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].

• Weakness

  They may seek medical advice due to progressive distal limb weakness and subsequent muscle wasting. [symptoma.com]

  Symptoms include: Difficulty breathing Difficulty swallowing Choking easily Drooling Gagging Head drop due to weakness of the neck muscles Muscle cramps Muscle contractions called fasciculations Muscle weakness that slowly gets worse Commonly involves [checkorphan.org]

  A person with bulbar weakness may become hoarse or tired after speaking at length, or speech may become slurred. In addition to weakness, the other cardinal signs of ALS are muscle wasting and persistent twitching (fasciculation). [medical-dictionary.thefreedictionary.com]

  Signs and symptoms might include: Difficulty walking or doing normal daily activities Tripping and falling Weakness in your leg, feet or ankles Hand weakness or clumsiness Slurred speech or trouble swallowing Muscle cramps and twitching in your arms, [mayoclinic.org]

• Inflammation

  […] recovery following a stroke[1] and to treat amyotrophic lateral sclerosis (ALS).[2] The label carries a warning about the potential for hypersensitivity reactions to edaravone, and adverse effects include bruising, gait disturbances, headache, skin inflammation [en.wikipedia.org]

  A new theory called chronic cerebral vascular insufficiency (CCSVI) suggests that slow blood drainage from the brain (due to narrowed or deformed veins) results in iron deposits, which cause inflammation and lead to MS symptoms. [verywell.com]

  Increasing evidence also suggests that various types of glial support cells and inflammation cells of the nervous system may play an important role in the disease. [medicinenet.com]

  Most people with MS fall into one of these four categories of the disease : Clinically isolated syndrome: This is the first episode of symptoms caused by inflammation and damage to the myelin covering on nerves in the brain or spinal cord. [healthline.com]

  Oxidative stress Other CNS Brainstem: Loss of motor neurons: Sparing of extraocular nuclei Precentral cortex: Loss of Betz & other pyramidal cells Sural nerve 39 Axons: Normal or Mildly reduced number Vessels, Epineurial: Some patients with perivascular inflammation [neuromuscular.wustl.edu]

• Difficulty Walking

  As the disease progresses, patients may lose hand and arm function, and experience difficulty walking, speaking, and even breathing. Respiratory failure is often the cause of death, and the average survival time from diagnosis is around 3-5 years. [youtube.com]

  Signs and symptoms might include: Difficulty walking or doing normal daily activities Tripping and falling Weakness in your leg, feet or ankles Hand weakness or clumsiness Slurred speech or trouble swallowing Muscle cramps and twitching in your arms, [mayoclinic.org]

  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]

• Military Personnel

  One study has reported that military personnel deployed in the Gulf region during the 1991 war were more likely to develop ALS than military personnel deployed elsewhere. [medicalnewstoday.com]

• Surgical Procedure

  Caldera DL, Nussbaum SR. et aL Multifactorial index of cardiac risk in noncardiac surgical procedures. ‎ Seite 94 - Mangano DT, Layug EL, Wallace A, Tateo I. Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. ‎ [books.google.de]

• Pneumonia

  They are also at higher risk of getting food, liquids or saliva into the lungs, which can cause pneumonia. A feeding tube can reduce these risks and ensure proper hydration and nutrition. [mayoclinic.org]

  […] islet autotransplantation Acute pancreatitis: Acute peritonitis Macroamylasemia Macrolipasemia Malabsorption syndromes/processes Perforated viscus Chronic pancreatitis: Ampullary carcinoma Cholangitis Cholecystitis Chronic gastritis Community-acquired pneumonia [centogene.com]

  Complications of ALS include: Breathing in food or fluid ( aspiration ) Loss of ability to care for self Lung failure Pneumonia Pressure sores Weight loss Call your provider if: You have symptoms of ALS, particularly if you have a family history of the [medlineplus.gov]

  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. [symptoma.com]

• Respiratory Insufficiency

  Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig disease or Charcot disease, is the most common form of motor neurone disease 1,4 resulting in progressive weakness and eventual death due to respiratory insufficiency. [radiopaedia.org]

  One study (Pinto 1999) was a controlled study of exercise in ALS patients with respiratory insufficiency. One study (Sivak 1982) was an anecdotal study. [cochranelibrary.com]

  Most cases of ALS present with asymmetric focal apendicular weakness progressing with bulbar dysfunction, quadriparesis and respiratory insufficiency leading to death in about two to three years after onset1. [scielo.br]

• Dysphagia

  Interestingly, ALS4 patients don't develop bulbar palsy; they don't suffer from dysarthria or dysphagia. Furthermore, respiratory muscles are spared from the disease. [symptoma.com]

  Symptoms include progressive weakness, atrophy, fasciculation, dysphagia, and eventual paralysis of respiratory function. [patientslikeme.com]

  Symptoms and course In patients with typical ALS, the symptoms are primarily those of weakness, which may start in the hands or legs or be manifested by slurred speech and dysphagia. [alzheimer-europe.org]

  Affected individuals may have difficulty swallowing (dysphagia), and speech may be slowed. [rarediseases.org]

• Muscle Weakness

  The disease follows a slowly progressive course and muscle weakness eventually entails muscle wasting. [symptoma.com]

  Symptoms include: Difficulty breathing Difficulty swallowing Choking easily Drooling Gagging Head drop due to weakness of the neck muscles Muscle cramps Muscle contractions called fasciculations Muscle weakness that slowly gets worse Commonly involves [checkorphan.org]

  weakness and wasting, in association with pyramidal signs, normal sensation, and absence of bulbar involvement, leading to degeneration of motor neurons in the brain and spinal cord. [orpha.net]

• Muscle Cramp

  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]

  ALS symptoms in children include: Weakness in hand and leg muscles Difficulty in swallowing and breathing Slurred speech Muscles cramps, spasms, and twitches Difficulty in holding the body upright [ Read: Attention Deficit Disorder (ADD) In Children ] [momjunction.com]

  Signs and symptoms might include: Difficulty walking or doing normal daily activities Tripping and falling Weakness in your leg, feet or ankles Hand weakness or clumsiness Slurred speech or trouble swallowing Muscle cramps and twitching in your arms, [mayoclinic.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]

  Frequent, albeit unspecific, symptoms are weight loss and muscle cramps. [clinicaladvisor.com]

• Myopathy

  This panel covers genes implicated in patients with ALS and frontotemporal dementia, BSCL2 -related neurologic disorders, DCTN1 -related distal hereditary motor neuronopathy type VIIB, GBE1 -related adult polyglucosan body disease, and inclusion body myopathy [blueprintgenetics.com]

  Mutations in VCP have also been identified in patients with inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD). [mgz-muenchen.de]

  ALS21 (formerly the vocal cord and pharyngeal dysfunction with distal myopathy type 2) presents with adult-onset dystal myopathy with inclusion body myopathy-like features and vocal cord and pharyngeal weakness, occasionally with lower limbs brisk reflexes [scielo.br]

  SMA1 must be distinguished from other causes of neonatal hypotonia which include CNS malformations, metabolic diseases, infections, and congenital myopathies. [neuropathology-web.org]

  […] of sporadic ALS with or without FTD TBK1 ✓ FTDALS4 1-4% of hereditary FTD and/or ALS TFG ✓ Hereditary motor and sensory neuropathy, Okinawa type ( HMSNO ) Rare UBQLN2 ✓ ALS15 Rare VAPB ✓ Finkel type Spinal Muscular Atrophy Rare VCP ✓ Inclusion Body Myopathy [invitae.com]

• Muscle Twitch

  […] and, in some cases, genetic cause. [2] Early symptoms may include muscle 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]

  ALS often begins with muscle twitching and weakness in a limb, or slurred speech. Eventually, ALS affects control of the muscles needed to move, speak, eat and breathe. There is no cure for this fatal disease. [mayoclinic.org]

• Muscle Spasm

  Certain medicines help control muscle spasms and even help slow the disease from worsening. Physical therapy can help patients to maintain their muscle control as the disease progresses. [momjunction.com]

  Baclofen may reduce muscle spasms. Nuedexta might help keep emotions in check ( pseudobulbar affect ). Mexiletine might reduce painful muscle cramps. A number of medicines including Robinul, Elavil, and Botox, may help reduce salivation. [als.net]

  spasms, and overactive reflexes (hyperreflexia). [rarediseases.info.nih.gov]

• Fear

  ^ Doctor confirms Joost's fears, 2014-08-22 ^ "«Я еще живой!»". Федерации спортивной гимнастики России. Retrieved 3 November 2019. [en.wikipedia.org]

  Anger, denial, fear, and a sense of loss are common reactions. For those who have been through a lengthy diagnosis process and the anguish of not having a diagnosis, finally knowing that they have ALS may actually bring a feeling of relief. [caregiver.org]

  Although rare, many patients are both aware and fearful of it. [ 1 ] It is therefore important in primary care to understand the presentation and to be able confidently to reassure worried patients who are unlikely to have a diagnosis of MND. [patient.info]

• Hyperreflexia

  This autosomal-dominant form of ALS is characterized by early-onset, muscle atrophy, weakness, and hyperreflexia. We evaluated a cohort of ALS4 patients to identify features of disease that could be used to quantify severity and track progression. [n.neurology.org]

  […] and positive waves) + decreased recruitment in ≥ 3 extremities reinnervation abnormal spontaneous fibrillation & fasciculation potentials normal sensory studies (SNAP, sensory nerve action potentials) Differentials Peripheral compressive neuropathy hyperreflexia [orthobullets.com]

  ALS4 usually starts early in life, and symptoms include muscle weakness and abnormally sensitive reflexes (hyperreflexia), a sign of upper motor neuron damage. [alsnewstoday.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]

  […] develop symptoms of both upper and lower motor dysfunction, but the symptoms, rate of progression, and severity varies from person to person.[5] Signs of upper motor neuron dysfunction include the Babinski sign, muscle spasms, and overactive reflexes (hyperreflexia [rarediseases.info.nih.gov]

• Babinski Sign

  Typical symptoms include distal muscle weakness and atrophy, brisk deep-tendon reflexes and a positive Babinski sign (Chen et al. Am J Hum Genet 74:1128-1135, 2004). [preventiongenetics.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]

  During neurological examination, pyramidal signs can be observed. ALS4 patients show hyperreflexia, have brisk deep-tendon reflexes and the Babinski sign is present. [symptoma.com]

  All people with JALS eventually develop symptoms of both upper and lower motor dysfunction, but the symptoms, rate of progression, and severity varies from person to person.[5] Signs of upper motor neuron dysfunction include the Babinski sign, muscle [rarediseases.info.nih.gov]

• Clumsiness

  Signs and symptoms might include: Difficulty walking or doing normal daily activities Tripping and falling Weakness in your leg, feet or ankles Hand weakness or clumsiness Slurred speech or trouble swallowing Muscle cramps and twitching in your arms, [mayoclinic.org]

  Early symptoms often include clumsiness, abnormal limb fatigue, muscle cramps and twitches, and slurred speech. Symptoms will spread to all parts of the body as ALS progresses. [medicalnewstoday.com]

  […] extensor weakness manual muscle testing elicits muscle cramping upper motor neuron (UMN) signs spasticity hyperreflexia (+) Hoffman's (+) Babinski's spastic dysarthria lower motor neuron (LMN) signs muscular atrophy weakness clinical fasciculations clumsiness [orthobullets.com]

  The primary symptoms of upper motor neuron disease are stiffness, slowness and clumsiness of movement. The symptoms usually begin in one limb or in the mouth or throat, later spreading to other parts of the body. [memory.ucsf.edu]

• Limb Weakness

  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]

  They may seek medical advice due to progressive distal limb weakness and subsequent muscle wasting. [symptoma.com]

  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]

  Signs LMD dysfunction in the limbs manifests as weakness, atrophy, fasciculations and hyporeflexia. The thighs are often a site of marked fasciculation. [patient.info]

• Paresis

  ALS2 (alsin; chromosome 2q33.1; ALS2): Autosomal recessive mutations in ALS2 lead to childhood-onset (average age of onset is 6.5 years) spastic paresis, spasticity of the facial musculature, uncontrollable laughing, spastic dysarthria, spastic gait, [mgz-muenchen.de]

  Neuron Disease with Ophthalmoplegia & Extrapyramidal disorders 4 Onset 4th to 7th decade Often bulbar dysfunction: Dysarthria Motor Weakness: Bulbar, Arms & Legs Upper motor neuron signs Variably present Tendon reflexes: Brisk or Normal Ocular Gaze paresis [neuromuscular.wustl.edu]

  ALS HNRNPA1 (Heterogeneous Nuclear Ribonucleoprotein A1; 12q13.13) – 2013 AD ALS20, IBM with early-onset Paget disease without FTD type 3 DCTN1 (Dynactin 1; 2p13.1) – 2003 AD ALS, Perry syndrome, Distal hereditary motor neuronopathy with vocal paresis [scielo.br]

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].

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.

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.