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Amyotrophic Lateral Sclerosis Type 8

Amyotrophic Lateral Sclerosis 8

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 8 (ALS8) is one of many subtypes of familial ALS. It has been related to mutations in the VAPB gene, a protein-coding gene whose product is a type IV membrane protein possibly involved in vesicle trafficking. ALS8 is inherited in an autosomal dominant manner. Affected individuals suffer from a slowly progressive form of ALS, with first symptoms manifesting in early adulthood.


Presentation

ALS8 patients may seek medical advice due to postural tremor, fasciculations, and/or cramps. Muscle weakness may be noted at the very beginning of the disease, or may not manifest until years later. All these symptoms of lower motor neuron disease may initially be limited to one or two extremities, but eventually spread to the other limbs: Nearly all patients described by Nishimura et al. showed lower motor neuron signs in all four limbs [1]. Bulbar palsy is a common feature of ALS8 and is apparent in about half of all patients [1] [2]. The patients' sensibility is usually unaltered, although minor sensory impairment has been reported [1]. Accordingly, electrophysiological studies typically reveal abnormal spontaneous activity (fasciculations, fibrillations, sharp waves) as well as reduced motor unit recruitment, but normal amplitudes of action potentials of sensory nerves [1].

Pyramidal signs such as hyperreflexia have only been described in one single patient [1].

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]
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]
Respiratory Disorders
  • Indeed, several members of the Brazilian family described by Nishimura et al. and a close relative of the British patient were known to have died of respiratory disorders.[symptoma.com]
Muscle Cramp
  • Tremor, fasciculations, and muscle cramps are the most common presenting symptoms, but the majority of patients eventually develops muscle weakness and atrophy as well as bulbar palsy.[symptoma.com]
Muscle Weakness
  • Progressive muscle weakness and atrophy eventually leads to respiratory paralysis and death.[symptoma.com]
Hyperreflexia
  • Pyramidal signs such as hyperreflexia have only been described in one single patient.[symptoma.com]
Tremor
  • Tremor, fasciculations, and muscle cramps are the most common presenting symptoms, but the majority of patients eventually develops muscle weakness and atrophy as well as bulbar palsy.[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]. However, VAPB mutations have been detected in patients suffering from ALS clinically different from ALS8 [6].

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 VAPB 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].

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 [9]. The application of α-tocopherol has been proposed as a complementary measure to slow down disease progression in milder cases [10]. 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 [10] [11]:

  • Muscle cramps experienced by ALS8 patients are painful and disabling [1]. They may be resolved by muscle relaxants like quinine, levetiracetam, baclofen, or dantrolene.
  • 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.
  • Weakness of the respiratory muscles requires ventilatory assistance.
  • 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.
  • 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 eventually leads to respiratory paralysis and death. Indeed, several members of the Brazilian family described by Nishimura et al. and a close relative of the British patient were known to have died of respiratory disorders [1] [2]. However, ALS8 follows a slowly progressive course and mean survival times are significantly longer than those reported for classical ALS: Nishimura and colleagues calculated their patients' mean age at symptom onset to be 38 years, and their mean age at death to be 50 years [1]. By contrast, total mean survival times of ALS patients were estimated to be three to four years [12].

Etiology

In 2004, Nishimura and colleagues studied a Brazilian family of Caucasian ancestry affected by ALS. They carried out genealogical and genetic analyses to define the mode of inheritance and to possibly relate the disease to mutations at chromosomal or DNA sequence level. Effectively, they could confirm the disease to be inherited in an autosomal dominant manner and were able to relate it to chromosomal locus 20q13. In detail, the locus has been found to span the region between markers D20S430 and D20S173, which corresponds to about 2.7 Mbp. Presumably, this region comprises 17 to 23 genes and a single pseudogene [1].

Later on, the same research group identified a missense mutation in the VAPB gene of ALS8 patients [6]: This gene is located at 20q13.33 and encodes for vesicle-associated membrane protein-associated protein B. It locates to plasma and intracellular vesicle membranes and is known to be involved in the unfolded protein response displayed by the endoplasmatic reticulum upon the accumulation of misfolded proteins within that organelle [13]. Accordingly, mutations in the VAPB gene translate into an inadequate unfolded protein response and an exaggerated accumulation of abnormal proteins. In addition to this, mutated VAPB protein seems to lose solubility and contributes to the formation of presumably cytotoxic aggregates [14].

Epidemiology

ALS is the most common motor neuron disease in adults. Both men and women may develop classical ALS as well as ALS8 [1]. ALS patients' mean age at symptom onset is 60 years [12]. By contrast, individuals affected by ALS8 were reported to manifest first symptoms at a mean age of 38 years [1]. It shall be mentioned, though, that an elder individual who has not been diagnosed with ALS8 until the age of 73 years has been reported later [2]. This person's age at symptom onset is unknown.

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 [12]. Familial ALS is generally inherited in an autosomal dominant manner, as is the case with ALS8. To date, ALS8 has been diagnosed in Brazilian patients of Caucasian ancestry and a single person from the United Kingdom [1] [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 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 [15]. As for ALS8 and mutated VAPB proteins, their intracellular accumulation has been shown by a Japanese group of cell biologists [13] [14].

Prevention

No recommendations can be given to prevent the onset of sporadic ALS, other than avoiding certain risk factors [12]. 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 ALS8.

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. While studying the background of ALS in a three-generation family living in Brazil, Nishimura et al. found the disease to be linked to mutations in the VAPB gene [1] [6]. This gene encodes for vesicle-associated membrane protein-associated protein B and mutations in this gene have been shown to trigger the intracellular accumulation of misfolded proteins, including, but not limited to, the VAPB protein itself [13] [14]. ALS linked to mutations in the VAPB gene has been designated ALS8 [11].

ALS8 is a slowly progressive form of ALS. Tremor, fasciculations, and muscle cramps are the most common presenting symptoms, but the majority of patients eventually develops muscle weakness and atrophy as well as bulbar palsy [1]. Diagnosis of ALS relies on well-defined diagnostic criteria and is mainly clinical, with the identification of ALS8 requiring additional genetic analyses. Similar to classical ALS, ALS8 is uniformly fatal. However, mean survival times exceed ten years and thus, are significantly longer than those calculated for the classical variant of the disease [1].

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 are South American and European families whose members present mutations in a gene called VAPB. This particular condition has later been designated amyotrophic lateral sclerosis 8 (ALS8).

Postural tremor, fasciculations, and/or cramps are most commonly reported as first symptoms. Muscle weakness, the clinical hallmark of classical ALS, may be noted at the same time or may not manifest until years later. Eventually, the disease spreads to all four limbs and muscles of the trunk, and possibly causes speech and swallowing difficulties. There is no cure; affected individuals generally die of respiratory failure due to respiratory paralysis. However, ALS8 is a slowly progressive form of ALS, and mean survival times exceed ten years.

References

Article

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  2. Chen HJ, Anagnostou G, Chai A, et al. Characterization of the properties of a novel mutation in VAPB in familial amyotrophic lateral sclerosis. J Biol Chem. 2010; 285(51):40266-40281.
  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. Nishimura AL, Mitne-Neto M, Silva HC, et al. A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet. 2004; 75(5):822-831.
  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. Talbott EO, Malek AM, Lacomis D. The epidemiology of amyotrophic lateral sclerosis. Handb Clin Neurol. 2016; 138:225-238.
  13. Kanekura K, Nishimoto I, Aiso S, Matsuoka M. Characterization of amyotrophic lateral sclerosis-linked P56S mutation of vesicle-associated membrane protein-associated protein B (VAPB/ALS8). J Biol Chem. 2006; 281(40):30223-30233.
  14. Suzuki H, Kanekura K, Levine TP, et al. ALS-linked P56S-VAPB, an aggregated loss-of-function mutant of VAPB, predisposes motor neurons to ER stress-related death by inducing aggregation of co-expressed wild-type VAPB. J Neurochem. 2009; 108(4):973-985.
  15. 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 20:09