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Genotype-phenotype relationship in hereditary amyotrophic lateral sclerosis.

Yamashita S, Ando Y - Transl Neurodegener (2015)

Bottom Line: Thus, genetic factors play a role in all types of ALS, to a greater or lesser extent.During the decade of upheaval, the evolution of molecular genetics technology has rapidly advanced our genetic knowledge about the causes of ALS, and the relationship between the genetic subtypes and clinical phenotype.Uncovering the identity of the genetic factors in ALS will not only improve the accuracy of ALS diagnosis, but may also provide new approaches for preventing and treating the disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556 Japan.

ABSTRACT
Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease. It is characterized by neuronal loss and degeneration of the upper motor neurons (UMNs) and lower motor neurons (LMNs), and is usually fatal due to respiratory failure within 3-5 years of onset. Although approximately 5-10 % of patients with ALS have an inherited form of the disease, the distinction between hereditary and apparently sporadic ALS (SALS) seems to be artificial. Thus, genetic factors play a role in all types of ALS, to a greater or lesser extent. During the decade of upheaval, the evolution of molecular genetics technology has rapidly advanced our genetic knowledge about the causes of ALS, and the relationship between the genetic subtypes and clinical phenotype. In this review, we will focus on the possible genotype-phenotype correlation in hereditary ALS. Uncovering the identity of the genetic factors in ALS will not only improve the accuracy of ALS diagnosis, but may also provide new approaches for preventing and treating the disease.

No MeSH data available.


Related in: MedlinePlus

A family with the MATR3 S85C mutation. a Family tree of cases with the MATR3 S85C mutation. The detailed clinical information was previously described [67]. b Short-T1 inversion recovery MR images revealed fatty and degenerative changes in the gluteus, quadriceps, and hamstring muscles of patient 1 and the paraspinal and gluteus muscles of patient 2. c Needle electromyography demonstrated chronic denervation in the vastus lateralis muscles of patients 1 and 2. d Muscle biopsy from patients 1 and 2 showed severe fatty and myopathic changes with rimmed vacuoles. Immunohistochemical analysis demonstrated p62- or TDP-43-positive sarcoplasmic granular staining in degenerating myofibers of patient 1. The observation of chronic denervation and renervation on electromyography and muscle biopsy, split hand syndrome, and decremental motor responses to repetitive nerve stimulation (data not shown) suggest the involvement of lower motor neurons in patients 1 and 2
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Fig2: A family with the MATR3 S85C mutation. a Family tree of cases with the MATR3 S85C mutation. The detailed clinical information was previously described [67]. b Short-T1 inversion recovery MR images revealed fatty and degenerative changes in the gluteus, quadriceps, and hamstring muscles of patient 1 and the paraspinal and gluteus muscles of patient 2. c Needle electromyography demonstrated chronic denervation in the vastus lateralis muscles of patients 1 and 2. d Muscle biopsy from patients 1 and 2 showed severe fatty and myopathic changes with rimmed vacuoles. Immunohistochemical analysis demonstrated p62- or TDP-43-positive sarcoplasmic granular staining in degenerating myofibers of patient 1. The observation of chronic denervation and renervation on electromyography and muscle biopsy, split hand syndrome, and decremental motor responses to repetitive nerve stimulation (data not shown) suggest the involvement of lower motor neurons in patients 1 and 2

Mentions: A recent study using exome sequencing revealed mutations in the matrin-3 (MATR3) gene in FALS and FTD cases [65]. Initially, the S85C mutation in the MATR3 gene was reported as the cause of autosomal dominant distal myopathy with vocal cord paralysis (VCPDM) in large multi-generational families [66]. The phenotype observed in some patients carrying MATR3 mutations is still controversial. However, the clinical phenotype might be markedly similar to that observed in patients with mutations in VCP, hnRNPA1, and HNRNPA2B1 as MSP. We examined 2 sisters with VCPDM and S85C mutations in the MATR3 gene (Fig. 2) [67]. Both patients showed no UMN symptoms clinically; however, they showed chronic denervation and renervation on electromyography and muscle biopsy, split hand syndrome, and decremental motor responses to repetitive nerve stimulation, suggesting the involvement of LMNs [67].Fig. 2


Genotype-phenotype relationship in hereditary amyotrophic lateral sclerosis.

Yamashita S, Ando Y - Transl Neurodegener (2015)

A family with the MATR3 S85C mutation. a Family tree of cases with the MATR3 S85C mutation. The detailed clinical information was previously described [67]. b Short-T1 inversion recovery MR images revealed fatty and degenerative changes in the gluteus, quadriceps, and hamstring muscles of patient 1 and the paraspinal and gluteus muscles of patient 2. c Needle electromyography demonstrated chronic denervation in the vastus lateralis muscles of patients 1 and 2. d Muscle biopsy from patients 1 and 2 showed severe fatty and myopathic changes with rimmed vacuoles. Immunohistochemical analysis demonstrated p62- or TDP-43-positive sarcoplasmic granular staining in degenerating myofibers of patient 1. The observation of chronic denervation and renervation on electromyography and muscle biopsy, split hand syndrome, and decremental motor responses to repetitive nerve stimulation (data not shown) suggest the involvement of lower motor neurons in patients 1 and 2
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4513711&req=5

Fig2: A family with the MATR3 S85C mutation. a Family tree of cases with the MATR3 S85C mutation. The detailed clinical information was previously described [67]. b Short-T1 inversion recovery MR images revealed fatty and degenerative changes in the gluteus, quadriceps, and hamstring muscles of patient 1 and the paraspinal and gluteus muscles of patient 2. c Needle electromyography demonstrated chronic denervation in the vastus lateralis muscles of patients 1 and 2. d Muscle biopsy from patients 1 and 2 showed severe fatty and myopathic changes with rimmed vacuoles. Immunohistochemical analysis demonstrated p62- or TDP-43-positive sarcoplasmic granular staining in degenerating myofibers of patient 1. The observation of chronic denervation and renervation on electromyography and muscle biopsy, split hand syndrome, and decremental motor responses to repetitive nerve stimulation (data not shown) suggest the involvement of lower motor neurons in patients 1 and 2
Mentions: A recent study using exome sequencing revealed mutations in the matrin-3 (MATR3) gene in FALS and FTD cases [65]. Initially, the S85C mutation in the MATR3 gene was reported as the cause of autosomal dominant distal myopathy with vocal cord paralysis (VCPDM) in large multi-generational families [66]. The phenotype observed in some patients carrying MATR3 mutations is still controversial. However, the clinical phenotype might be markedly similar to that observed in patients with mutations in VCP, hnRNPA1, and HNRNPA2B1 as MSP. We examined 2 sisters with VCPDM and S85C mutations in the MATR3 gene (Fig. 2) [67]. Both patients showed no UMN symptoms clinically; however, they showed chronic denervation and renervation on electromyography and muscle biopsy, split hand syndrome, and decremental motor responses to repetitive nerve stimulation, suggesting the involvement of LMNs [67].Fig. 2

Bottom Line: Thus, genetic factors play a role in all types of ALS, to a greater or lesser extent.During the decade of upheaval, the evolution of molecular genetics technology has rapidly advanced our genetic knowledge about the causes of ALS, and the relationship between the genetic subtypes and clinical phenotype.Uncovering the identity of the genetic factors in ALS will not only improve the accuracy of ALS diagnosis, but may also provide new approaches for preventing and treating the disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556 Japan.

ABSTRACT
Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease. It is characterized by neuronal loss and degeneration of the upper motor neurons (UMNs) and lower motor neurons (LMNs), and is usually fatal due to respiratory failure within 3-5 years of onset. Although approximately 5-10 % of patients with ALS have an inherited form of the disease, the distinction between hereditary and apparently sporadic ALS (SALS) seems to be artificial. Thus, genetic factors play a role in all types of ALS, to a greater or lesser extent. During the decade of upheaval, the evolution of molecular genetics technology has rapidly advanced our genetic knowledge about the causes of ALS, and the relationship between the genetic subtypes and clinical phenotype. In this review, we will focus on the possible genotype-phenotype correlation in hereditary ALS. Uncovering the identity of the genetic factors in ALS will not only improve the accuracy of ALS diagnosis, but may also provide new approaches for preventing and treating the disease.

No MeSH data available.


Related in: MedlinePlus