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 6 (ALS6) is one of many subtypes of familial ALS. It has been related to mutations in the FUS gene, a protein-coding gene whose product is part of the heterogeneous nuclear ribonucleoprotein complex, which, in turn, regulates gene expression and RNA processing. ALS6 patients suffer from typical ALS, with first symptoms manifesting in adulthood. An association with other neurodegenerative diseases has been reported in isolated cases.
ALS6 is clinically indistinguishable from other types of sporadic or familial ALS. First symptoms manifest in adulthood, at a mean age of 44 years  . Affected individuals claim muscle weakness, most commonly in the upper limbs and neck, or in the legs. Muscle weakness subsequently spreads to the other limbs and bulbar muscles may become involved. Bulbar palsy preceding limb muscle weakness has repeatedly been described and may be observed in up to one third of ALS6 patients , but bulbar involvement doesn't seem to be a constant feature in ALS6: Some patients don't develop dysarthria or dysphagia at any point in time .
Vance and colleagues haven't observed any cognitive deficits in ALS6 patients , suggesting ALS6 not to be associated with frontotemporal dementia, parkinsonism, or other neurodegenerative disorders. By contrast, Yan et al. reported ALS6 in patients suffering from such diseases .
Affected individuals claim muscle weakness, most commonly in the upper limbs and neck, or in the legs. Muscle weakness subsequently spreads to the other limbs and bulbar muscles may become involved. [symptoma.com]
[…] hand muscles Wasting of hand muscles Weak forearm muscles Wasting of forearm muscles Weak leg muscles Wasting of leg muscles Weak body muscles Wasting of body muscles Weak face muscles Wasting of face muscles Progressive muscle weakness Progressive muscle [checkorphan.org]
Over time, muscle weakness causes affected individuals to lose the use of their hands and arms. Breathing becomes difficult because the muscles of the respiratory system weaken. [ncbi.nlm.nih.gov]
When the motor neurons can no longer send impulses to the muscles, the muscles begin to waste away (atrophy), causing increased muscle weakness. [my.clevelandclinic.org]
Progressive Muscular Atrophy (PMA) A progressive neurological disease in which the lower motor neurons deteriorate. If the upper motor neurons are not affected within two years, the disease usually remains a pure lower motor neuron disease. [my.clevelandclinic.org]
Neuronal loss in central nervous system MedGen UID: 342515 •Concept ID: C1850496 • Finding Proximal amyotrophy MedGen UID: 342591 •Concept ID: C1850794 • Disease or Syndrome Amyotrophy (muscular atrophy) affecting the proximal musculature. [ncbi.nlm.nih.gov]
Study of 962 patients indicates progressive muscular atrophy is a form of ALS. Neurology (2009). doi:10.1212/WNL.0b013e3181c1dea3 Visser, J. et al. Disease course and prognostic factors of progressive muscular atrophy. Arch. [mda.org]
Lateral Sclerosis Benign Focal Amyotrophy of ALS Infantile Spinal Muscular Atrophy, ALS Juvenile Spinal Muscular Atrophy, Included Kugelberg-Welander Disease Primary Lateral Sclerosis Progressive Bulbar Palsy, Included Spinal Muscular Atrophy, Type ALS [rarediseases.org]
Very early-onset (generally before 6 years up to adolescence) with prominent distal muscular atrophy and eventually cerebellar ataxia are clues to diagnosis, mimicking spinal muscular atrophy with pyramidal signs and some forms of hereditary distal motor [scielo.br]
The earliest symptoms include muscle twitching, cramping, stiffness, or weakness. Affected individuals may develop slurred speech (dysarthria) and, later, difficulty chewing or swallowing (dysphagia). [ncbi.nlm.nih.gov]
Symptoms include: Muscle weakness Tripping Falling Loss of motor control in hands and arms Difficulty speaking Difficulty swallowing Difficulty breathing Persistent fatigue Twitching Spasticity Muscle twitching Exaggerated reflexes Muscle cramps Weak [checkorphan.org]
Clinical Signs, Symptoms, and Diagnostics Symptoms and signs associated with these pathological changes include: Muscle fasciculation, more commonly known as muscle twitches Difficulty walking, moving your arms, speaking, and swallowing And, eventually [study.com]
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]
Over the course of the disease, they develop muscle weakness and atrophy in all four limbs, and possibly bulbar palsy associated with dysarthria and dysphagia. [symptoma.com]
Affected individuals may develop slurred speech (dysarthria) and, later, difficulty chewing or swallowing (dysphagia). [ncbi.nlm.nih.gov]
Patients then develop motor neuron degeneration leading to facial muscle spasticity, spastic dysarthria, and spastic gait. Some patients are reported to have uncontrolled laughter and weeping (pseudobulbar syndrome). [orpha.net]
[…] perish, the ventral roots thin and the limb, tongue, and oropharynx muscles become amyotrophic.1 However, one-third of patients experience bulbar disease, manifesting as challenges with speaking, chewing, or swallowing.1 Signs of bulbar disease include dysarthria [ajmc.com]
After approximately 3 years, he noticed weakness of the shoulders, and a symmetrical proximal paresis of the upper limbs was found on neurologic examination. [jamanetwork.com]
Spastic paresis could be present at the beginning or in the fully developed stage of the disease. [intechopen.com]
The D90A-homozygous mutation is associated with slowly progressive paresis in the legs that gradually spreads up to the arms, thoracic and bulbar musculature, with atypical non-motor features such as ataxia, neuralgic, aching pain, heat sensations, and [translationalneurodegeneration.biomedcentral.com]
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   . Currently, revised El Escorial criteria are applied in most clinical trials. Those criteria are as follows :
- 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 :
- 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 .
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. Genetic analyses also provide both physicians and scientists with an appropriate tool to identify carriers and family members at risk, and to promote research  . Additionally, ALS patients known to carry mutations that possibly predispose for frontotemporal dementia or parkinsonism - as is the case with FUS mutations - may be referred for neuropsychological tests  .
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 . The application of α-tocopherol has been proposed as a complementary measure to slow down disease progression in milder cases . Otherwise, only palliative treatment can be provided. In this context, ALS patients benefit from a multidisciplinary approach that aims at maintaining their ability to cope with everyday life and to communicate with their fellows for as long as possible  :
- Bulbar palsy results in speech disturbances and swallowing difficulties and largely affects the patients' quality of life. Therefore, they should be offered support by speech therapists and nutritionists. Modern technical devices enable ALS patients to express their thoughts even if they can only provide minimal input. Also, it may be helpful to mash solid foods to facilitate their intake by dysphagic patients, but most patients eventually require a gastrostomy tube.
- 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.
- Weakness of the respiratory muscles requires ventilatory assistance.
- Finally, ALS patients should be offered psychological support. Some patients develop depressions and have to be treated with antidepressants.
If ALS6 patients suffer from associated neurodegenerative disorders such as dementia or parkinsonism, these should be treated according to the respective guidelines. Unfortunately though, they can neither be cured at this moment.
In 2009, two independent groups of researchers have described familial ALS related to mutations of the FUS gene on chromosome 16 - a total of thirteen mutations have been identified in the respective studies  . Other mutations have been identified later on and at this time, 58 ALS-associated mutations of the FUS gene are known . The FUS gene is also referred to as FUS/TLS or fused in sarcoma/translated in liposarcoma gene . Its gene product generally locates to the nucleus and has been identified as part of the heterogeneous nuclear ribonucleoprotein complex. Kwiatkowski and colleagues have shown mutant forms of the protein to accumulate within the cytosol of neurons . Similarly, Vance et al. have observed cytosolic inclusions and postulated that anomalies regarding the regulation of transcription, RNA splicing and transport account for ALS6-related neurodegeneration .
Of note, FUS mutations have been detected in patients suffering from apparently sporadic ALS  . This fact supports the hypothesis of ALS being a multifactorial disease with mutations of the FUS gene being one of many variables that may predispose an individual for this motor neuron disease. Presumably, additional genetic and environmental factors determine whether someone carrying FUS mutations does develop ALS or not, and whether the course of the disease corresponds to what would be expected for ALS6.
ALS is the most common motor neuron disease in adults; it affects both men and women. ALS patients' mean age at symptom onset is 60 years . By contrast, individuals affected by ALS6 were reported to manifest first symptoms at a mean age of 44 years  . 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 . About 10% of all those cases are familial. Familial ALS is generally inherited in an autosomal dominant manner, but the mode of inheritance has not yet been definitively clarified for ALS6: Both homozygous mutations and heterozygous mutations have been associated with this form of ALS . Additionally, FUS mutations have reduced penetrance . By now, FUS-related ALS has been described in Caucasian, Asian, and African patients .
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 misfolded proteins. Sequence anomalies, e.g., of genes like FUS, 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 .
As for ALS6 and mutated FUS proteins, their cytosolic accumulation has been shown by different authors  . Common FUS mutations affect the protein's C-terminal domain and this domain has been found to be crucial for its nuclear localization. Mutated proteins don't locate to the nucleus, form stress granules in the cytosol, and exert neurotoxic effects .
No recommendations can be given to prevent the onset of sporadic ALS, other than avoiding certain risk factors . By contrast, genetic analyses may facilitate the identification of carriers and as-of-yet asymptomatic patients in families affected by familial ALS . Prenatal diagnoses may become feasible if the disease can be related to well-defined DNA sequence anomalies, but this does not yet apply to ALS6.
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 FUS gene, which encodes for a nuclear RNA-binding protein. ALS linked to mutations in the FUS gene has been designated ALS6. Presumably, mutations of the FUS gene result in the accumulation of cytotoxic granules within neurons, but little is actually known about the etiology and pathogenesis of ALS6 and other types of ALS, other than that it is characterized by the death of motor neurons in the cortex, brain stem, and spinal cord. The disease follows a progressive course and ultimately leads to death by respiratory failure.
Familial ALS may be associated with frontotemporal dementia, and this also applies to ALS6. However, the most common clinical presentation of ALS6 is that of "pure ALS", i.e., in early stages of the disease, patients experience muscle weakness, particularly in their arms or legs. Over the course of the disease, they develop muscle weakness and atrophy in all four limbs, and possibly bulbar palsy associated with dysarthria and dysphagia. Besides these lower motor neuron signs, upper motor neuron signs are characteristic of ALS: ALS patients suffer from hyperreflexia and present with an increased muscle tone, and while those complaints are initially limited to certain body regions, they spread in a similar manner to amyotrophy.
Diagnosis of ALS relies on well-defined diagnostic criteria and is mainly clinical, with the identification of ALS6 requiring additional genetic analyses. Mean survival times are three to four years and patients should be treated by a multidisciplinary team to preserve life quality for as long as possible, despite the fact that there is no cure for this disease.
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 families whose members present mutations in a gene called FUS. FUS-related ALS has later been designated amyotrophic lateral sclerosis 6 (ALS6).
With regards to clinical presentation, diagnosis, treatment, and prognosis, ALS6 doesn't differ from classical ALS. Similar to other forms of ALS, ALS6 may be associated with neurodegenerative disorders like frontotemporal dementia or parkinsonism, but few such cases have been reported to date.
- Vance C, Rogelj B, Hortobágyi T, et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009; 323(5918):1208-1211.
- Yan J, Deng HX, Siddique N, et al. Frameshift and novel mutations in FUS in familial amyotrophic lateral sclerosis and ALS/dementia. Neurology. 2010; 75(9):807-814.
- Kwiatkowski TJ, Jr., Bosco DA, Leclerc AL, et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science. 2009; 323(5918):1205-1208.
- 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.
- 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.
- de Carvalho M, Dengler R, Eisen A, et al. Electrodiagnostic criteria for diagnosis of ALS. Clin Neurophysiol. 2008; 119(3):497-503.
- 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.
- 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.
- Levin J, Kurz A, Arzberger T, Giese A, Höglinger GU. The Differential Diagnosis and Treatment of Atypical Parkinsonism. Dtsch Arztebl Int. 2016; 113(5):61-69.
- Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology. 1998; 51(6):1546-1554.
- 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.
- Soriani MH, Desnuelle C. Care management in amyotrophic lateral sclerosis. Rev Neurol (Paris). 2017; 173(5):288-299.
- 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.
- Talbott EO, Malek AM, Lacomis D. The epidemiology of amyotrophic lateral sclerosis. Handb Clin Neurol. 2016; 138:225-238.
- Lattante S, Rouleau GA, Kabashi E. TARDBP and FUS mutations associated with amyotrophic lateral sclerosis: summary and update. Hum Mutat. 2013; 34(6):812-826.
- Hewitt C, Kirby J, Highley JR, et al. Novel FUS/TLS mutations and pathology in familial and sporadic amyotrophic lateral sclerosis. Arch Neurol. 2010; 67(4):455-461.
- 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.
- Ito D, Seki M, Tsunoda Y, Uchiyama H, Suzuki N. Nuclear transport impairment of amyotrophic lateral sclerosis-linked mutations in FUS/TLS. Ann Neurol. 2011; 69(1):152-162.