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Familial amyotrophic lateral sclerosis

Leo McCluskey, MD, MBE
Dana Falcone, MS, CGC
Section Editors
Jeremy M Shefner, MD, PhD
Ira N Targoff, MD
Benjamin A Raby, MD, MPH
Deputy Editor
John F Dashe, MD, PhD


Amyotrophic lateral sclerosis (ALS) is one specific type of the more general group of motor neuron diseases. These disorders variably affect motor neurons located in the anterior (ventral) horn regions of the spinal cord, the cranial nerve motor nuclei in the pons and medulla, and the frontal cortex. Familial amyotrophic lateral sclerosis accounts for 5 to 10 percent of all ALS cases.

ALS is a relentlessly progressive neurodegenerative disorder that causes muscle weakness, disability, and eventually death. The hallmark of ALS is the combination of upper motor neuron (UMN) and lower motor neuron (LMN) involvement. The LMN findings of weakness, atrophy, and fasciculations are a direct consequence of muscle denervation, hence the term "amyotrophic." The UMN findings of hyperreflexia and spasticity result from degeneration of the lateral corticospinal tracts in the spinal cord, which are gliotic and hardened to palpation at autopsy, hence the term "lateral sclerosis."

This topic review will discuss familial ALS. The epidemiology and clinical features of ALS are discussed separately. (See "Epidemiology and pathogenesis of amyotrophic lateral sclerosis" and "Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease".)


Familial ALS accounts for approximately 5 to 10 percent of all ALS cases [1,2], with the rest being sporadic (idiopathic) in origin. In our series of 399 cases of ALS at the University of Pennsylvania with a four-generation pedigree, 10 percent of individuals had an affected first or second-degree relative [2].

Familial ALS is phenotypically and genetically heterogeneous. Although most familial ALS cases follow an autosomal dominant inheritance pattern, recessive and X-linked forms have been described. At least 15 different loci are thought to harbor ALS-causing mutations. The nomenclature of ALS1 through ALS15 arises from the order of their discovery and not from any particular clinical classification. Many of the types listed have been described only in one or two families, and genotype-phenotype correlation is stronger for some forms of genetic ALS than for others. In most individual cases, it may be difficult to determine on clinical grounds alone if ALS is familial or sporadic, especially at the onset of disease. The presence of atypical features such as young age of onset, sensory loss, and of course a positive family history of ALS, other neurodegenerative disorders, and dementia should alert the clinician to the possibility of familial ALS.


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Literature review current through: Nov 2016. | This topic last updated: Fri Dec 02 00:00:00 GMT+00:00 2016.
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