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Amyotrophic Lateral Sclerosis Type 4


Amyotrophic lateral sclerosis (ALS) is a progressive and generally fatal motor neuron disease. Most cases are sporadic, but high familial incidence is observed occasionally. Amyotrophic lateral sclerosis 4 (ALS4) is one of many subtypes of familial ALS. It has been related to mutations in the SETX gene, a protein-coding gene whose product is possibly involved in nucleic acid processing. ALS4 is inherited in an autosomal dominant manner. Affected individuals suffer from a slowly progressive distal neuropathy and present pyramidal signs. Contrary to classical ALS, first symptoms don't manifest in adulthood but in adolescence, and affected individuals have a near-to-normal life expectancy.


In general, symptom onset occurs in patients aged less than 25 years [1]. However, SETX mutations have also been detected in ALS patients who didn't experience any complaints until their late third or even fourth decade of life [2]. They may seek medical advice due to progressive distal limb weakness and subsequent muscle wasting. It is important to note that symptom onset may have occurred years before they present to the physician: Because disease progression is slow, first manifestations are not necessarily understood as pathological conditions [2]. Interestingly, ALS4 patients don't develop bulbar palsy; they don't suffer from dysarthria or dysphagia. Furthermore, respiratory muscles are spared from the disease. The patients' sensibility is usually unaltered, although minimal sensory impairment has been reported in those of advanced age [1]. Accordingly, electrophysiological studies typically reveal a chronic motor neuronopathy characterized by reduced amplitudes of compound muscle action potentials, positive sharp waves, and fibrillations, but normal amplitudes of action potentials of sensory nerves. Nerve conduction velocities are within reference ranges [1]. Proximal muscles are less severely affected than distal muscles.

During neurological examination, pyramidal signs can be observed. ALS4 patients show hyperreflexia, have brisk deep-tendon reflexes and the Babinski sign is present. Care should be taken when interpreting reflex tests that rely on contractions of atrophic muscles: In this scenario, upper motor neuron signs may easily be overlooked [3].

  • Interestingly, 22% (11/49) of the patients had unambiguous upper and lower motor neuron signs but were asymptomatic at the time of initial evaluation.[academic.oup.com]
  • By contrast, genetic analyses may facilitate the identification of carriers and as-of-yet asymptomatic patients in families affected by familial ALS.[symptoma.com]
  • […] closing Tongue Movements: Slow Bulk: Often relatively preserved for degree of dysfunction Respiratory failure May occur in isolation: Male Female Associations Loss of sense of taste Weight loss Depression Arm weakness Shorter survival Early stages Often asymptomatic[neuromuscular.wustl.edu]
Difficulty Walking
  • People with limb-onset ALS may rely on a cane, walker, or wheelchair due to difficulties walking and maintaining balance. Late stages of ALS As the disease progresses, muscles become paralyzed.[als.net]
Wheelchair Bound
  • ALS4-related amyotrophy may cause minor gait disorders or render people wheelchair-bound; upper-limb muscle wasting may interfere with determined task requiring dexterity or with the patient's ability to cope with everyday life.[symptoma.com]
Muscle Twitch
  • twitching, cramping, stiffness, or weakness, slurred speech, and/or difficulty chewing or swallowing.[rarediseases.info.nih.gov]
  • Fasciculation Other names Muscle twitch Pronunciation Specialty Neurology A fasciculation, or muscle twitch, is a small, local, involuntary muscle contraction and relaxation which may be visible under the skin.[en.wikipedia.org]
  • Muscle twitches and cramps are common; they occur because degenerating axons (long fibers extending from nerve-cell bodies) become “irritable.” Symptoms may be limited to a single body region, or mild symptoms may affect more than one region.[mda.org]
  • Early signs and symptoms of ALS include: muscle cramps and muscle twitching weakness in hands, legs, feet or ankles difficulty speaking or swallowing The senses, including hearing, sight, smell, taste, and touch, are not affected by ALS.[als.net]
  • The earliest symptoms include muscle twitching, cramping, stiffness, or weakness. Affected individuals may develop slurred speech (dysarthria) and, later, difficulty chewing or swallowing (dysphagia).[ghr.nlm.nih.gov]
  • ALS4 patients show hyperreflexia, have brisk deep-tendon reflexes and the Babinski sign is present.[symptoma.com]
  • […] difficulty muscle cramping urinary frequency or incontinence (late findings) sensory remains normal Physical exam neck ptosis (neck drop) due to neck extensor weakness manual muscle testing elicits muscle cramping upper motor neuron (UMN) signs spasticity hyperreflexia[orthobullets.com]
  • On physical exam, signs of hyperreflexia, spasticity, fasciculations, and muscle atrophy are present in an asymmetric fashion. Tongue fasciculations are also present. No sensory loss is noted.[medbullets.com]
  • Clinical manifestations include progressive weakness, atrophy, fasciculation, hyperreflexia, dysarthria, dysphagia, and eventual paralysis of respiratory function.[icd10data.com]
  • Clinical Loss of fine motor skills, triad of atrophic weakness of hands and forearms; leg spasticity; generalised hyperreflexia. Management Possibly riluzole.[medical-dictionary.thefreedictionary.com]
Limb Weakness
  • Although most patients had upper (90%) and lower (92%) limb weakness on examination, lower limb weakness was usually more severe (Table 1 ). Pathological hyper-reflexia was present in 84% (41/49) and clonus was seen in 20% (10/49).[academic.oup.com]
  • They may seek medical advice due to progressive distal limb weakness and subsequent muscle wasting.[symptoma.com]
  • Among patients with ALS, fasciculation frequency is not associated with the duration of ALS and is independent of the degree of limb weakness and limb atrophy.[en.wikipedia.org]
  • Multifocal motor neuropathy with conduction block: Often presents in young or middle-aged men as unilateral distal upper limb weakness with little evidence of wasting initially.[patient.info]
  • See also Aran-Duchenne muscular atrophy. amyotrophic lateral sclerosis A chronic, progressive, degenerative, motor neurone disease, characterised by upper limb weakness, atrophy and focal neurologic signs.[medical-dictionary.thefreedictionary.com]
Babinski Sign
  • ALS4 patients show hyperreflexia, have brisk deep-tendon reflexes and the Babinski sign is present.[symptoma.com]
  • There are no standard laboratory tests for upper motor neuron disease, but spasticity (a specific type of stiffness), abnormally brisk tendon reflexes, Babinski’s sign and diminished fine motor coordination are seen as diagnostic signs on examination.[memory.ucsf.edu]
  • sign positive) Flexor ( normal; Babinski's sign negative) Extraneous muscle activity No fasciculations/fibrillations Fasciculations and fibrillations amyotrophic lateral sclerosis (ā·mī· ·trō·fik laˑ·t ·r l skl ·rōˑ·sis), n a fatal neurological condition[medical-dictionary.thefreedictionary.com]
  • Lower motor neuron loss causes initially increased electrical excitability leading to fasciculations, and later muscle weakness and atrophy; upper motor neuron involvement causes spasticity, clonus, hyperactive tendon reflexes, and Babinski signs.[neuropathology-web.org]
  • An abnormal reflex commonly called Babinski’s sign also indicates upper motor neuron damage.[checkrare.com]
  • Of note, recessive loss-of-function mutations in the SETX gene have been associated with ataxia-oculomotor apraxia. This disease is characterized by cerebellar ataxia, oculomotor apraxia, and late peripheral neuropathy.[symptoma.com]
  • […] binding protein gene (TBP); Spinocerebellar ataxia type 14 (SCA14): Protein kinase C gamma gene (PRKCG); Dentatorubral-pallidoluysian atrophy (DRPLA): Atrophin 1 gene (ATN1); Friedreich's ataxia (FA-FRDA): Frataxin gene (FXN); Ataxia with oculomotor apraxia[cnr.it]
  • […] tension, Amyotrophic lateral sclerosis 12 AD 13 61 PRF1 Lymphoma, non-Hodgkin, Aplastic anemia, adult-onset, Hemophagocytic lymphohistiocytosis AR 24 183 REEP1 Spastic paraplegia, Distal hereditary motor neuronopathy AD 16 60 SETX Ataxia with oculomotor apraxia[blueprintgenetics.com]
  • Reflexes are graded on a scale of 0–4: 0 areflexia; 1 reduced reflex; 2 normal; 3 brisk; 4 clonus. Deep tendon reflexes: B biceps; T triceps; P patella; A ankle. Plantar responses: FP flexor plantar; EP extensor plantar; NR no response.[academic.oup.com]


ALS diagnosis relies on the identification of upper motor neuron and lower motor neuron signs, to be observed in patients suffering from a progressive neurodegenerative disease that cannot be explained by other conditions. To facilitate ALS diagnosis, diagnostic criteria have been defined on various occasions [4] [5] [6]. Currently, revised El Escorial criteria are applied in most clinical trials. Those criteria are as follows [4]:

  • Clinical evidence of upper motor neuron degeneration
  • Clinical, electrophysiological, or neuropathological evidence of lower motor neuron degeneration
  • Disease progression, spread of symptoms and signs
  • Absence of electrophysiological or pathological evidence of other diseases that may explain neurological findings
  • Absence of imaging evidence of other diseases that may explain neurological findings

Furthermore, the central nervous system is divided into four regions, namely the bulbar, cervical, thoracic and lumbosacral region as indicated in the previous paragraph. The presence of symptoms related to the function of any of those four regions allows for a more precise diagnosis of clinically definite, clinically probable, clinically probable if laboratory-supported, and clinically possible ALS [4]:

  • Clinically definite ALS requires the presence of upper and lower motor neuron signs in at least three out of four regions
  • Clinically probable ALS is diagnosed with upper and lower motor neuron signs in at least two out of four regions, and some upper motor neuron signs rostral to lower motor neuron signs
  • Clinically probable if laboratory-supported ALS is defined as the presence of upper and lower motor neuron signs in one region only, or the presence of only upper motor neuron signs in one region and lower motor neuron signs in at least two regions, with lower motor signs generally being present on electromyography
  • Clinically possibly ALS implies the presence of upper and lower motor neuron signs in one region only, or the presence of only upper motor neuron signs in at least two regions, or the presence of lower motor neuron signs rostral to upper motor neuron signs, if supporting laboratory results cannot be provided

A positive family history of ALS augments the certainty of diagnosis and may even justify the diagnosis of clinically definite ALS if the respective criteria are not completely fulfilled [4]. However, SETX mutations have been detected in patients suffering from apparently sporadic ALS [2].

This fact highlights the importance of genetic studies. Even though molecular biological analyses are not required for the diagnosis of ALS, they are necessary to determine the subtype. In fact, the identification of sequence anomalies may accelerate the diagnostic process: If SETX mutations are known to cause ALS in a determined family, a more targeted approach to diagnosis becomes feasible. Thus, genetic analyses provide both physicians and scientists with an appropriate tool to identify carriers and family members at risk, and to promote research [7] [8].


There is no cure, and disease progression can hardly be halted. Riluzole is the only pharmacological compound approved for ALS therapy; it is assumed to reduce glutamate toxicity. It has been reported to increase survival times and to delay the onset of life-threatening symptoms such as laryngospasm and respiratory paralysis, but its efficacy is very limited [9]. Furthermore, neither laryngospasm nor respiratory paralysis are to be expected in ALS4 patients, so decisions regarding the usefulness of riluzole have to be made on a case-by-case basis. The application of α-tocopherol has been proposed as a complementary measure to slow down disease progression in milder cases and may be considered here [10]. Otherwise, only palliative treatment can be provided. In this context, ALS4 patients benefit from a multidisciplinary approach that aims at maintaining their mobility and their ability to cope with everyday life for as long as possible [10] [11]:

  • Occupational and physical therapy are required to deal with limited mobility. At the same time, orthopedic devices and wheelchairs should be provided to improve mobility and autonomy.
  • Spasticity and muscle cramps may be resolved by muscle relaxants like quinine, levetiracetam, baclofen, or dantrolene, but they are less frequently observed in ALS4 patients than in those suffering from classical ALS.
  • Even though ALS4 is known to spare the respiratory muscles, the patients' respiratory function should be checked regularly.
  • Finally, ALS patients should be offered psychological support. Some patients develop depressions and have to be treated with antidepressants.


ALS4-related amyotrophy may cause minor gait disorders or render people wheelchair-bound; upper-limb muscle wasting may interfere with determined task requiring dexterity or with the patient's ability to cope with everyday life. Fortunately, the disease does neither cause bulbar palsy nor respiratory paralysis, thereby reducing the likelihood of aspiration pneumonia due to dysphagia and respiratory failure - which are the most common causes of death in ALS patients. ALS4 is a slowly progressive form of ALS and while it may considerably reduce quality of life, affected individuals are assumed to have a normal or near-to-normal life expectancy [1] [11].


ALS4 is the only juvenile-onset form of ALS that is inherited in an autosomal dominant manner. It maps to chromosome 9q34 and has been related to distinct mutations of the SETX gene [3]. In detail, it has been proposed that ALS4 may be triggered by gain-of-function mutations of SETX [12]. SETX encodes for senataxin, a protein of as-of-yet unknown function. However, SETX is known to contain a 7-motif DNA/RNA helicase domain with strong homology to genes IGHMBP2 and RENT1. The latter encode for proteins with helicase activity and thus, a role in DNA and/or RNA processing may be assumed for senataxin. Senataxin has been referred to as "genome guardian" and studies on Saccharomyces cerevisiae cells expressing mutant yeast homologs of human senataxin indicate a role of the respective gene in managing oxidative stress, maintaining mitochondrial membrane potentials and cytosolic calcium levels [12] [13].

Of note, recessive loss-of-function mutations in the SETX gene have been associated with ataxia-oculomotor apraxia. This disease is characterized by cerebellar ataxia, oculomotor apraxia, and late peripheral neuropathy. Similar to ALS4, it follows a slowly progressive course [14].


The global incidence of ALS has been estimated to 1-2.6 per 100,000 people per year, and its prevalence amounts to 6 per 100,000 inhabitants [15]. About 10% of all those cases are familial. Familial ALS is generally inherited in an autosomal dominant manner, as is the case with ALS4, a juvenile-onset form of ALS. Chen and colleagues studied four families affected by ALS4 and they calculated the patients' average at at symptom onset to be 6, 8, 17, and 21 years, respectively [1]. Both men and women may develop ALS4. To date, SETX-related ALS has been diagnosed in patients of European and North American ancestry [1].

Sex distribution
Age distribution


Despite extensive research, the pathophysiology of ALS remains poorly understood. The death of motor neurons is the hallmark of the disease and entails muscle weakness and atrophy, but its causes could not yet be clarified. Neuronal death has been speculated to be due to the accumulation of protein aggregates which, in turn, consist of abnormal proteins. Sequence anomalies, e.g., of genes like SETX, may be the cause of irregularities in the amino acid sequence, post-translational modification and intracellular transport of any protein, may alter their physical properties, their propensity to bind to specific targets, and their susceptibility to degradation [16].


No recommendations can be given to prevent the onset of sporadic ALS, other than avoiding certain risk factors [15]. By contrast, genetic analyses may facilitate the identification of carriers and as-of-yet asymptomatic patients in families affected by familial ALS [7]. Prenatal diagnoses may become feasible if the disease can be related to well-defined DNA sequence anomalies, but this does not yet apply to ALS4.


ALS is the most common motor neuron disease. ALS patients may be genetically predisposed to develop the disease, and distinct genes have been associated with its familial form. One of those genes is the SETX gene, which encodes for senataxin. ALS linked to mutations in the SETX gene has been designated ALS4 [1] [3]. Of note, the same disease may also be referred to as distal hereditary motor neuronopathy with pyramidal features [1].

ALS4 is a rather mild form of ALS, with juvenile-onset muscle weakness and atrophy but sparing of the bulbar and respiratory muscles. The disease follows a slowly progressive course and ALS4 patients are assumed to have an almost normal life expectancy [1] [11]. Nevertheless, distal limb amyotrophy may eventually become the cause of severe disability. As of today, genetic and environmental factors affecting the severity of ALS4 have not been identified. Effective treatment cannot be provided and therapy mainly aims at maintaining the patients' mobility and quality of life.

Patient Information

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease that typically manifests in adulthood. Little is known about the causes of ALS, but at least a minor proportion of ALS patients seems to be genetically predisposed. This condition is reflected in an increased familial incidence, i.e., relatives of an ALS patient carrying certain gene defects are much more likely to develop the disease than the general population. In this context, ALS has been associated with distinct chromosome and gene anomalies. For instance, there are European and North American families whose members present mutations in a gene called SETX. SETX-related ALS has later been designated amyotrophic lateral sclerosis 4 (ALS4).

ALS4 is a relatively mild form of ALS, although symptoms manifest early:

  • Affected individuals may experience muscle weakness in childhood or adolescence. The disease follows a slowly progressive course and muscle weakness eventually entails muscle wasting. The distal muscles of the limbs are most severely affected and those suffering from ALS4 may require physical therapy, orthopedic aids or wheelchairs later in life. Causal treatment is not available. Also, current knowledge does not allow for a reliable prognosis as to the course and final severity in individual cases, though.
  • Fortunately, bulbar and respiratory muscles are spared, so ALS4 patients don't develop dysarthria, dysphagia, and respiratory failure. However, these are common complications and frequent causes of death in other forms of ALS. ALS4 patients are assumed to have a near-to-normal life expectancy.



  1. Chen YZ, Bennett CL, Huynh HM, et al. DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet. 2004; 74(6):1128-1135.
  2. Hirano M, Quinzii CM, Mitsumoto H, et al. Senataxin mutations and amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2011; 12(3):223-227.
  3. Chance PF, Rabin BA, Ryan SG, et al. Linkage of the gene for an autosomal dominant form of juvenile amyotrophic lateral sclerosis to chromosome 9q34. Am J Hum Genet. 1998; 62(3):633-640.
  4. Brooks BR. El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial "Clinical limits of amyotrophic lateral sclerosis" workshop contributors. J Neurol Sci. 1994; 124 Suppl:96-107.
  5. Brooks BR, Miller RG, Swash M, Munsat TL. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000; 1(5):293-299.
  6. de Carvalho M, Dengler R, Eisen A, et al. Electrodiagnostic criteria for diagnosis of ALS. Clin Neurophysiol. 2008; 119(3):497-503.
  7. Crook A, Williams K, Adams L, Blair I, Rowe DB. Predictive genetic testing for amyotrophic lateral sclerosis and frontotemporal dementia: genetic counselling considerations. Amyotroph Lateral Scler Frontotemporal Degener. 2017; 18(7-8):475-485.
  8. Wagner KN, Nagaraja HN, Allain DC, Quick A, Kolb SJ, Roggenbuck J. Patients with sporadic and familial amyotrophic lateral sclerosis found value in genetic testing. Mol Genet Genomic Med. 2017.
  9. Martinez A, Palomo Ruiz MD, Perez DI, Gil C. Drugs in clinical development for the treatment of amyotrophic lateral sclerosis. Expert Opin Investig Drugs. 2017; 26(4):403-414.
  10. Soriani MH, Desnuelle C. Care management in amyotrophic lateral sclerosis. Rev Neurol (Paris). 2017; 173(5):288-299.
  11. Kinsley L, Siddique T. Amyotrophic Lateral Sclerosis Overview. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2107.
  12. Groh M, Albulescu LO, Cristini A, Gromak N. Senataxin: Genome Guardian at the Interface of Transcription and Neurodegeneration. J Mol Biol. 2017; 429(21):3181-3195.
  13. Sariki SK, Sahu PK, Golla U, Singh V, Azad GK, Tomar RS. Sen1, the homolog of human Senataxin, is critical for cell survival through regulation of redox homeostasis, mitochondrial function, and the TOR pathway in Saccharomyces cerevisiae. Febs j. 2016; 283(22):4056-4083.
  14. Gros-Louis F, Gaspar C, Rouleau GA. Genetics of familial and sporadic amyotrophic lateral sclerosis. Biochim Biophys Acta. 2006; 1762(11-12):956-972.
  15. Talbott EO, Malek AM, Lacomis D. The epidemiology of amyotrophic lateral sclerosis. Handb Clin Neurol. 2016; 138:225-238.
  16. Blokhuis AM, Groen EJ, Koppers M, van den Berg LH, Pasterkamp RJ. Protein aggregation in amyotrophic lateral sclerosis. Acta Neuropathol. 2013; 125(6):777-794.

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Last updated: 2019-07-11 20:07