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Amyotrophic Lateral Sclerosis Type 10

FTD-ALS

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 10 (ALS10) is one of many subtypes of familial ALS. It has been related to mutations in the TARDBP gene, a protein-coding gene whose product is a DNA and RNA-binding protein involved in the regulation of transcription and splicing. ALS10 patients suffer from typical ALS, with first symptoms manifesting in adulthood. An association with other neurodegenerative diseases has been reported. ALS10 is inherited in an autosomal dominant manner.


Presentation

ALS10 is clinically indistinguishable from other types of sporadic or familial ALS. Affected individuals may claim muscle weakness, often limited one arm or leg, or present with dysarthria and dysphagia, symptoms characteristic of bulbar palsy. In this regard, spinal-onset ALS10 seems to be more common than bulbar-onset ALS10 [1]. But as the disease progresses, most ALS10 patients lose muscle strength in all four limbs and many develop bulbar palsy, independent of the site of onset [2]. Muscle weakness is followed by atrophy, and fasciculations are very common, too [3]. Fasciculations of the tongue are often observed and patients may eventually show tongue amyotrophy.

Besides those lower motor neuron signs, ALS patients may show distinct symptoms of upper motor neuron disease. Hyperreflexia and an increase of muscle tone are most characteristic and may be detected in muscles of face, larynx and pharynx (bulbar region), neck, arms, and diaphragm (cervical region), abdomen and back (thoracic region), and legs (lumbosacral region). The fact that hyperreflexia may be detected in regions of muscle atrophy is considered to be highly indicative of ALS [3]. In some ALS10 patients, lower motor neuron signs predominate the clinical presentation [1].

The patients' sensibility is usually unaltered. Accordingly, electrophysiological studies typically reveal abnormal spontaneous activity (e.g., fibrillations, fasciculations, and positive sharp waves) as well as enlongated, large motor unit potentials and reduced motor unit recruitment, but normal amplitudes of action potentials of sensory nerves [2] [4].

ALS10 may be associated with frontotemporal dementia [5]. While some authors state that few such cases have been reported to date [6], others consider dementia to be a common feature in ALS10 patients [7]. In isolated cases, ALS10 has been reported to be associated with parkinsonism or Parkinson's disease [8].

Amyloidosis
  • An autosomal dominant inherited form of amyloidosis.[icd10data.com]
  • Kwong LK, Uryu K, Trojanowski JQ, Lee VM (2008) TDP-43 proteinopathies: neurodegenerative protein misfolding diseases without amyloidosis. Neurosignals 16: 41–51. View Article Google Scholar 4.[journals.plos.org]
Asymptomatic
  • By contrast, genetic analyses may facilitate the identification of carriers and as-of-yet asymptomatic patients in families affected by familial ALS.[symptoma.com]
  • Higher levels were also reported in symptomatic carriers of causative mutations than asymptomatic carriers [ 23 ].[journals.plos.org]
Limited Mobility
  • 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.[symptoma.com]
Dysphagia
  • Affected individuals may develop slurred speech (dysarthria) and, later, difficulty chewing or swallowing (dysphagia).[icdlist.com]
  • TNFRSF1A C9orf72 HLA-DRB1 For most patients with ALS, the initial signs and symptoms are dysarthria or dysphagia. asymmetric limb weakness. muscle atrophy and weight loss.[journals.lww.com]
  • Affected individuals may claim muscle weakness, often limited one arm or leg, or present with dysarthria and dysphagia, symptoms characteristic of bulbar palsy. In this regard, spinal-onset ALS10 seems to be more common than bulbar-onset ALS10.[symptoma.com]
  • Clinical manifestations include progressive weakness, atrophy, fasciculation, hyperreflexia, dysarthria, dysphagia, and eventual paralysis of respiratory function.[icd10data.com]
  • […] management, which may increase survival and improve quality of life, should be emphasized. 2 Noninvasive ventilation is effective in prolonging survival, slowing the rate of decline in forced vital capacity, and enhancing quality of life. 3,4 Because dysphagia[nejm.org]
Fasciculation of the Tongue
  • Fasciculations of the tongue are often observed and patients may eventually show tongue amyotrophy. Besides those lower motor neuron signs, ALS patients may show distinct symptoms of upper motor neuron disease.[symptoma.com]
  • Within a month, the patient had slurred speech, difficulty in swallowing liquids and fasciculations of the tongue.[aafp.org]
Muscle Weakness
  • Progressive muscle weakness and atrophy leads to respiratory paralysis and death within years of symptom onset.[symptoma.com]
  • 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.[icdlist.com]
  • ICD-9: 335.20 PROGRESSION Regardless of the part of the body first affected by the disease, muscle weakness and atrophy spread to other parts of the body as the disease progresses.[secure.ssa.gov]
  • Signs and symptoms include muscle weakness, atrophy, and fasciculation. Amyotrophic lateral sclerosis (als) is a nervous system disease that attacks nerve cells called neurons in your brain and spinal cord.[icd10data.com]
  • But, progressive muscle weakness and paralysis are universally experienced. As the weakness continues to spread, the disease eventually affects walking, speech, swallowing, and breathing.[knoppbio.com]
Dysarthria
  • TNFRSF1A C9orf72 HLA-DRB1 For most patients with ALS, the initial signs and symptoms are dysarthria or dysphagia. asymmetric limb weakness. muscle atrophy and weight loss.[journals.lww.com]
  • Affected individuals may claim muscle weakness, often limited one arm or leg, or present with dysarthria and dysphagia, symptoms characteristic of bulbar palsy. In this regard, spinal-onset ALS10 seems to be more common than bulbar-onset ALS10.[symptoma.com]
  • Affected individuals may develop slurred speech (dysarthria) and, later, difficulty chewing or swallowing (dysphagia).[icdlist.com]
  • Clinical manifestations include progressive weakness, atrophy, fasciculation, hyperreflexia, dysarthria, dysphagia, and eventual paralysis of respiratory function.[icd10data.com]
  • 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]
Hyperreflexia
  • The fact that hyperreflexia may be detected in regions of muscle atrophy is considered to be highly indicative of ALS. In some ALS10 patients, lower motor neuron signs predominate the clinical presentation.[symptoma.com]
  • Upper motor neuron findings in ALS include hyperreflexia and spasticity. amyotrophy and fasciculations. bowel and bladder dysfunction. The most common cause of death in ALS is heart failure. liver failure. respiratory failure.[journals.lww.com]
  • Clinical manifestations include progressive weakness, atrophy, fasciculation, hyperreflexia, dysarthria, dysphagia, and eventual paralysis of respiratory function.[icd10data.com]
  • The diagnostic process consists of a history and physical examination, repeated at regular intervals, to document progressive hyperreflexia, fasciculations, and upper and lower motor neuron involvement.[aafp.org]
  • Symptoms Upper motor neuron symptoms of ALS include hyperreflexia (overactive reflexes), clonus (involuntary, rhythmic muscle contraction and relaxation) and spasticity.[pharmaceutical-journal.com]
Bradykinesia
  • Signs of parkinsonism include unusually slow movements (bradykinesia), stiffness, and tremors. Affected members of the same family can have different combinations of signs and symptoms. [ Read More ][icdlist.com]
  • The proband (Sar-403) is a 77-year-old, congenital deaf-mute woman, who developed resting tremor and bradykinesia in her right limbs and at the age of 76.[link.springer.com]
Babinski Sign
  • 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]
Paresis
  • Vocal difficulties associated with ALS can mimic spasmodic dysphonia (if vocal spasms predominate) or vocal fold paresis (if vocal fold weakness and flaccid symptoms predominate).[voicefoundation.org]

Workup

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 [9] [10] [11]. Currently, revised El Escorial criteria are applied in most clinical trials. Those criteria are as follows [10]:

  • 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 [10]:

  • 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 [10]. However, TARDBP mutations have also been detected in patients suffering from sporadic ALS [1] [12]. This fact highlights the importance of genetic studies and the necessity of interpreting their results in the context of anamnestic and clinical data.

Even though molecular biological analyses are not required for the diagnosis of ALS, they are necessary to determine the subtype. Indeed, the identification of sequence anomalies may accelerate the diagnostic process: If TARDBP mutations are known to cause ALS in a determined family, a more targeted approach to diagnosis becomes feasible. By contrast, the identification of TARDBP mutations in patients suffering from sporadic ALS may improve the understanding of the pathophysiology of the disease. 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. In conclusion, genetic analyses provide both physicians and scientists with an appropriate tool to identify carriers and family members at risk, and to promote research [13] [14].

Alternaria
  • ., 2012 ), in addition to resistance against rust ( Uromyces appendiculatus ), leaf spot ( Alternaria alternata ), and anthracnose ( Colletotrichum lindemuthianum ) ( Vieira et al., 2002 ), highlighting the importance of this line as a source of broad[frontiersin.org]

Treatment

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 [15]. The application of α-tocopherol has been proposed as a complementary measure to slow down disease progression in milder cases [16]. 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 [3] [16]:

  • 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 ALS10 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.

Prognosis

Progressive muscle weakness and atrophy leads to respiratory paralysis and death within years of symptom onset [2]. Mean survival times cannot be provided for ALS10, but mean survival times of ALS patients in general were calculated to be three to four years [17].

Etiology

In early 2008, several research groups reported ALS patients who carried mutations in the TARDBP gene [1] [2] [4] [12]. Some of those patients were diagnosed with sporadic ALS, while others had a positive family history of the disease.

The TARDBP gene encodes for TDP-43, a DNA and RNA binding protein. It has initially been characterized as a transcriptional repressor regulating HIV-1 gene expression, but has later been found to affect DNA transcription and RNA splicing with regards to other genes. For instance, it may be involved in pathological splicing of the cystic fibrosis transmembrane receptor, thereby contributing to the onset of cystic fibrosis. Furthermore, TDP-43 has been proposed to act as a scaffold for nuclear bodies, and that's possibly how this protein predisposes for ALS [18].

Besides genetic factors, environmental influences are assumed to play a major role in ALS pathogenesis. With regards to such environmental influences, the following have been identified and confirmed as risk factors for ALS [17]:

Epidemiology

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 [17]. With regards to the ALS10, symptom onset has been reported to occur at any point in time between the early fourth decade of life and old age >80 years [2] [4]. 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 [17]. About 10% of all those cases are familial, and TARDBP mutations have been detected in several kindreds of distinct ethnic groups that didn't carry mutations in the SOD1 gene [3]. Of note, mutations in the SOD1 gene presumably account for 20% of all cases of familial ALS [3]. The frequency of TARDBP mutations in familial ALS has been estimated to be 4-5% [19]. Familial ALS is generally inherited in an autosomal dominant manner, as is the case with ALS10 [19].

Sex distribution
Age distribution

Pathophysiology

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. In general, it can be said that sequence anomalies, e.g., of genes like TARDBP, 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 [20]. In this context, neuronal death has been speculated to be due to the intracellular accumulation of protein aggregates which, in turn, consist of misfolded proteins or of substrates insufficiently degraded by a defective proteasome. Studies regarding the precise composition of such neuronal inclusions revealed high contents of hyperphosphorylated TDP-43 [1] [12]. As has been mentioned above, TDP-43 may indeed serve as a scaffold for protein aggregates, thereby paving the way for the accumulation of neurotoxic inclusions and triggering neurodegeneration [12] [18].

Prevention

No recommendations can be given to prevent the onset of sporadic ALS, other than avoiding the risk factors mentioned above. By contrast, genetic analyses may facilitate the identification of carriers and as-of-yet asymptomatic patients in families affected by familial ALS [13]. Prenatal diagnoses may become feasible if the disease can be related to well-defined DNA sequence anomalies, but this does not yet apply to ALS10.

Summary

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 TARDBP gene, which encodes for protein TDP-43. ALS linked to mutations in the TARDBP gene has been designated ALS10 [3] [19]. Presumably, mutations of the TARDBP gene result in the formation of cytotoxic protein aggregates within neurons, but little is actually known about the etiology and pathogenesis of ALS10 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 other neurodegenerative diseases, and this also applies to ALS10. However, the most common clinical presentation of ALS10 is that of "pure ALS", i.e., in early stages of the disease, patients experience muscle weakness, particularly in their arms or legs, or bulbar palsy associated with dysarthria and dysphagia. Over the course of the disease, they develop amyotrophy in all four limbs. 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 ALS10 requiring additional genetic analyses. Mean survival times of ALS patients 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.

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 several families of different origin whose members present mutations in a gene called TARDPB. This particular condition has later been designated amyotrophic lateral sclerosis 10 (ALS10).

With regards to clinical presentation, diagnosis, treatment, and prognosis, ALS10 doesn't differ from classical ALS.

References

Article

  1. Kabashi E, Valdmanis PN, Dion P, et al. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet. 2008; 40(5):572-574.
  2. Kühnlein P, Sperfeld AD, Vanmassenhove B, et al. Two German kindreds with familial amyotrophic lateral sclerosis due to TARDBP mutations. Arch Neurol. 2008; 65(9):1185-1189.
  3. 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.
  4. Gitcho MA, Baloh RH, Chakraverty S, et al. TDP-43 A315T mutation in familial motor neuron disease. Ann Neurol. 2008; 63(4):535-538.
  5. Benajiba L, Le Ber I, Camuzat A, et al. TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration. Ann Neurol. 2009; 65(4):470-473.
  6. Floris G, Borghero G, Cannas A, et al. Clinical phenotypes and radiological findings in frontotemporal dementia related to TARDBP mutations. J Neurol. 2015; 262(2):375-384.
  7. Van Deerlin VM, Leverenz JB, Bekris LM, et al. TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol. 2008; 7(5):409-416.
  8. Quadri M, Cossu G, Saddi V, et al. Broadening the phenotype of TARDBP mutations: the TARDBP Ala382Thr mutation and Parkinson's disease in Sardinia. Neurogenetics. 2011; 12(3):203-209.
  9. 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.
  10. 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.
  11. de Carvalho M, Dengler R, Eisen A, et al. Electrodiagnostic criteria for diagnosis of ALS. Clin Neurophysiol. 2008; 119(3):497-503.
  12. Sreedharan J, Blair IP, Tripathi VB, et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science. 2008; 319(5870):1668-1672.
  13. 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.
  14. 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.
  15. 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.
  16. Soriani MH, Desnuelle C. Care management in amyotrophic lateral sclerosis. Rev Neurol (Paris). 2017; 173(5):288-299.
  17. Talbott EO, Malek AM, Lacomis D. The epidemiology of amyotrophic lateral sclerosis. Handb Clin Neurol. 2016; 138:225-238.
  18. Buratti E, Baralle FE. Multiple roles of TDP-43 in gene expression, splicing regulation, and human disease. Front Biosci. 2008; 13:867-878.
  19. Chen S, Sayana P, Zhang X, Le W. Genetics of amyotrophic lateral sclerosis: an update. Mol Neurodegener. 2013; 8:28.
  20. 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 20:06