Amyotrophic lateral sclerosis

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Description from OMIM

Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. ALS usually begins with asymmetric involvement of the muscles in middle adult life. Approximately 10% of ALS cases are familial (Siddique and Deng, 1996). ALS is sometimes referred to as 'Lou Gehrig disease' after the famous American baseball player who was diagnosed with the disorder. Rowland and Shneider (2001) and Kunst (2004) provided extensive reviews of ALS. Some forms of ALS occur with frontotemporal dementia (FTD). Familial ALS is distinct from a form of ALS with dementia reported in cases on Guam (105500) (Espinosa et al., 1962; Husquinet and Franck, 1980), in which the histology is different and dementia and parkinsonism complicate the clinical picture. Genetic Heterogeneity of Amyotrophic Lateral Sclerosis ALS is a genetically heterogeneous disorder, with several causative genes and mapped loci. ALS6 (608030) is caused by mutation in the FUS gene (137070) on chromosome 16p11; ALS8 (608627) is caused by mutation in the VAPB gene (605704) on chromosome 13; ALS9 (611895) is caused by mutation in the ANG gene (105850) on chromosome 14q11; ALS10 (612069) is caused by mutation in the TARDBP gene (605078) on 1p36; ALS11 (612577) is caused by mutation in the FIG4 gene (609390) on chromosome 6q21; ALS12 (613435) is caused by mutation in the OPTN gene (602432) on chromosome 10p; ALS14 (613954) is caused by mutation in the VCP gene (601023) gene on chromosome 9p13; ALS15 (300857) is caused by mutation in the UBQLN2 gene (300264) on chromosome Xp11; ALS17 (614696) is caused by mutation in the CHMP2B gene (609512) on chromosome 3p11; ALS18 (614808) is caused by mutation in the PFN1 gene (176610) on chromosome 17p13; ALS19 (615515) is caused by mutation in the ERBB4 gene (600543) on chromosome 2q34; ALS20 (615426) is caused by mutation in the HNRNPA1 gene (164017) on chromosome 12q13; ALS21 (606070) is caused by mutation in the MATR3 gene (164015) on chromosome 5q31; ALS22 (616208) is caused by mutation in the TUBA4A gene (191110) on chromosome 2q35; and ALS23 (617839) is caused by mutation in the ANXA11 gene (602572) on chromosome 10q23. See also FTDALS (105550), caused by mutation in the C9ORF72 gene (614260) on chromosome 9p21. Loci associated with ALS have been found on chromosomes 18q21 (ALS3; 606640) and 20p13 (ALS7; 608031). Intermediate-length polyglutamine repeat expansions in the ATXN2 gene (601517) contribute to susceptibility to ALS (ALS13; 183090). Susceptibility to ALS24 (617892) is conferred by mutation in the NEK1 gene (604588) on chromosome 4q33, and susceptibility to ALS25 (617921) is conferred by mutation in the KIF5A gene (602821) on chromosome 12q13. Susceptibility to ALS has been associated with mutations in other genes, including deletions or insertions in the gene encoding the heavy neurofilament subunit (NEFH; 162230); deletions in the gene encoding peripherin (PRPH; 170710); and mutations in the dynactin gene (DCTN1; 601143). Some forms of ALS show juvenile onset. See juvenile-onset ALS2 (205100), caused by mutation in the alsin (606352) gene on 2q33; ALS4 (602433), caused by mutation in the senataxin gene (SETX; 608465) on 9q34; ALS5 (602099), caused by mutation in the SPG11 gene (610844) on 15q21; and ALS16 (614373), caused by mutation in the SIGMAR1 gene (601978) on 9p13.

Prevalence of clinical parameters (%)

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Number of patients in the reference Percent affected patients (Between 0 and 1, eg. 0.1 = 10%)
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List of symptoms

Symptom/sign Organ system Percent affected Pubmed id Added on(yyyy-mm-dd) Edit/add reference
Limb wasting nervous 100 % 17296839 2012-06-10
Hyperactive reflexes nervous 100 % 19487653 2012-08-24
Muscle weakness skeletal 100 % 19487653 2012-08-24
Pyramidal signs nervous 99 % 17296839 2012-06-10
Muscle atrophy skeletal 90 % 19487653 2012-08-24
Bulbar dysfunction nervous 88 % 17296839 2012-06-10
Dysphagia nervous 80 % 19487653 2012-08-24
Dysdiadochokinesia nervous 78 % 19487653 2012-08-24
Weight loss multi 70 % 19487653 2012-08-24
Fasciculations skeletal 70 % 19487653 2012-08-24
Areflexia nervous 70 % 19487653 2012-08-24
Dysarthria nervous 60 % 19487653 2012-08-24
Spasticity nervous 22 % 21702734 2012-06-10
Muscle atrophy skeletal 22 % 21702734 2012-06-10
Dementia nervous 8 % 17296839 2012-06-10

List of references:

Differentiation between primary lateral sclerosis and amyotrophic lateral sclerosis: examination of symptoms and signs at disease onset and during follow-up.
Maria Carmela Tartaglia, Ann Rowe, Karen Findlater, J B Orange, Gloria Grace, Michael J Strong,

Motor neuron diseases can affect the upper motor neuron and/or the lower motor neuron. Both amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) are motor neuron diseases, and there is much debate as to whether these are 2 separate disorders or simply 2 points on a continuum.

Archives of neurology - Feb 2007

Clinical features that distinguish PLS, upper motor neuron-dominant ALS, and typical ALS.
P H Gordon, B Cheng, I B Katz, H Mitsumoto, L P Rowland,

To determine how clinical features at the first evaluation and in follow-up can be used to suggest a diagnostic outcome for patients with only upper motor neuron (UMN) signs at disease onset.

Neurology - Jun 2009

Uncovering amyotrophic lateral sclerosis phenotypes: clinical features and long-term follow-up of upper motor neuron-dominant ALS.
Mario Sabatelli, Marcella Zollino, Marco Luigetti, Alessandra Del Grande, Serena Lattante, Giuseppe Marangi, Mauro Lo Monaco, Francesca Madia, Emiliana Meleo, Giulia Bisogni, Amelia Conte,

The aim of our study was to analyse the natural history and clinical features of upper motor neuron- dominant (UMN-D) ALS. We studied a large series of sporadic ALS patients admitted in a single referral centre over a 23-year period. UMN-D phenotype was compared with other ALS forms, including classic ALS, flail arm and progressive muscular atrophy. Seven hundred and thirty-four sporadic ALS patients were included of which 163 had UMN-D ALS. The mean age of onset in UMN-D ALS (52 years) was 10 years lower than in classic ALS (61.4 years, p < 0.0001); sex ratio by age groups significantly differed with respect to other phenotypes. The pattern of spread of lower motor neuron signs in UMN-D was characterized by early involvement of upper limb muscles and late impairment of respiratory muscles. Duration of the disease was longer in the UMN-D group (56 months) than in classic ALS (33 months, p < 0.001). The UMN-D phenotype was a strong independent predictor of long survival. In summary, UMN-D ALS showed significant differences in age of onset, sex ratio, pattern of spreading and prognosis with respect to other ALS forms, most probably reflecting biological differences.

Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases - Jul 2011