Familial amyotrophic lateral sclerosis

INTRODUCTION — 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 ALS 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 and lower motor neuron involvement. The lower motor neuron findings of weakness, atrophy, and fasciculations are a direct consequence of muscle denervation, hence the term "amyotrophic." The upper motor neuron 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".)

OVERVIEW — Familial ALS accounts for approximately 5 to 10 percent of all ALS cases [1,2]. More than 20 causative genes have been identified. Among these, the two most common are C9ORF72 and SOD1, which together make up nearly 50 percent of familial ALS.

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. The nomenclature of ALS1 through ALS26 arises from the order of their discovery and not from any particular clinical classification. Many of the genetic variants 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. A positive family history of ALS, other neurodegenerative disorders, and dementia or the presence of atypical features such as young age of onset or sensory loss, should alert the clinician to the possibility of familial ALS. However, the absence of a positive family history does not entirely exclude a diagnosis of familial ALS.

GENETIC TESTING AND COUNSELING — Genetic testing for specific ALS-causing pathogenic genetic variants is typically used for specific indications. These include the following (table 1):

●Determining treatment eligibility with the antisense oligonucleotide tofersen for patients with SOD1-associated ALS. (See 'ALS1 (SOD1 gene)' below.)

●Providing risk information and subsequent counseling for unaffected at-risk family members of an affected relative with an established genetic cause (table 1) is the most common use of genetic testing for ALS. (See "Genetic counseling: Family history interpretation and risk assessment".)

●Testing to confirm the diagnosis of ALS is used in rare cases of early-stage disease (ie, clinically suspected and clinically possible ALS by El Escorial criteria), with or without a family history of ALS. The discovery of an ALS-related gene can change the diagnosis to clinically definite laboratory-supported familial ALS. In cases where the diagnosis is clear, genetic testing has little or no additional value in making the diagnosis of ALS and will not impact medical management or treatment options. (See "Diagnosis of amyotrophic lateral sclerosis and other forms of motor neuron disease", section on 'Diagnosis'.)

●Genetic testing may play a role in making an alternative diagnosis of Kennedy syndrome and late-onset Tay-Sachs disease, two genetic disorders that can mimic some of the clinical features of ALS. This is discussed separately. (See "Diagnosis of amyotrophic lateral sclerosis and other forms of motor neuron disease", section on 'Genetic testing' and "Diagnosis of amyotrophic lateral sclerosis and other forms of motor neuron disease", section on 'Differential diagnosis'.)

●Genetic testing may be a prerequisite for participation in a clinical trial involving specific genetic subtypes of ALS, such as C9ORF72- or SOD1-associated ALS.

●Genetic testing may provide limited prognostic information, such as predicting rapid progression in individuals with the A4V SOD1 pathogenic genetic variant. However, genetic testing should not be used for this purpose, because the phenotypic variability seen in familial ALS makes such predictions unreliable at the level of individual cases. (See "Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease", section on 'Clinical patterns of progression'.)

A glossary of genetic terms is available in a table (table 2) and, in an expanded form, in a separate topic. (See "Genetics: Glossary of terms".)

Recurrence risk within a family — For familial ALS, the recurrence risk of ALS in a given family (ie, whether or not another family member will develop ALS) is estimated primarily by determining the inheritance pattern. The mode of inheritance in familial ALS can be autosomal dominant, autosomal recessive, or (rarely) X-linked. Autosomal dominant inheritance is by far the most common pattern of inheritance observed in hereditary ALS.

The mode of inheritance is determined by analysis of the family history and the results of genetic testing, if available. Thus, a detailed pedigree covering at least three generations should be obtained that includes the affected individual's parents, siblings, children, grandparents, aunts and uncles, nieces and nephews, and first cousins. Information to be collected should include current age, health status, age at death, cause of death, medical diagnoses, history of dementia, and any possible symptoms of ALS that may have gone undiagnosed.

Of note, the family history may be falsely negative due to a number of factors, including failure to recognize the disorder in family members, death from other causes prior to ALS symptom onset, non-paternity, or late onset or reduced penetrance of the disease in affected family members.

With sporadic ALS, it is generally believed that the recurrence risk of ALS is not significantly higher than the risk in the general population when there is only one family member affected with ALS. The recurrence risk would increase should another family member be diagnosed with ALS. The recurrence risk may be as high as 50 percent if multiple family members are affected with ALS. However, the exact recurrence risk for ALS cannot be determined in the absence of a positive genetic test.

Who should be tested? — Genetic testing for at least SOD1 and C9ORF72 is encouraged in all patients, as genotype-specific therapies are in clinical trials and pathogenic genetic variants are occasionally identified in patients without a family history. An updated list of clinical trials available to patients with specific ALS genotypes can be found online at ClinicalTrials.gov. (See 'C9ORF72 gene' below and "Disease-modifying treatment of amyotrophic lateral sclerosis", section on 'Experimental therapy'.)

While any willing individual with ALS can have testing, a genetic cause is most likely to be found in those who have a family history of autosomal dominant disease or juvenile-onset ALS with suspected autosomal recessive inheritance. Genetic testing may also be useful in individuals with familial ALS who lack a clear family history consistent with an autosomal dominant disease, a situation that may occur because of reduced penetrance or limited information about important family members. However, the likelihood of identifying a pathogenic variant in a gene associated with ALS is reduced in this setting. As noted earlier, the most common use of genetic testing for ALS is to provide risk information and subsequent counseling for unaffected at-risk family members.

In patients with a family history suggesting autosomal dominant inheritance, genetic testing can provide prognostic information. As examples, the finding of a C9ORF72 pathogenic variant (see 'C9ORF72 gene' below) implies a high risk for the development of comorbid frontotemporal dementia (FTD) with ALS, while the finding of the A4V SOD1 pathogenic variant (see 'ALS1 (SOD1 gene)' below) augurs a poor prognosis due to rapid progression and an average life expectancy of only 1.5 years after the onset of symptoms. However, the impact of a positive genetic test on clinical care in patients with ALS is limited, since the treatment options are few and management is mainly symptomatic.

Individuals with ALS who do not have a positive family history may also pursue genetic testing, as apparently sporadic cases of ALS have been reported to carry a pathogenic genetic variant in one of the genes currently associated with familial ALS, including TARDBP, C9ORF72, SOD1, ANG, FUS, OPTN, and SETX, or in one of the genes likely to be susceptibility factors for ALS, including NEK1, ATXN2 and survival of motor neuron 1, telomeric (SMN1). In these cases, the lack of family history suggests either low penetrance or a de novo mutation of a gene associated with ALS. In addition, the absence of family history with apparently sporadic ALS makes it difficult to quantify the risk of ALS for unaffected family members with the same pathogenic variant. (See "Epidemiology and pathogenesis of amyotrophic lateral sclerosis", section on 'Genetic susceptibility in sporadic ALS'.)

Anyone diagnosed with ALS or any adult with a family history of ALS who is considering genetic testing should first meet with a genetic counselor or a physician knowledgeable about familial ALS to discuss the genetic basis of the disease as well as the medical, psychologic, economic, and familial implications. Those pursuing testing should be informed of a number of issues and limitations of genetic testing.

●The predictive value of a positive genetic test can be limited by a number of factors, including lack of population-based data on penetrance (ie, the likelihood of developing disease given inheritance of a disease-causing pathogenic variant) and variable expressivity (ie, phenotypic variations in the way the disease is expressed). Thus, the ability of the genetic test to predict phenotype (ie, the clinical validity) may be limited.

●The impact of a positive genetic test for ALS for the purpose of clinical care is essentially nil, since the treatment options are limited and management is mainly symptomatic.

Additional concerns that should be addressed by genetic counseling include the following:

●The meaning of a positive or negative test, including the slight possibility of false-positive or -negative results

●The risk of variants of unknown significance

●Psychosocial issues related to family dynamics

●Disclosing genetic information to at-risk family members

●The possibility of genetic discrimination

●Financial risks impacting life, disability, and long-term care insurance

These issues are explored in detail separately. (See "Genetic testing", section on 'Ethical, legal, and psychosocial issues' and "Genetic counseling: Family history interpretation and risk assessment".)

In families where a likely pathogenic variant in a gene associated with ALS has not been previously identified, testing is most likely to identify pathogenic variants in the affected family members with ALS, rather than at-risk members. Therefore, it is preferable to begin searching for variants by gene sequencing in affected members, and then subsequently perform targeted genotyping of identified pathogenic variants in potentially at-risk individuals. Once a disease-causing variant has been identified, other family members may choose to be tested for the same pathogenic variant regardless of whether or not they have symptoms. (See 'Unaffected family members' below.)

For ethical reasons, genetic testing is not appropriate for children and adolescents at risk for adult-onset ALS. There are a number of potential risks (eg, lack of autonomy, discrimination, stigmatization, anxiety) associated with the predictive testing of minors, and there is no compelling benefit because preventive treatment is unavailable [3].

How the test is done — Genetic testing can be done on a blood, saliva, or tissue sample. The sample is then analyzed for pathogenic variants in the specific gene(s) of interest.

●Full gene sequencing is considered the gold standard for identifying both known and novel variants in a gene and involves analyzing the entire coding region of the gene. Full gene sequencing will detect most pathogenic variants in the tested gene.

●Targeted mutation analysis (genotyping) involves testing for a specific pathogenic variant or set of variants in the gene of interest and will only detect pathogenic variants in the tested region(s) of the gene but will not identify all variants in the gene of interest. Targeted mutation analysis is often used for predictive testing in at-risk family members to identify pathogenic variants already known to exist in affected family members (ie, as identified through sequencing).

Genes to test — Clinical genetic testing for inherited (familial) forms of ALS is available to look for causative pathogenic variants in several genes associated with ALS. Approximately 13 to 20 percent of familial ALS is linked to pathogenic variants in the SOD1 gene, and approximately 40 percent of these are linked to hexanucleotide repeats in the C9ORF72 gene [4]. In addition, pathogenic variants in the FUS gene, ANG gene, TARDBP gene, and FIG4 gene may account for as much as 5, 2, 5, and 3 percent of familial ALS, respectively. (See 'ALS1 (SOD1 gene)' below and 'C9ORF72 gene' below and 'ALS6 (FUS gene)' below and 'ALS9 (ANG gene)' below and 'ALS10 (TARDBP gene)' below and 'ALS11 (FIG4 gene)' below.)

If the patient has juvenile-onset ALS, a multigene panel that includes genetic testing for SPG11, SETX, ALS2, and SPTCL1 would be appropriate. (See 'Autosomal dominant' below and 'Autosomal recessive' below.)

Multigene genetic testing panels are commercially available for all the above listed genes as well as other less common genes. However, not all pathogenic genetic variants associated with ALS have been identified. Commercial testing for some patients with a genetic susceptibility to ALS may be negative. Additionally, multigene panels may also include other genetic variants not associated with ALS. These factors should be addressed when discussing genetic testing and when revealing the results of genetic testing to patients. (See 'Interpretation' below.)

Laboratories offering testing — Some laboratories offer free genetic testing panels for ALS and neurodegenerative disease, which has made obtaining this testing much easier and has largely removed the financial barrier to genetic testing in ALS. Information on laboratories offering genetic testing for ALS is available online at the Genetic Testing Registry. The Genetic Testing Registry website is a publicly funded central location for voluntary submission of medical genetics test information by providers.

Interpretation — To properly interpret genetic test results for ALS genes, it is necessary to know whether the person who is being tested has ALS and whether a pathogenic variant in the family has already been identified.

Patients with ALS — For individuals with ALS who do not already have a known pathogenic genetic variant, there are three possible types of test results as follows:

●A positive test result means that the individual has a disease-causing (pathogenic) variant or variants and that the cause of ALS observed in the family has been identified. A positive result also further defines the risk to develop ALS for other family members. Interpretation of the ALS risk to other family members depends on the mode of inheritance of the gene with the variant(s). (See 'Recurrence risk within a family' above.)

●A negative test result means that the individual does not have a pathogenic variant in the tested gene or genes. However, a negative result does not rule out entirely the possibility of a genetic cause for the following reasons:

•Not all genes may have been tested. For example, if only testing for SOD1 was ordered, a negative result would not rule out the possibility of a pathogenic variant in TARDBP, FUS, FIG4, or ANG.

•Not all base positions of a targeted gene may have been adequately tested. For sequencing, this may occur if the assay was designed to target coding regions only, ignoring functional noncoding regions (such as regulatory or intronic regions). Also, gene coverage may be incomplete due to assay failure. In these instances, the individual may harbor pathogenic variants that are simply missed. In the context of targeted genotyping (testing of a limited number of variants) one can only confidently report a negative result for those specific variants tested. For example, a negative result from genotyping of the most common SOD1 pathogenic variant in North America, A4V, only excludes that variant but does not rule out any of the other 139 known SOD1 variants.

•Not all genetic causes of ALS have been identified.

●A variant of unknown significance (VUS) result means that a change was found in the genetic sequence of the gene, but the laboratory cannot yet make a clear determination as to whether it is a pathogenic variant or a benign polymorphism. Benign polymorphisms are common variations in DNA that do not cause disease.

When a VUS is identified, it is suggested that the variant be tracked through the family, which involves testing multiple affected and unaffected family members. However, tracking a variant through a family for an adult-onset condition can be challenging; since ALS typically affects older individuals, family members from the preceding generation may already be deceased and unable to contribute a DNA sample. In addition, when an unaffected family member tests positive for the variant, it is not clear whether this individual will develop ALS in the future or if the variant is benign. It can take years to determine whether or not a VUS is pathogenic.

For individuals with a diagnosis of ALS who are part of a family with a known familial pathogenic variant, a positive test result confirms that the individual did inherit the known pathogenic genetic variant and supports that variant as the cause of ALS for the individual. A negative result means that the individual did not inherit the known pathogenic variant; therefore, the cause of ALS for the individual is unknown. In this scenario, the individual would be considered to have sporadic ALS. This is known as a phenocopy. A second sample may be sent for genetic testing to confirm the result.

Unaffected family members — Unaffected family members considering genetic testing for ALS are often concerned about possible symptoms of ALS. In such cases, a neurologic evaluation to look for evidence of ALS and a discussion with a trained genetic counselor can help alleviate concern.

Known family genetic variant — Testing an asymptomatic person who is at risk for inheriting a known pathogenic genetic variant is called presymptomatic (or predictive) testing. For presymptomatic testing, a variant must have been first identified in the family so that the clinician knows the appropriate test to order. The possible test results are as follows:

●A positive test result means that the individual has a pathogenic variant and is at risk to develop ALS. The probability that the individual will develop symptoms of ALS will depend on factors such as penetrance and expressivity. Penetrance and expressivity information is available for some genes, such as C9ORF72, SOD1, and FUS, but is limited for the other ALS genes. In general, the penetrance of most of the autosomal dominantly inherited ALS genes is above 90 percent.

●A negative test result means that the individual does not have a pathogenic variant in the tested gene and is not at risk for the familial form of ALS.

Family members may have different opinions about whether or not to pursue presymptomatic testing, as this is a very personal decision that can be confusing and emotionally difficult. Meeting with a trained genetic counselor and a psychologic evaluation are recommended to help the individual throughout the testing process; multiple counseling sessions are optimal, including pre-decision, pretest, and post-test counseling [5].

No known family genetic variant — Presymptomatic (or predictive) genetic testing for an unaffected individual with a family history of ALS but no known familial pathogenic variant is not recommended, because it is difficult to determine the appropriate test to order and interpret the meaning of negative or inconclusive genetic test results.

●A negative test result would mean that the individual did not have a pathogenic variant in the tested gene or genes. However, this finding would not rule out the possibility that they have inherited a genetic form of ALS. In this situation there are three possible scenarios to explain the history of ALS observed in the family:

•It is due to a pathogenic variant in one of the tested genes, and the individual did not inherit the variant. The patient is not at an increased risk of developing ALS.

•It is due to an unknown gene, and it is unknown if the individual inherited the pathogenic variant. The patient may be at an increased risk of developing ALS.

•It is due to environmental factors and is not genetic.

●A VUS means that a change was found in the genetic sequence of the gene, but the laboratory cannot make a clear determination as to whether it is a pathogenic variant or a benign polymorphism. This individual may or may not develop ALS in the future.

Differences between clinical and research genetic testing — The purpose of clinical genetic testing is primarily for diagnosis or presymptomatic genetic testing (table 1). The testing is performed in an accredited laboratory. A report of the results is generated and is part of the patient's official medical record. There is a charge for clinical testing, which may or may not be covered by insurance.

The purpose of research genetic testing is to discover and to better understand the genetic factors of ALS. Patient identifiers and information remain confidential, and results do not become part of the patient's official medical record. There is no fee when participating in a research study, and generally results are not returned to participants. Many individuals choose to participate in research genetic testing to help advance the ALS field for the benefit of others with or without ALS now and for future generations.

AUTOSOMAL DOMINANT — The majority of familial ALS cases follow an autosomal dominant inheritance pattern. In autosomal dominant inheritance, having a pathogenic variant in only one copy of a gene is sufficient for an individual to develop the condition. Typically, the copy of the gene with the pathogenic variant is inherited from a parent (as opposed to de novo mutations, which are uncommon), and most individuals with an autosomal dominant condition will have a positive family history. Each child of a parent with a dominant pathogenic variant has a 50 percent chance of inheriting the copy of the gene with the variant and being at risk to develop ALS.

Autosomal dominant pathogenic variants in apparently sporadic ALS can occur due to de novo (new) mutations, reduced penetrance, or insufficient family history information. The frequency of de novo mutations in ALS is unknown. The recurrence risk for siblings and children of an apparently sporadic ALS case with an autosomal dominant pathogenic variant depends on whether or not the affected individual has an inherited or a de novo mutation. If the individual with ALS inherited the pathogenic variant from a parent, there is a 50 percent chance the individual's siblings and children will inherit the variant and be at risk to develop ALS. In the case of a de novo mutation, the recurrence risk for siblings would be low, but the recurrence risk for children would be 50 percent.

The most common autosomal dominantly inherited forms of familial ALS are caused by pathogenic variants in the chromosome 9 open reading frame 72 (C9ORF72) gene (see 'C9ORF72 gene' below) and the superoxide dismutase type 1 (SOD1) gene (see 'ALS1 (SOD1 gene)' below) described in the following sections.

C9ORF72 gene — Repeat expansions of the C9ORF72 gene on chromosome 9p21 are causally linked to classic ALS, frontotemporal dementia (FTD), and ALS with FTD [6-13]. C9ORF72 expansions are the most common cause of familial ALS, accounting for approximately 40 percent of cases in European populations and approximately 2 percent of familial cases in Chinese, Japanese, Korean, and Iranian populations [10,11,14,15]. They also account for approximately 5 percent of nonfamilial (sporadic, or singleton) ALS cases in European populations [16].

The C9ORF72 gene encodes an uncharacterized protein that is highly conserved among species. The hexanucleotide repeat expansion seen in ALS-FTD cases tends to be large, usually in the range of 500 to 3500 repeats, and varies between different tissue types in the same individual. Repeat length does not show a consistent relationship with survival. A positive association has been observed between repeat length and age of onset in some but not all studies [17-19]. A variety of mechanisms are thought to underlie motor neuron death as a result of C9ORF72 repeat expansion. These include both toxic gain of function and loss of function mechanisms [20].

ALS caused by C9ORF72 (C9ALS) has a similar natural history compared with sporadic (singleton) ALS. In large cohorts of patients with C9ALS, the median age of onset is approximately 58 years, and median survival is approximately 30 to 36 months from diagnosis [17]. Approximately 50 percent of individuals with pathogenic variants are symptomatic by age 58, and 100 percent are symptomatic by age 80 [21,22]. Limb onset is more common than bulbar onset (54 versus 39 percent). Compared with sporadic ALS, C9ALS is more likely to manifest with comorbid FTD (50 versus 12 percent) [16]. Older age and bulbar onset are associated with worse overall survival [23].

The cognitive features of ALS and the manifestations of FTD are reviewed separately. (See "Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease", section on 'Cognitive symptoms' and "Frontotemporal dementia: Clinical features and diagnosis".)

ALS1 (SOD1 gene) — Familial ALS1 is linked to pathogenic variants of the copper-zinc (Cu,Zn) SOD1 gene localized in chromosome 21q22 [24]. Heterozygous genetic variants in SOD1 account for approximately 15 percent of familial ALS cases in European populations and 30 percent of cases in Chinese, Japanese, Korean, and Iranian populations [14]. Most are inherited in an autosomal dominant manner. Approximately 50 percent of individuals with pathogenic variants are symptomatic by age 46, and 90 percent are symptomatic by age 70 [25]. Over 180 variants of the SOD1 gene have been reported [26,27]. Variants in the gene are thought to exert their pathogenic effects primarily through a toxic gain of function [28]. The clinical features of ALS1 are variable, as illustrated by the following observations:

●The A4V missense variant is the most prevalent genetic variant in familial ALS1 and accounts for approximately 41 percent of patients with SOD1 pathogenic variants [29]. It typically has a rapid progression with an average life expectancy of 1.5 years after the onset of symptoms [30]. Upper motor neuron involvement is either absent or mild, but pathologic abnormalities in systems other than the motor neurons are more frequent [31].

●The I113T pathogenic variant [24] is the second most common type, accounting for 16 percent of SOD1 pathogenic variants. This variant has variable penetrance that can be low [32]. The mean age of onset is 59 years. The clinical course is variable, ranging from quite rapid progression and death within two years to very slow progression that can span 20 years [32-34]. Both upper and lower motor neuron findings occur. Posterior column involvement has been reported in one patient [35].

●Families with the A4T pathogenic variant in the SOD1 gene have a variable disease onset and duration. In one large kindred, the age of onset ranged from 32 to 60 years, with a mean of 46 years [36]. Weakness in the legs was the most frequent early symptom, and there was a predominance of lower motor neuron signs. Bulbar and respiratory muscle involvement occurred in all individuals. The mean time from onset of symptoms to death was 14 months. One male with onset at age 37 had a more slowly developing form and was alive but severely affected 76 months after diagnosis. With this one exception, the severity was similar to that of the A4V pathogenic variant [36].

●Among 17 patients from three Japanese ALS1 families with the SOD1 H46R heterozygous genetic variant, the age of disease onset ranged from 32 to 60 years (average 44.3), the age of death ranged from 46 to older than 88 years (average 59 years), and the mean disease duration was greater than 12 years [37]. The initial symptom was distal leg weakness in all patients. This relatively slow disease progression is in keeping with the clinical observation that bulbar involvement was minimal in these families; only 1 out of the 12 reported patients had tongue atrophy. Dementia was uniformly absent in these patients.

●Another report described three members of a familial ALS1 pedigree with a rare A89V SOD1 pathogenic variant [38]. This variant is characterized by incomplete penetrance, variable age of onset, and an associated painful sensory neuropathy. In these three patients, the disease onset was late in two and early in one. The early-onset patient was a 15-year-old male who presented with a one-year history of a progressive bilateral symmetric leg and arm weakness. The weakness was associated with sporadic cramps and fasciculations in the limbs and chest muscles but no bulbar involvement. On exam, he had brisk jaw reflexes, weak neck flexion and extension, bilateral weakness and atrophy of the upper and lower extremities, increased tone, hyperactive deep tendon reflexes, and a left Babinski response.

●In a report involving 20 patients, the G93C pathogenic variant was associated with a purely lower motor neuron phenotype and absence of bulbar involvement [39]. The mean age of onset was 46 years and disease progression was slow, with an average survival of nearly 13 years.

Rare patients with homozygous pathogenic variants in SOD1 have been described with variable phenotypes [40-45]. Homozygous truncating pathogenic variants in SOD1 causing complete absence of SOD1 enzyme have been associated with a particularly severe phenotype, including early-onset progressive spastic tetraparesis with little or no evidence of lower motor neuron involvement [42,43].

Tofersen is an antisense oligonucleotide that targets SOD1 to reduce pathologic translation and protein expression that was approved by the United States Food and Drug Administration in April 2023 for patients with ALS associated with SOD1 variants. Tofersen for ALS is discussed in greater detail separately. (See "Disease-modifying treatment of amyotrophic lateral sclerosis", section on 'Tofersen for SOD1-associated ALS'.)

ALS3 — Familial ALS3 has been linked to the WDR7 gene in the 18q21 region [46,47]. The average age of onset was 43 years. Leg onset was most common. Both upper and lower motor neuron signs occurred. Other central nervous system pathways were not involved. The mean life expectancy was five years.

ALS4 (SETX gene) — Familial ALS4 is a juvenile form with an average age of onset in the second decade [48-50]. It has been linked to the SETX gene on chromosome 9q34 coding for senataxin, a DNA and RNA helicase. It most commonly begins with fairly symmetric distal weakness and atrophy of the hands and feet. Proximal weakness occurs later. Upper motor neuron signs occur, but bulbar involvement is uncommon. The clinical course is extremely slow. Progression to a nonambulatory status does not occur until the fifth or sixth decades. Minor sensory changes can occur in older individuals.

Pathologically, the disorder is characterized by loss of upper and lower motor neurons as well as dorsal root ganglion neurons and posterior column fiber loss. Recessive pathogenic variants in SETX have been linked to inherited ataxia, oculomotor apraxia, and peripheral neuropathy [51-54].

ALS6 (FUS gene) — Pathogenic variants in the fused in sarcoma (FUS) gene (also known as the TLS gene) on chromosome 16 have been linked to familial ALS6 in multiple families from multiple ethnic groups [55-58]. The phenotype is notable for onset at an average age of 45 years, with an average survival of 33 to 41 months [56,57]. However, there is a wide variation in the duration of symptoms, with one reported patient surviving for 18 years [57]. In a series of 18 patients, the onset was cervical more often than lumbar or bulbar [56]. FUS pathogenic variants have also been identified in a few patients with familial ALS and FTD or parkinsonism [57]. In cases in which pathologic specimens were obtained, there was severe lower motor neuron loss in the spinal cord and to a lesser degree in the brainstem [56].

FUS pathogenic variants are estimated to occur in approximately 3 percent of familial ALS cases in European populations and 6 percent of familial ALS cases in Chinese, Japanese, Korean, and Iranian populations [14]. Both autosomal dominant and recessive inheritance patterns have been described [55].

The FUS protein is normally found in the nucleus, where it is involved in transcription regulation, RNA splicing, and RNA transport [55,56]. Thus, it is functionally similar to the TAR DNA binding protein (TARDBP) gene described below. Furthermore, cellular expression studies reveal that pathogenic variant forms of FUS protein have aberrant localization in the cytoplasm of neurons, similar to the pathology of TARDBP gene variants in familial ALS. These findings suggest that forms of ALS due to FUS and TARDBP pathogenic variants share a common pathogenic mechanism related to impaired RNA metabolism. (See 'ALS10 (TARDBP gene)' below.)

ALS7 — Familial ALS7 has been linked to chromosome 20p13 in a single family [59]. The mean onset was in the sixth decade, with a mean life expectancy of three years after onset. It is characterized by both upper and lower motor neuron signs.

ALS8 (VAPB gene) — Familial ALS8 was initially linked to chromosome 20q13.33 in a single Brazilian family [60]. It is characterized by onset in the third to the fifth decade with manifestations that include cramps, fasciculations, and at times lower motor neuron weakness. Upper motor neuron findings are less common. Some individuals manifest sensory loss, a postural tremor, or both. The course is slowly progressive. The cause is a missense variant form of the VAMP associated protein B and C (VAPB) gene [61]. The same VAPB pathogenic variant has been identified in additional families with clinically heterogeneous types of motor neuron disease, including ALS8, typical severe ALS with rapid progression, and late-onset spinal muscular atrophy [61-63].

ALS9 (ANG gene) — Missense variants in the ANG gene coding for the protein angiogenin have been identified in Irish, Scottish, and Scandinavian individuals, some with and some without a dominant family history of ALS [64,65]. Pathogenic forms of the ANG gene result in functional loss of angiogenic activity [66]. The angiogenin protein promotes vascularization of tissue and is required for the activity of vascular endothelial growth factor (VEGF).

The clinical course associated with ANG pathogenic variants is that of progressive upper and lower motor neuron disease with a wide range of onset age and survival [64,65]. The frequency of bulbar onset, approximately 50 percent, is greater than that of sporadic ALS. One patient with an ANG variant initially presented with parkinsonism, followed five years later by manifestations of upper and lower motor neuron disease and features characteristic of FTD [67].

ALS10 (TARDBP gene) — The TAR DNA binding protein 43 (TDP-43) is a major component of ubiquitinated inclusions in sporadic ALS, FTD with ubiquitin-positive/tau-negative inclusions, ALS with FTD, and familial ALS (with the exception of SOD1-related and FUS-related familial ALS1). (See "Epidemiology and pathogenesis of amyotrophic lateral sclerosis", section on 'Intracellular inclusions'.)

Pathogenic variants in the TARDBP gene on chromosome 1p36.22 that encodes TDP-43 are the cause of autosomal dominant familial ALS10 and may be a rare cause of sporadic ALS [68-72]. These pathogenic variants account for approximately 4 percent of familial ALS cases in European populations and 2 percent of familial ALS cases in Chinese, Japanese, Korean, and Iranian populations [14].

Although the phenotype is variable, the clinical features of ALS in patients with TARDBP pathogenic variants compared with patients who have sporadic ALS include a greater likelihood for earlier onset, upper limb onset, and slower progression [73]. Some patients develop cognitive impairment or FTD. Other studies have identified TARDBP variants in apparently sporadic and familial forms of FTD with and without motor neuron disease [74].

ALS11 (FIG4 gene) — Familial ALS11 is an autosomal dominant form of ALS caused by pathogenic variants in the FIG4 phosphoinositide 5-phosphatase (FIG4) gene on chromosome 6q21 [75].

In a study that screened DNA from 473 patients (364 with sporadic ALS and 109 with familial ALS), pathogenic variants in the FIG4 gene were identified in nine patients (2 percent), including six with sporadic ALS and three with familial ALS [75]. Upper motor neuron features were prominent. The protein encoded by FIG4 is a phosphoinositide 5-phosphatase that regulates a signaling lipid involved with membrane vesicle trafficking.

Charcot-Marie-Tooth disease type 4J (CMT4J) is an allelic disorder caused by FIG4 pathogenic genetic variants. The phenotype of CMT4J is notable for autosomal recessive inheritance, early childhood to adult onset, and involvement of both motor and sensory neurons. (See "Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis", section on 'CMT4'.)

ALS12 (OPTN gene) — Pathogenic variants within the optineurin (OPTN) gene are the cause of ALS12, as first identified in two Japanese families [76]. Age of onset was 33 to 54 years, and progression was slow. Patients with ALS-FTD have also been described [77]. Later reports identified OPTN variants in 1 to 2 percent of familial ALS and 0 to 3.5 percent of sporadic ALS cases [78,79]. Although classified as an autosomal dominant disorder, autosomal recessive cases have also been reported [76].

ALS13 (ATXN2 gene) — Mounting evidence suggests an association between intermediate length polyglutamine expansions in the ataxin 2 (ATXN2) gene and increased risk of ALS. This issue is discussed separately [80]. (See "Epidemiology and pathogenesis of amyotrophic lateral sclerosis", section on 'Genetic susceptibility in sporadic ALS'.)

ALS14 (VCP gene) — A pathogenic variant in the valosin-containing protein (VCP) gene was first identified in an Italian family as the cause of ALS14 [81]. Additional VCP pathogenic variants have since been identified in other familial ALS cases, suggesting that VCP pathogenic variants are responsible for 1 to 2 percent of familial ALS cases [81,82].

Pathogenic variants in VCP are also the cause of some but not all cases of an autosomal dominant familial syndrome characterized by inclusion body myopathy (IBM) associated with Paget disease of bone (PDB) and FTD (IBMPFD) [83,84]. There is mounting evidence that the spectrum of IBMPFD includes familial ALS [82,84]. The valosin-containing protein is implicated in numerous cellular functions, including pathways involved in ubiquitin-dependent protein degradation and autophagy. Variant valosin-containing protein may act by disrupting autophagy, resulting in the deposition of TDP-43 inclusions within the cytoplasm of affected cells [85]. (See "Epidemiology and pathogenesis of amyotrophic lateral sclerosis", section on 'Intracellular inclusions'.)

ALS17 (CHMP2B gene) — Case reports have associated pathogenic variants in the chromatin modifying protein 2b (CHMP2B) gene in both sporadic and dominantly inherited disorders referred to as chromosome 3-linked FTD (FTD3). While predominately associated with FTD3, late-onset (seventh to eighth decades) bulbar ALS with and without FTD has also been associated with CHMP2B pathogenic variants [86,87].

ALS18 (PFN1 gene) — Pathogenic variants in the profilin 1 (PFN1) gene located on chromosome region 17p13.2 have been found in seven families with ALS displaying an autosomal dominant mode of inheritance [88]. The phenotype is notable for limb onset of ALS in middle age (average 45 years). The PFN1 protein regulates actin polymerization and has multiple other cellular functions. Pathogenic variants of the PFN1 gene may play a role in ALS pathogenesis on the basis of reduced levels of bound actin, inhibition of axon growth, and a propensity to form intracellular aggregates compared with wild-type PFN1.

ALS19 (ERBB4 gene) — Pathogenic genetic variants in the ERBB4 gene located on chromosome region 2p34 have been found in three families with onset of classic ALS. A heterozygous missense variant was first identified in one family that included three Japanese siblings who were diagnosed between the ages of 60 and 70. Subsequently, the same missense variant was identified in one Canadian individual with familial ALS, and a different missense variant was identified in a Japanese individual with sporadic ALS [89].

ALS20 (HNRNPA1/A2B1 genes) — The heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) and A2/B1 (HNRNPA2B1) genes encode for RNA binding proteins (RBPs), which play an important role in regulating RNA function and metabolism. The role of HNRNPA1 and HNRNPA2B1 in ALS was first suggested by a study that combined whole-exome sequencing with linkage analysis in families with autosomal dominant presentations of multisystem proteinopathy [90]. One of these families, with a pathogenic variant in HNRNPA2B1, had a rare inherited syndrome characterized by features of IBM associated with PDB, FTD, and ALS (also known as IBMPFD/ALS). Subsequently, exome screening of 212 familial ALS cases in which known ALS genes were excluded identified a causative pathogenic variant within the HNRNPA1 protein in one patient [90].

These genetic variants, which involve prion-like domains of the HNRNPA1 and HNRNPA2B1 proteins, appear to exacerbate the intrinsic tendency of RBPs to assemble into self-seeding fibrils, thereby leading to excess fibril formation and eventual neurodegeneration with cytoplasmic inclusions [90]. Pathogenic variants affecting a number of other RBPs are linked to ALS, including TDP-43, FUS, matrin 3 (MATR3), and TIA1 [91]. In many of these cases, the affected RBPs also become depleted from the nucleus and deposited in cytoplasmic inclusions. (See 'ALS10 (TARDBP gene)' above and "Epidemiology and pathogenesis of amyotrophic lateral sclerosis", section on 'Intracellular inclusions' and "Epidemiology and pathogenesis of amyotrophic lateral sclerosis", section on 'Altered RNA processing'.)

ALS21 (MATR3 gene) — Pathogenic variants in the MATR3 gene on chromosome 5q31 coding for a nuclear matrix protein proposed to stabilize messenger RNA species were initially linked to a disorder manifesting as vocal cord and pharyngeal weakness with distal limb weakness ascribed to a myopathy. However, subsequent follow-up of these patients demonstrated progressive upper and lower motor neuron findings with respiratory failure ascribed to a progressive disorder of motor neurons [92].

ALS22 (TUBA4A gene) — Pathogenic variants in the microtubule network assembly gene, tubulin alpha 4a (TUBA4A), have been demonstrated to produce progressive upper and lower motor neuron signs, usually with spinal onset, and in some cases progressive cognitive decline consistent with frontotemporal dementia [93].

ALS23 (ANXA11 gene) — Located on chromosome 10q22.3, the annexin A11 (ANXA11) gene codes for a family of calcium-dependent phospholipid-binding proteins involved in vesicular trafficking. Pathogenic variants have been noted in both familial and sporadic ALS [94].

ALS24 (NEK1 gene) — Pathogenic variants in the NIMA-related kinase 1 (NEK1) gene that codes for a serine/threonine kinase involved in cell cycle regulation have been associated with a progressive upper and lower motor neuron disorder consistent with ALS. Cognitive dysfunction has not been described, although one patient was noted on magnetic resonance imaging to have hippocampal and temporal lobe atrophy [95,96].

Additionally, NEK1 variants have been associated with 3 percent of sporadic ALS cases, suggesting that the gene can not only cause familial ALS but also increase the risk of development of sporadic ALS in carriers of these variants [96].

ALS25 (KIF5A gene) — Multiple lines of evidence implicate the kinesin family member 5A (KIF5A) gene in ALS [97,98]. Splice-site variants in the C-terminal domain of the KIF5A gene were identified in two families with ALS. A separate study found an excess of rare functional variants in familial ALS cases compared with controls, all of which localized to the C-terminal cargo-binding region of the gene [97,98]. This is in contrast with other pathogenic variants that localize to the N-terminal motor domain of KIF5A that have been previously described in patients with hereditary spastic paraplegia, Charcot-Marie-Tooth type 2, and neonatal intractable myoclonus.

Most patients manifest a classic ALS phenotype, with focal asymmetric onset of upper and lower motor neuron dysfunction in early to mid-adulthood. Limited available data support a highly penetrant loss-of-function mechanism related to dysfunction in intracellular transport [97].

ALS26 (TIA1 gene) — Pathogenic variants in the T cell-restricted intracellular antigen-1 (TIA1) gene were identified by whole genome sequencing of a multigenerational European family with ALS-FTD [99]. Most patients had the symptom onset occur between the ages of 51 and 74 years old. The mean duration of disease was 3 years (range 1 to 6 years). All had typical features of ALS, and several had evidence of FTD [100].

Neuropathologic studies in patients with variants in the TIA1 gene have shown typical features of ALS but also the presence of structures resembling Lewy bodies. In vitro studies found that variant forms of the TIA1 protein undergo temperature- and concentration-dependent formation of amyloid-like fibrils, suggesting that protein aggregation plays a role in motor neuron death [100].

ALS27 (SPTLC1 gene) — Variants in exon 2 of the serine palmitoyltransferase, long-chain base subunit-1 gene (SPTLC1) have been associated with an early childhood form of ALS in seven families [101]. These children typically present with lower extremity spasticity and upper motor neuron signs followed by eventual lower motor neuron involvement. Disease progression was significantly slower than sporadic ALS and mirrored other juvenile forms of ALS. Children in most families develop onset of symptoms from three to eight years old. Pathologic variants resulted from de novo mutations or autosomal dominance inheritance.

SPTLC1 is an important regulator of sphingolipid synthesis. Dysregulation of sphingolipids results in accumulation of sphingolipid species which are variably toxic to different types of neurons. Other variants in the SPTLC1 gene have also been described in patients with hereditary sensory and autonomic neuropathy, type 1. Limited evidence suggests that ALS-associated variants lead to unregulated sphingolipid production whereas HSAN1-associated variants result in increased production of deoxysphingolipids and this may underlie the genotype-phenotype correlations [101]. (See "Hereditary sensory and autonomic neuropathies", section on 'HSAN1'.)

Others

●DAO gene – A variant in the D-amino acid oxidase (DAO) gene on chromosome region 12q24 has been associated with classic adult-onset familial ALS in a three-generational kindred from England [102]. Features included upper and lower motor neuron involvement and bulbar signs but no cognitive impairment. The mean age at time of death was 44 years (range 42 to 55 years).

DAO is a flavoprotein that catalyzes the oxidative deamination of D-serine, a co-agonist in the activation of the N-methyl-D-aspartate (NMDA) glutamate receptor subtype. The R199W DAO variant identified in this study causes a loss of enzyme activity, which could lead to cell death via excitotoxicity from enhanced NMDA receptor activation.

●NEFH gene – Familial ALS linked to a variant of the neurofilament heavy chain (NEFH) gene located on chromosome 22q12.1-q13.1 has been noted in a Scandinavian kindred [103]. Variable features included monomelic amyotrophy, dementia, and bulbar dysfunction. One percent of sporadic ALS patients have been reported to have a genetic variant of the NEFH gene. Its role in the disease is uncertain.

●SQSTM1 gene – Following upon the knowledge that protein degradation pathways are implicated in ALS and FTD, two groups screened large cohorts of patients with ALS and FTD and found variants in the sequestosome 1 (SQSTM1) gene [104,105]. The SQSTM1 gene encodes for the p62 protein, which binds ubiquitin and is involved in protein degradation and autophagy. SQSTM1 genetic variants were noted in both familial and sporadic cases of ALS and FTD. While one study reports heterozygous inheritance consistent with dominant genetics [104], the other is silent on this subject [105]. The precise role of this gene in the pathogenesis of ALS is not well defined.

●CYLD gene – A missense variant in CYLD lysine 63 deubiquitinase (CYLD) has been identified in a European family with ALS and FTD [106]. The variant leads to inhibition of nuclear factor kappa B (NF-kB) signaling and impaired autophagy. The autophagy pathway has also been implicated in other genetic forms of ALS, including OPTN and SQSTM1.

AUTOSOMAL RECESSIVE — Recessively inherited familial ALS includes ALS2, ALS5, and ALS16. In autosomal recessive inheritance, a pathogenic variant of both copies of a gene is necessary in order for an individual to develop the condition. Typically, parents of an affected individual do not have the condition themselves but are obligate carriers for the pathogenic variant. The siblings of an individual with an autosomal recessive condition have the highest recurrence risk. Siblings have a 25 percent likelihood of inheriting both copies of the gene with the pathogenic variant and developing ALS, a 50 percent likelihood of being an unaffected carrier for the condition, and a 25 percent likelihood of being an unaffected noncarrier for the condition. Unless an individual's partner is also a carrier for the same disease gene, all children of an individual with autosomal recessive ALS will be unaffected carriers of the condition. In autosomal recessive inheritance, there may be no family history of the condition in previous generations because a single copy of a gene variant may be passed silently through a family.

The ALS2, SPG11, spatacsin vesicle trafficking associated (SPG11), and SIGMAR1 genes are inherited in an autosomal recessive pattern. Additionally, certain pathogenic variants in some ALS genes that are usually associated with autosomal dominant inheritance can also be inherited in an autosomal recessive pattern. Examples include the SOD1, FUS, and OPTN genes. (See 'ALS1 (SOD1 gene)' above and 'ALS6 (FUS gene)' above and 'ALS12 (OPTN gene)' above.)

ALS2 (ALS2 gene) — Familial ALS2 is caused by a pathogenic variant in exons 3 or 4 of the ALS2 gene coding for Alsin, a putative GTPase regulatory protein, on chromosome 2q33 [107,108]. The mean age of onset is in the first decade. Clinical features involve the development of upper motor neuron signs in the face and lower limbs, greater than in the upper limbs. Mild lower motor neuron findings develop slowly in the distal legs, more so than the arms. The course is markedly slow with note of difficulty walking in the fifth decade. In addition, there are variant phenotypes and allelic disorders:

●One affected patient had ALS onset by age 2 and progression to anarthria and was nonambulatory by age 18 [109].

●Another report described juvenile onset of ALS associated with generalized dystonia and cerebellar signs in two consanguineous families [110].

●A deletion in exon 9 of the ALS2 gene is responsible for recessively inherited childhood-onset primary lateral sclerosis (PLS), at times associated with gaze paresis [111].

●Frame shift variants in various locations within the ALS2 gene that produce a premature stop codon have been associated with recessively inherited infantile-onset familial spastic paraparesis [112].

ALS5 (SPG11 gene) — Familial ALS5, the most common form of autosomal recessive familial ALS, has been linked to pathogenic variants of the SPG11 gene on chromosome 15q15-q22 [113,114]. The onset is in the second decade and is characterized by the development of lower motor neuron signs that exceed the upper motor neuron findings. Distal involvement is usually greater than proximal, and arms are usually involved more than legs. Bulbar involvement occurs late.

Pathogenic variants involving SPG11 are also the cause of hereditary spastic paraplegia with a thin or atrophied corpus callosum [115]. However, the clinical features of patients with ALS5 and SPG11 variants differ from those associated with hereditary spastic paraplegia due to the presence of bulbar symptoms, upper motor neuron involvement, and pathologic manifestations of ALS [114]. In addition, the patients with familial ALS5 have not developed the corpus callosum thinning, ocular abnormalities, cognitive deficits, or psychiatric problems that are observed in SPG11-related hereditary spastic paraplegia. (See "Disorders affecting the spinal cord", section on 'Hereditary spastic paraplegias'.)

ALS16 (SIGMAR1 gene) — Familial ALS16 has been reported in one consanguineous Saudi Arabian family in which six family members developed an early-childhood onset condition consistent with juvenile ALS. A homozygous variant affecting a highly conserved amino acid in the transmembrane domain of the SIGMAR1 gene was identified. Affected family members demonstrated lower limb spasticity with hyperreflexia and weakness at a very young age (1 to 2 years) that progressed to hand and forearm muscle weakness by age 9 to 10 years followed by paralysis of the forearm and triceps. Two affected family members were nonambulatory by the age of 20. Cognition was preserved, and none of the affected family members had respiratory or bulbar muscle weakness [116].

Others

●SYNE1 gene – Variants in the synaptic nuclear envelope protein 1 (SYNE1) gene have been associated with cerebellar ataxia syndromes. The SYNE1 gene is a ubiquitously expressed protein that participates in connecting the nuclear plasma membrane to the actin cytoskeleton [117]. It plays a role in maintaining neuronal connections, especially in the cerebellum. (See "Overview of cerebellar ataxia in adults", section on 'Autosomal recessive ataxias'.)

Case reports of juvenile-onset ALS associated with heterozygous and homozygous variants in the SYNE1 gene include one patient from Japan and two siblings from India [118,119]. The patients presented in the second decade of life with lower extremity weakness and wasting associated with spasticity. Cerebellar features developed later in the slowly progressive course. The genetic specific factors that result in ALS or cerebellar phenotypes are unknown.

●ERLIN1 gene – Variants in the endoplasmic reticulum lipid raft-associated 1 (ERLIN1) gene have been associated with recessive hereditary spastic paraplegia [120]. In addition, multiple members of a family from Turkey were reported as having early onset ALS characterized by lower extremity weakness and hyperreflexia as well as hand atrophy [121]. The disease course was very slow with progression over decades.

X-LINKED DOMINANT — In X-linked dominant inheritance, the gene responsible for the condition is located on the X chromosome, and only one copy of the gene with the pathogenic variant is necessary to cause the disease. Therefore, unlike X-linked recessive inheritance, both males and females may be affected. If a father has an X-linked dominant condition, all of his female children will inherit the disease and none of his male children will inherit the disease. If a mother has an X-linked dominant disease, there is a 50 percent likelihood that either her female or male children will inherit the condition.

ALS15 (UBQLN2 gene) — In unrelated families from North America and Europe, a form of dominantly inherited ALS with reduced penetrance in females has been linked to variants of the ubiquilin 2 (UBQLN2) gene located at Xp11.21 [122,123]. In the first report, the age of onset ranged from 16 to 71 years and was earlier in males, while mean disease duration was approximately four years and was similar in males and females [122]. A frontotemporal lobar type of dementia accompanied some cases of ALS.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Motor neuron disease".)

SUMMARY

●Clinical clues to genetic origin – Familial amyotrophic lateral sclerosis (ALS) is phenotypically and genetically heterogeneous. 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, a positive family history of ALS, other neurodegenerative disorders, and dementia should alert the clinician to the possibility of familial ALS. (See 'Introduction' above.)

●Genetic testing – Clinical genetic testing for inherited (familial) forms of ALS is available to look for causative pathogenic variants in several genes. Genetic testing for specific ALS-causing pathogenic genetic variants is typically used for specific indications (table 1). The most common use of genetic testing for ALS is to provide risk information and subsequent counseling for unaffected at-risk family members. (See 'Genetic testing and counseling' above.)

To properly interpret genetic test results for ALS genes, it is necessary to know whether the person being tested has ALS and whether a pathogenic variant in the family has already been identified. The recurrence risk of ALS in a given family (ie, whether or not another family member will develop ALS) is estimated primarily by determining the inheritance pattern. (See 'Interpretation' above.)

●Autosomal dominant types – The majority of familial ALS cases follow an autosomal dominant inheritance pattern. (See 'Autosomal dominant' above.)

•Repeat expansions in the C9ORF72 gene and pathogenic variants in the SOD1 gene are the most common causes of familial ALS. In addition, pathogenic variants in the FUS gene and the TARDBP gene are relatively common causes of familial ALS. (See 'C9ORF72 gene' above and 'ALS1 (SOD1 gene)' above and 'ALS6 (FUS gene)' above and 'ALS10 (TARDBP gene)' above.)

•Less common forms of autosomal dominant familial ALS include ALS3, ALS4, ALS7, ALS8, ALS9, ALS11, ALS12, ALS14, ALS17, ALS18, and ALS caused by pathogenic variants of the DAO, NEFH, and KIF5A genes. (See 'Autosomal dominant' above.)

●Autosomal recessive types – Autosomal recessive forms of familial ALS are associated with variants of the ALS2, SPG11, and SIGMAR1 genes. (See 'Autosomal recessive' above and 'ALS2 (ALS2 gene)' above and 'ALS5 (SPG11 gene)' above.)

●X-linked dominant types – An X-linked dominant form of familial ALS is associated with UBQLN2 gene pathogenic variants. (See 'X-linked dominant' above and 'ALS15 (UBQLN2 gene)' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Dana Falcone, MS, LCGC, who contributed to earlier versions of this topic review.