubiquilin-2 (UBQLN2), optineurin (OPTN) and others.However, no animal model fully replicates the spectrum of phenotypes in the human disease and it is difficult to assess how a therapeutic effect in disease models can predict efficacy in humans.Promising gene therapies raised possibilities for treating differently the major mutations in familial ALS cases.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Neuroscience, Research Centre of Institut Universitaire en Santé Mentale de Québec, Laval University, 2601 Chemin de la Canardière, Québec, QC, G1J 2G3, Canada. vincent.picher-martel.1@ulaval.ca.

ABSTRACT
Amyotrophic Lateral Sclerosis (ALS) is the most frequent motor neuron disease in adults. Classical ALS is characterized by the death of upper and lower motor neurons leading to progressive paralysis. Approximately 10 % of ALS patients have familial form of the disease. Numerous different gene mutations have been found in familial cases of ALS, such as mutations in superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43), fused in sarcoma (FUS), C9ORF72, ubiquilin-2 (UBQLN2), optineurin (OPTN) and others. Multiple animal models were generated to mimic the disease and to test future treatments. However, no animal model fully replicates the spectrum of phenotypes in the human disease and it is difficult to assess how a therapeutic effect in disease models can predict efficacy in humans. Importantly, the genetic and phenotypic heterogeneity of ALS leads to a variety of responses to similar treatment regimens. From this has emerged the concept of personalized medicine (PM), which is a medical scheme that combines study of genetic, environmental and clinical diagnostic testing, including biomarkers, to individualized patient care. In this perspective, we used subgroups of specific ALS-linked gene mutations to go through existing animal models and to provide a comprehensive profile of the differences and similarities between animal models of disease and human disease. Finally, we reviewed application of biomarkers and gene therapies relevant in personalized medicine approach. For instance, this includes viral delivering of antisense oligonucleotide and small interfering RNA in SOD1, TDP-43 and C9orf72 mice models. Promising gene therapies raised possibilities for treating differently the major mutations in familial ALS cases.

No MeSH data available.


Related in: MedlinePlus

Clinical findings in Amyotrophic lateral sclerosis (ALS). Signs and symptoms are divided by affected motor neuron. Both upper motor neurons (UMN) and lower motor neurons (LMN) have to be affected for the diagnosis of ALS. Different combination of LMN and UMN signs can be observed. Limb onset is found in around 65 % of patients but most patients will develop signs in both bulbar region and limbs within the course of disease. Up to 50 % of ALS patients may have symptoms of Fronto-Temporal dementia
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Fig2: Clinical findings in Amyotrophic lateral sclerosis (ALS). Signs and symptoms are divided by affected motor neuron. Both upper motor neurons (UMN) and lower motor neurons (LMN) have to be affected for the diagnosis of ALS. Different combination of LMN and UMN signs can be observed. Limb onset is found in around 65 % of patients but most patients will develop signs in both bulbar region and limbs within the course of disease. Up to 50 % of ALS patients may have symptoms of Fronto-Temporal dementia

Mentions: ALS affects both upper (UMN) and lower motor neurons (LMN). It has a wide phenotypic variability determined primarily by three main features: site of onset, rate of progression and relative number of UMN and LMN deficits [5]. Classical spinal onset generally starts with an asymmetric weakness in a limb and the patient will consult a physician because of an unexplained foot drop with or without falls [6]. Weakness will progressively spread to other contiguous limb regions and finally reach respiratory muscles after a few months [5]. Clinical examinations could reveal lower motor neurons signs which include weakness, muscle atrophy, fasciculations and reduced reflexes, whereas upper motor neurons signs include hypertonia, hyperreflexia, Babinski’s sign and Hoffman’s sign [7] (Fig. 2). The onset of symptoms is gradual. It is uncommon for patients to complain about sensory deficit or paresthesia. However, electrophysiological and pathological studies confirmed that response to stimuli can be altered and a loss of large caliber axon was observed [8, 9]. Furthermore, a combination of spinal diffusion tensor imaging (DTI) and electrophysiological recordings demonstrated a subclinical sensory deficit in 85 % of patients with ALS [10].Fig. 2


From animal models to human disease: a genetic approach for personalized medicine in ALS.

Picher-Martel V, Valdmanis PN, Gould PV, Julien JP, Dupré N - Acta Neuropathol Commun (2016)

Clinical findings in Amyotrophic lateral sclerosis (ALS). Signs and symptoms are divided by affected motor neuron. Both upper motor neurons (UMN) and lower motor neurons (LMN) have to be affected for the diagnosis of ALS. Different combination of LMN and UMN signs can be observed. Limb onset is found in around 65 % of patients but most patients will develop signs in both bulbar region and limbs within the course of disease. Up to 50 % of ALS patients may have symptoms of Fronto-Temporal dementia
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4940869&req=5

Fig2: Clinical findings in Amyotrophic lateral sclerosis (ALS). Signs and symptoms are divided by affected motor neuron. Both upper motor neurons (UMN) and lower motor neurons (LMN) have to be affected for the diagnosis of ALS. Different combination of LMN and UMN signs can be observed. Limb onset is found in around 65 % of patients but most patients will develop signs in both bulbar region and limbs within the course of disease. Up to 50 % of ALS patients may have symptoms of Fronto-Temporal dementia
Mentions: ALS affects both upper (UMN) and lower motor neurons (LMN). It has a wide phenotypic variability determined primarily by three main features: site of onset, rate of progression and relative number of UMN and LMN deficits [5]. Classical spinal onset generally starts with an asymmetric weakness in a limb and the patient will consult a physician because of an unexplained foot drop with or without falls [6]. Weakness will progressively spread to other contiguous limb regions and finally reach respiratory muscles after a few months [5]. Clinical examinations could reveal lower motor neurons signs which include weakness, muscle atrophy, fasciculations and reduced reflexes, whereas upper motor neurons signs include hypertonia, hyperreflexia, Babinski’s sign and Hoffman’s sign [7] (Fig. 2). The onset of symptoms is gradual. It is uncommon for patients to complain about sensory deficit or paresthesia. However, electrophysiological and pathological studies confirmed that response to stimuli can be altered and a loss of large caliber axon was observed [8, 9]. Furthermore, a combination of spinal diffusion tensor imaging (DTI) and electrophysiological recordings demonstrated a subclinical sensory deficit in 85 % of patients with ALS [10].Fig. 2

Bottom Line: Numerous different gene mutations have been found in familial cases of ALS, such as mutations in superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43), fused in sarcoma (FUS), C9ORF72, ubiquilin-2 (UBQLN2), optineurin (OPTN) and others.However, no animal model fully replicates the spectrum of phenotypes in the human disease and it is difficult to assess how a therapeutic effect in disease models can predict efficacy in humans.Promising gene therapies raised possibilities for treating differently the major mutations in familial ALS cases.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Neuroscience, Research Centre of Institut Universitaire en Santé Mentale de Québec, Laval University, 2601 Chemin de la Canardière, Québec, QC, G1J 2G3, Canada. vincent.picher-martel.1@ulaval.ca.

ABSTRACT
Amyotrophic Lateral Sclerosis (ALS) is the most frequent motor neuron disease in adults. Classical ALS is characterized by the death of upper and lower motor neurons leading to progressive paralysis. Approximately 10 % of ALS patients have familial form of the disease. Numerous different gene mutations have been found in familial cases of ALS, such as mutations in superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43), fused in sarcoma (FUS), C9ORF72, ubiquilin-2 (UBQLN2), optineurin (OPTN) and others. Multiple animal models were generated to mimic the disease and to test future treatments. However, no animal model fully replicates the spectrum of phenotypes in the human disease and it is difficult to assess how a therapeutic effect in disease models can predict efficacy in humans. Importantly, the genetic and phenotypic heterogeneity of ALS leads to a variety of responses to similar treatment regimens. From this has emerged the concept of personalized medicine (PM), which is a medical scheme that combines study of genetic, environmental and clinical diagnostic testing, including biomarkers, to individualized patient care. In this perspective, we used subgroups of specific ALS-linked gene mutations to go through existing animal models and to provide a comprehensive profile of the differences and similarities between animal models of disease and human disease. Finally, we reviewed application of biomarkers and gene therapies relevant in personalized medicine approach. For instance, this includes viral delivering of antisense oligonucleotide and small interfering RNA in SOD1, TDP-43 and C9orf72 mice models. Promising gene therapies raised possibilities for treating differently the major mutations in familial ALS cases.

No MeSH data available.


Related in: MedlinePlus