Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS)Recommended panel testing at Breda Genetics for this condition:

Amyotrophic lateral sclerosis (ALS2, ANG, ATXN2, C9orf72, CHMP2B, CHGB, DCTN1, FIG4, FUS, NEFH, OPTN, PFN1, PRPH2, SETX, SIGMAR1, SOD1, SPG20, TARDBP, UBQLN2, VAPB, VCP, VEGFA)


Amyotrophic lateral sclerosis (ALS) is a complex multifactorial neurodegenerative disorder characterized by progressive loss of upper motor neuron (UMN) and lower motor neuron (LMN), but it is increasingly recognized to be a more disseminated disease. Astrocytes, oligodendrocytes and microglia are also damaged in ALS. Clinical heterogeneity is typical of ALS (age and site of onset, disease duration) and there is no single test or procedure to establish the diagnosis of ALS. Most cases are diagnosed based on symptoms, physical signs, progression, electromyography (EMG), and tests to exclude the overlapping conditions. The prevalence of ALS is of 1 to 3 every 100,000 newly diagnosed patients each year. Familial ALS (FALS) represents about 5 ~ 10 % of ALS cases, whereas the vast majority of patients are sporadic.

Detailed clinical description

ALS symptoms include pain, fatigue, breathing, strength, difficulty to move, problems in sleep, eating, speaking, excessive saliva, and mucus. Dysphagia may contribute to significant malnutrition, pneumonia, and mortality in amyotrophic lateral sclerosis. Sympathetic skin response (SSR) is also impaired in ALS, mainly in lower extremities, maybe due to the damage to the unmyelinated postganglionic fibers.

Peripheral nerve sonography (especially of the distal ulnar nerve) has been proposed as a biomarker to monitor disease progression in amyotrophic lateral sclerosis.

As abnormalities in membrane excitability and Na+ channel function are characteristic of amyotrophic lateral sclerosis (ALS), flecainide (which is  a Na+ channel blocker and membrane stabiliser) has been tasted in ALS patients. Flecainide was safe and potentially biologically effective in ALS, stabilizing the peripheral axonal membrane function. Patients with amyotrophic lateral sclerosis (ALS) may benefit from brain-computer interfaces (BCI).

Given the wide genetic heterogeneity and the limited ratio of genetic cases, unraveling genotype-phenotype correlations may be of help in identifying patients for genetic testing.

Molecular genetics

To date, more than 20 causative genes have been identified in hereditary ALS. The superoxide dismutase 1 (SOD1) gene is the most commonly mutated gene, but pathogenic variants have been identified also in the ALS2, ANG, C9orf72, CHMP2B, CHGB, DCTN1, FIG4, FUS, NEFH, OPTN, PFN1, PRPH2, SETX, SIGMAR1, TARDBP, UBQLN2, VAPB, VCP, and VEGFA genes. Elden et al. (2010) proposed that intermediate-length ATXN2 polyQ repeats might confer genetic risk for ALS (ALS13). Troyer syndrome (SPG20 gene), so far identified only in Old Older Amish population from Ohio, is characterized by distal amyotrophy together with spastic paraparesis, dysarthria, and short stature.

Differential diagnosis

The differential diagnosis of ALS include: spinal and bulbar muscular atrophy (SBMA, Kennedy disease), adult polyglucosan body disease, spinal muscular atrophy (SMA, SMN1 gene), hereditary spastic paraplegias, hexosaminadase A deficiency (HEXA gene mutations), Silver syndrome, Charcot-Marie-Tooth disease type 2, inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD). Friedreich ataxia (FXN gene), a slowly progressive ataxia with mean onset between age ten and 15 years and usually before age 25 years, is typically associated with dysarthria, muscle weakness, spasticity in the lower limbs, scoliosis, bladder dysfunction, absent lower limb reflexes, and loss of position and vibration sense. Generalized, progressive weakness between age 20 and 50 years without antecedent symptoms or family history is also typical of the adult form of nemaline myopathy, in which dysarthria is common (ACTA1, NEB, TPM3, TPM2, TNNT1, and CFL2 genes).

The differential diagnosis with non genetic conditions for this case might include: polymyositis (proximal muscle weakness of shoulders, arms, and thighs, myalgias, and possible inflammation of the pharyngeal muscles), for which muscle biopsy is diagnostic, Guillain-Barré syndrome, and myasthenia gravis (in which onset with early or isolated oropharyngeal or limb weakness may rarely occur).

Recommended panel testing at Breda Genetics for this condition:

Amyotrophic lateral sclerosis (ALS2, ANG, ATXN2, C9orf72, CHMP2B, CHGB, DCTN1, FIG4, FUS, NEFH, OPTN, PFN1, PRPH2, SETX, SIGMAR1, SOD1, SPG20, TARDBP, UBQLN2, VAPB, VCP, VEGFA)


Sympathetic Skin Response in Amyotrophic Lateral Sclerosis. Hu F, Jin J, Qu Q, Dang J. J Clin Neurophysiol. 2016 Feb;33(1):60-5. PMID: 26844971

Flecainide in Amyotrophic Lateral Sclerosis as a Neuroprotective Strategy (FANS): A Randomized Placebo-Controlled Trial. Park SB, Vucic S, Cheah BC, Lin CS, Kirby A, Mann KP, Zoing MC, Winhammar J, Kiernan MC. EBioMedicine. 2015 Dec 1;2(12):1916-22. PMID: 26844270

Quantifying disease progression in amyotrophic lateral sclerosis using peripheral nerve sonography. Schreiber S1, Dannhardt-Stieger V, Henkel D, Debska-Vielhaber G, Machts J, Abdulla S, Kropf S, Kollewe K, Petri S, Heinze HJ, Dengler R, Nestor PJ, Vielhaber S. Muscle Nerve. 2016 Sep;54(3):391-7. PMID: 26840391

Defining Swallowing-Related Quality of Life Profiles in Individuals with Amyotrophic Lateral Sclerosis. Tabor L, Gaziano J, Watts S, Robison R, Plowman EK. Dysphagia. 2016 Jun;31(3):376-82. PMID: 26837611

Performance predictors of brain-computer interfaces in patients with amyotrophic lateral sclerosis. Geronimo A, Simmons Z, Schiff SJ. J Neural Eng. 2016 Apr;13(2):026002. PMID: 26824590

Patient-reported problematic symptoms in an ALS treatment trial. Raheja D, Stephens HE, Lehman E, Walsh S, Yang C, Simmons Z. Amyotroph Lateral Scler Frontotemporal Degener. 2016;17(3-4):198-205. PMID: 26824413

New ALS-Related Genes Expand the Spectrum Paradigm of Amyotrophic Lateral Sclerosis. Sabatelli M, Marangi G, Conte A, Tasca G, Zollino M, Lattante S. Brain Pathol. 2016 Mar;26(2):266-75. PMID: 26780671

New In Vitro Models to Study Amyotrophic Lateral Sclerosis. Myszczynska M, Ferraiuolo L. Brain Pathol. 2016 Mar;26(2):258-65. PMID: 26780562

Mice Overexpressing Both Non-Mutated Human SOD1 and Mutated SOD1(G93A) Genes: A Competent Experimental Model for Studying Iron Metabolism in Amyotrophic Lateral Sclerosis. Gajowiak A, Styś A, Starzyński RR, Bednarz A, Lenartowicz M, Staroń R, Lipiński P. Front Mol Neurosci. 2016 Jan 6;8:82. PMID: 26778957

Amyotrophic Lateral Sclerosis Overview. Kinsley L, Siddique T. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2001 Mar 23 [updated 2015 Feb 12]. PMID: 20301623

Posted in Academia, Disease cards, Last Update, Medical Genetics and tagged , , , , , , , , , , , , , , , , , , , , , , .

Leave a Reply

Your email address will not be published. Required fields are marked *