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Amyotrophic Lateral Sclerosis Type 7

ALS 7

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 7 (ALS7) may be one of many subtypes of familial ALS, but it remains a matter of discussion whether or not ALS7 constitutes an individual entity. It has been related to chromosomal locus 20ptel-p13. Those individuals who have been shown to have the respective genotype suffered from typical ALS with first symptoms manifesting in adulthood. ALS7 may be inherited in an autosomal dominant manner.


Presentation

The study published by Sapp and colleagues doesn't include details regarding the clinical presentation of ALS7 patients. However, the authors mention that all their patients met with generally accepted diagnostic criteria as described in the following section [1]. Accordingly, ALS7 patients are expected to develop limb muscle weakness in adulthood. Muscle weakness may initially be limited to one or two extremities, but subsequently spreads to the other limbs. As the disease progresses, ALS patients often develop bulbar palsy, which manifests as dysarthria and dysphagia, and symptomatic upper motor neuron disease:

  • In the long term, muscle weakness is followed by atrophy, but fasciculations are very common, too [2]. With regards to bulbar palsy, this condition is characterized by dysarthria and dysphagia. 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 [2].
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]
Overeating
  • Over the course of the disease, they develop muscle weakness and atrophy in all four limbs, and probably bulbar palsy associated with dysarthria and dysphagia.[symptoma.com]
  • She presented with a right-sided facial droop of short origin, being generally unwell and ‘off legs’ over 2 weeks with reduced appetite.[kundoc.com]
  • In Hawking's 2013 memoir "My Brief History," he wrote that at the time of his ALS diagnosis, "I thought my life was over and that I would never realize the potential I felt I had," according to the BBC.[livescience.com]
  • Clinical research studies supported by NINDS are looking into how ALS symptoms change over time in people with C9ORF72 mutations.[ninds.nih.gov]
  • Melcher's name appears over the Law Firm's information making it appear that: (1) he is somehow associated with that office, which he is not; and (2) that he received payment of fees which he did not.[leagle.com]
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]
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]
Muscle Weakness
  • Accordingly, ALS7 patients are expected to develop limb muscle weakness in adulthood. Muscle weakness may initially be limited to one or two extremities, but subsequently spreads to the other limbs.[symptoma.com]
  • Regardless of where the symptoms first appear, muscle weakness and atrophy spread to other parts of the body as the disease progresses.[ninds.nih.gov]
Muscle Twitch
  • Some of the early symptoms include: fasciculations (muscle twitches) in the arm, leg, shoulder, or tongue muscle cramps tight and stiff muscles (spasticity) muscle weakness affecting an arm, a leg, neck or diaphragm. slurred and nasal speech difficulty[ninds.nih.gov]
Short Arm
  • For instance, there is a US family whose members present sequence anomalies on the short arm of chromosome 20. This particular condition has later been designated amyotrophic lateral sclerosis 7 (ALS7).[symptoma.com]
Dysarthria
  • Over the course of the disease, they develop muscle weakness and atrophy in all four limbs, and probably bulbar palsy associated with dysarthria and dysphagia.[symptoma.com]
  • Individuals may develop problems with moving, swallowing (dysphagia), speaking or forming words (dysarthria), and breathing (dyspnea).[ninds.nih.gov]
Hyperreflexia
  • The fact that hyperreflexia may be detected in regions of muscle atrophy is considered to be highly indicative of ALS.[symptoma.com]

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 [3] [4] [5]. 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].

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 [6] [7].

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 [8]. The application of α-tocopherol has been proposed as a complementary measure to slow down disease progression in milder cases [9]. 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 [2] [9]:

  • 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.

Prognosis

Progressive muscle weakness and atrophy leads to respiratory paralysis and death within three years of symptom onset [1]. Thus, the mean duration of ALS7 may be somewhat shorter than that of ALS in general: Mean survival times of ALS patients were calculated to be three to four years [10].

Etiology

In 2003, Sapp and colleagues have studied sixteen pedigrees of US families known to be affected by familial ALS, but without evidence for mutations in the SOD1 gene [1]. Of note, mutations in the SOD1 gene presumably account for 20% of all cases of familial ALS [2]. In one of those families, the disease status of family members has been linked to chromosomal locus 20ptel [1]. In detail, the locus has been found to span the region from the telomere of the short arm of chromosome 20 to marker D20S199 on 20p13, which corresponds to about 1 Mbp [1]. The locus may comprise 20 to 24 genes. Data regarding the role of locus 20ptel-p13 in ALS7 pathogenesis are not available; genes in this locus that may be involved in the development of ALS have not yet been identified. Given the fact that chromosomal locus 20ptel-p13 has never again been related to ALS, doubts may arise as to whether ALS7 should be considered an individual entity or not [11].

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 [10]:

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 [10]. With regards to the ALS7 patients described by Sapp et al., their mean age at the appearance of first symptoms was 56 years [1]. 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 [10]. About 10% of all those cases are familial, but ALS7 has only ever been described in two members of the same family [1].

Familial ALS is generally inherited in an autosomal dominant manner and this mode of inheritance has also been postulated for ALS7: Samples were obtained from 25 members of said family, two of whom were suffering from ALS. They were siblings. They had thirteen more siblings, none of whom showed symptoms of ALS. By contrast, one third-degree relative and one distant relative had developed ALS previously [1]. Because neither of the affected individuals' parents has experienced ALS-related complaints despite one of them being an obligate heterozygote carrier of the ALS7-associated locus, incomplete penetrance may be assumed [2].

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. 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 regulatory or protein-coding genes on chromosomal locus 20ptel-p13, 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 [12].

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 [6]. Prenatal diagnoses may become feasible if the disease can be related to well-defined DNA sequence anomalies, but this does not yet apply to ALS7. Further research is required to identify those genes on chromosomal locus 20ptel-p13 that predispose for the development of this type of ALS.

Summary

ALS is the most common motor neuron disease. ALS patients may be genetically predisposed to develop the disease, and distinct chromosomal loci have been associated with its familial form. While studying the background of ALS in a five-generation family originating from the United States, Sapp et al. found the disease to be linked to chromosomal locus 20ptel-p13 [1]. Although such linkage has never been detected in another family, ALS linked to this locus has later been designated ALS7 [2]. Presumably, mutations of genes in locus 20ptel-p13 confer susceptibility to environmental risk factors that eventually trigger disease onset in adulthood [10]. But even though much has been speculated, very little is actually known about the etiology and pathogenesis of ALS7 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, but this has not yet been described for ALS7. The clinical presentation of ALS7 is that of "pure ALS", i.e., in early stages of the disease, patients experience muscle weakness in any of their extremities. Over the course of the disease, they develop muscle weakness and atrophy in all four limbs, and probably 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 as amyotrophy.

Diagnosis of ALS relies on well-defined diagnostic criteria and is mainly clinical, with the identification of ALS7 requiring additional genetic analyses. Mean survival times don't exceed three 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 is a US family whose members present sequence anomalies on the short arm of chromosome 20. This particular condition has later been designated amyotrophic lateral sclerosis 7 (ALS7).

With regards to clinical presentation, diagnosis, treatment, and prognosis, ALS7 doesn't differ from classical ALS.

References

Article

  1. Sapp PC, Hosler BA, McKenna-Yasek D, et al. Identification of two novel loci for dominantly inherited familial amyotrophic lateral sclerosis. Am J Hum Genet. 2003; 73(2):397-403.
  2. 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.
  3. 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.
  4. 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.
  5. de Carvalho M, Dengler R, Eisen A, et al. Electrodiagnostic criteria for diagnosis of ALS. Clin Neurophysiol. 2008; 119(3):497-503.
  6. 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.
  7. 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.
  8. 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.
  9. Soriani MH, Desnuelle C. Care management in amyotrophic lateral sclerosis. Rev Neurol (Paris). 2017; 173(5):288-299.
  10. Talbott EO, Malek AM, Lacomis D. The epidemiology of amyotrophic lateral sclerosis. Handb Clin Neurol. 2016; 138:225-238.
  11. Gros-Louis F, Gaspar C, Rouleau GA. Genetics of familial and sporadic amyotrophic lateral sclerosis. Biochim Biophys Acta. 2006; 1762(11-12):956-972.
  12. 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