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Amyotrophic Lateral Sclerosis 5

JALS

Amyotrophic lateral sclerosis (ALS) is a progressive and generally fatal neurodegenerative disorder. Most cases are sporadic, but high familial incidence is observed occasionally. Amyotrophic lateral sclerosis 5 (ALS5) is one of many subtypes of familial ALS. It has been related to mutations in the SPG11 gene, a protein-coding gene whose product is possibly involved in the recognition and repair of DNA damage in neurons. ALS5 is a juvenile-onset form of ALS and is inherited in an autosomal recessive manner. ALS5 patients suffer from slowly progressive muscle weakness beginning in their limbs and spreading to the bulbar muscles. Pyramidal signs may be noted in advanced stages of the disease.


Presentation

ALS5 is clinically indistinguishable from other types of sporadic or familial ALS presenting as pure ALS, i.e., ALS5 is not associated with frontotemporal dementia, parkinsonism, or other neurodegenerative disorders. However, first symptoms manifest much earlier in life, generally in childhood or adolescence.

Affected individuals claim muscle weakness, which is initially limited to the distal extremities, causing difficulties with grasping, writing, walking and other activities that require the use of hands and feet [1]. As the disease progresses, muscle weakness spreads to the tongue, to pharyngeal and laryngeal muscles. ALS5 patients then develop dysarthria and dysphagia. Loss of limb-muscle strength and bulbar palsy is followed by the atrophy of the affected musculature. Fasciculations are also common [2] [3]. Besides those lower motor neuron signs, ALS patients usually show distinct symptoms of upper motor neuron disease. In case of ALS5, however, pyramidal signs such as an increase of muscle tone, spastic gait, and hyperreflexia with extensor plantar responses appear late in the course of the disease [1]. Mild cognitive impairment has occasionally been observed in ALS5 patients, but somatosensory deficits are not characteristic of ALS5 [3]. Accordingly, electrophysiological studies typically reveal a chronic motor neuronopathy characterized by reduced amplitudes of compound muscle action potentials and abnormal spontaneous activity showing in positive sharp waves, fasciculations, and fibrillations. Sensory nerve action potentials as well as conduction velocities of motor and sensory nerves are normal [3]. Disease severity varies widely.

Weakness
  • Furthermore, juvenile-onset, slowly progressive limb muscle weakness is typical of amyotrophic lateral sclerosis 4.[symptoma.com]
  • Symptoms of ALS Symptoms of ALS usually start with weakness. This weakness may begin with just one limb. Muscles may cramp, stiffen or have a twitching called "fasciculations."[verywell.com]
  • A 20-year-old male presented with history of wasting and weakness of the left leg followed by wasting and weakness of the right upper limb, shoulder and chest for the last 5 years.[neurologyindia.com]
  • Patient 2 was a 13-year-old boy who presented with 4 months of weakness of right leg. One month after onset, weakness progressed to right arm.[atm.amegroups.com]
  • Distal weakness and atrophy was associated with pyramidal signs (43/49) and normal sensation (44/49). Motor conduction studies (n 8) showed reduced evoked amplitudes and normal conduction parameters.[jhu.pure.elsevier.com]
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]
Pharyngitis
  • As the disease progresses, muscle weakness spreads to the tongue, to pharyngeal and laryngeal muscles. ALS5 patients then develop dysarthria and dysphagia.[symptoma.com]
  • Syndrome, which may present with features of ALS and/or FTD 100% of Perry Syndrome, rare cause of isolated ALS/FTD FUS ALS6 4% of familial ALS and approximately 1% of sporadic ALS with or without FTD KIF5A ALS25 Unknown MATR3 * ALS21; Vocal cord and pharyngeal[invitae.com]
Dysphagia
  • ALS5 patients then develop dysarthria and dysphagia. Loss of limb-muscle strength and bulbar palsy is followed by the atrophy of the affected musculature. Fasciculations are also common.[symptoma.com]
  • Affected individuals may develop slurred speech (dysarthria) and, later, difficulty chewing or swallowing (dysphagia).[icdlist.com]
  • Characterized by leg weakness, spasticity, and bulbar symptoms like dysphagia and dysarthria Additional features include cognitive impairment, eye movement abnormalities, and urinary dysfunction.[unboundmedicine.com]
  • Clinical manifestations include progressive weakness, atrophy, fasciculation, hyperreflexia, dysarthria, dysphagia, and eventual paralysis of respiratory function.[icd10data.com]
Diplopia
  • Huang X....Fan D. 2017 5 Juvenile amyotrophic lateral sclerosis: Classical wine glass sign on magnetic resonance imaging. ( 27195035 ) Kumar S....Kohli N. 2016 6 De novo FUS P525L mutation in Juvenile amyotrophic lateral sclerosis with dysphonia and diplopia[malacards.org]
Muscle Weakness
  • Furthermore, juvenile-onset, slowly progressive limb muscle weakness is typical of amyotrophic lateral sclerosis 4.[symptoma.com]
  • ALS is characterized by progressive degeneration of motor neurons which results in muscle weakness and atrophy. An important gene associated with Amyotrophic Lateral Sclerosis Type 2 is ALS2 (amyotrophic lateral sclerosis 2 (juvenile)).[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.[icdlist.com]
  • There was global muscle weakness and atrophy of the right leg, and mild muscle atrophy in the left leg. Deep tendon reflexes were brisk in upper limbs and decreased in lower limbs. The Babinski sign was present in the right side.[atm.amegroups.com]
  • Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes.[ncbi.nlm.nih.gov]
Muscular Atrophy
  • […] progressive spinal muscular atrophy in that it was confined to the distal part of one lower limb and the proximal part of the contralateral upper limb, shoulder and chest.[neurologyindia.com]
  • atrophy and related syndromes G12.0 Infantile spinal muscular atrophy, type I [Werdnig-Hoffman] G12.1 Other inherited spinal muscular atrophy G12.2 Motor neuron disease G12.21 Amyotrophic lateral sclerosis G12.22 Progressive bulbar palsy G12.23 Primary[icd10data.com]
  • Spinal Muscular Atrophy. A Timely Review. Arch Neurol. 2011;68:979-984. PubMed . Harding BN, Kariya S, Monani UR, et al. Spectrum of Neuropathophysiology in Spinal Muscular Atrophy Type I. J Neuropathol Exp Neurol 2015;74:15-24. PubMed .[neuropathology-web.org]
  • 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]
Muscle Twitch
  • The earliest symptoms include muscle twitching, cramping, stiffness, or weakness. Affected individuals may develop slurred speech (dysarthria) and, later, difficulty chewing or swallowing (dysphagia).[icdlist.com]
  • Muscle twitches and cramps are common; they occur because degenerating axons (long fibers extending from nerve-cell bodies) become “irritable.” 1 Symptoms may be limited to a single body region, or mild symptoms may affect more than one region.[mda.org]
Dysarthria
  • 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]
  • ALS5 patients then develop dysarthria and dysphagia. Loss of limb-muscle strength and bulbar palsy is followed by the atrophy of the affected musculature. Fasciculations are also common.[symptoma.com]
  • Characterized by leg weakness, spasticity, and bulbar symptoms like dysphagia and dysarthria Additional features include cognitive impairment, eye movement abnormalities, and urinary dysfunction.[unboundmedicine.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]
Hyperreflexia
  • In case of ALS5, however, pyramidal signs such as an increase of muscle tone, spastic gait, and hyperreflexia with extensor plantar responses appear late in the course of the disease.[symptoma.com]
  • Motor neurons are nerve cells that control voluntary muscle activity. 0001288 Hyperreflexia Increased reflexes 0001347 Spasticity Involuntary muscle stiffness, contraction, or spasm 0001257 30%-79% of people have these symptoms Decreased muscle mass Underdeveloped[rarediseases.info.nih.gov]
  • In the patient, examinations revealed a steppage gait, atrophy of the bilateral interosseous and thenar muscles with a split-hand sign, mild weakness in the hands and lower limbs, hyperreflexia in all limbs with positive bilateral Babinski signs and Hoffmann[journal.frontiersin.org]
  • Clinical manifestations include progressive weakness, atrophy, fasciculation, hyperreflexia, dysarthria, dysphagia, and eventual paralysis of respiratory function.[icd10data.com]
Dystonia
  • ALS2 mutations: Juvenile amyotrophic lateral sclerosis and generalized dystonia.[discovery.ucl.ac.uk]
  • OBJECTIVE: To determine the genetic etiology in 2 consanguineous families who presented a novel phenotype of autosomal recessive juvenile amyotrophic lateral sclerosis associated with generalized dystonia.[foundationdystoniaresearch.org]
  • . ( 24562058 ) Sheerin U.M....Bhatia K.P. 2014 9 A novel splice-site mutation in ALS2 establishes the diagnosis of juvenile amyotrophic lateral sclerosis in a family with early onset anarthria and generalized dystonias. ( 25474699 ) Siddiqi S....Khor[malacards.org]
Spastic Gait
  • 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]
  • In case of ALS5, however, pyramidal signs such as an increase of muscle tone, spastic gait, and hyperreflexia with extensor plantar responses appear late in the course of the disease.[symptoma.com]
Spastic Gait
  • 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]
  • In case of ALS5, however, pyramidal signs such as an increase of muscle tone, spastic gait, and hyperreflexia with extensor plantar responses appear late in the course of the disease.[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 [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].

Even though molecular biological analyses are not required for the diagnosis of ALS, they are necessary to determine the subtype. In fact, not even the characteristic, predominantly lower motor neuron presentation of pediatric ALS5 patients allows for the identification of the ALS subtype: Amyotrophic lateral sclerosis 2, another form of early-onset ALS, preferentially manifests as spastic motor paralysis with scarce amyotrophy, but may also cause upper limb and bulbar amyotrophy with a bilateral pyramidal syndrome causing mild spasticity in all limbs [7]. Furthermore, juvenile-onset, slowly progressive limb muscle weakness is typical of amyotrophic lateral sclerosis 4 [8]. Beyond that, genetic analyses provide both physicians and scientists with an appropriate tool to identify carriers and family members at risk, and to promote research [9] [10].

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 [11]. The application of α-tocopherol has been proposed as a complementary measure to slow down disease progression in milder cases [12]. 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 [12] [13]:

  • 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

ALS5 is a slowly progressive from of ALS [2]. Affected individuals survive over several decades and the mean disease duration is 34 years [3].

Etiology

ALS5 is inherited in an autosomal recessive manner and has been mapped to chromosomal locus 5q15.1-q22 [2]. Subsequent studies allowed to relate ALS5 to the SPG11 gene, which encodes for spatacsin [3]. The SPG11 gene is ubiquitously expressed in the nervous system and spatacsin gene is known to be involved in axonal transport. It has also been proposed to play a role in neuronal maturation [14]. To date, more than a dozen pathogenic mutations of the SPG11 gene have been detected in patients that were homozygous or compound heterozygous for these mutations [3]. Of note, mutations in the SPG11 gene have also been related to autosomal recessive hereditary spastic paraplegia type 11 and autosomal recessive axonal Charcot-Marie-Tooth type 2X. Still, bulbar involvement and the absence of sensory impairment distinguish ALS5 from these entities [3].

Epidemiology

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, but this is not the case with ALS5, a juvenile-onset form of ALS. ALS5 patients' age at symptom onset ranges between 7-23 years, their mean age at symptom onset being 16 years [3]. Both men and women may develop ALS5. ALS5 has initially been diagnosed in families from North African and European countries [2], but targeted genetic analyses revealed SPG11 mutations to account for familial ALS in North and South America and East Asia, too [3].

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 genes like SPG11, may be the cause of irregularities in the amino acid sequence, post-translational modification and intracellular transport of any number of proteins, may alter their physical properties and functions, their propensity to bind to specific targets, and their susceptibility to degradation [16]. Somewhat surprisingly, though, neither Bunina bodies nor skein-like inclusions have been observed in brain tissue samples obtained from a deceased ALS5 patient [3], suggesting an entirely different pathogenesis for this form of the disease. Beyond that, some authors question the causal relationship between the presence of ALS-like inclusion bodies and neuronal loss [17]. Further research is required to shed more light on the pathogenetic events leading to the onset of sporadic and familial ALS.

Prevention

No recommendations can be given to prevent the onset of sporadic ALS, other than avoiding certain risk factors [15]. By contrast, genealogical and genetic analyses may facilitate the identification of carriers and as-of-yet asymptomatic patients in families affected by familial ALS [9]. Prenatal diagnoses may become feasible if the disease can be related to well-defined DNA sequence anomalies, but have not yet been reported for ALS5.

Summary

ALS is the most common motor neuron disorder. 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 SPG11 gene, which encodes for spatacsin. While sporadic ALS typically manifests in adulthood, mutations in the SPG11 gene give rise to a juvenile-onset form of the disease. ALS5 is, however not the only type of ALS with juvenile symptom onset: Mutations in genes ALS2 (amyotrophic lateral sclerosis 2), SETX (amyotrophic lateral sclerosis 4), and SIGMAR1 (amyotrophic lateral sclerosis 16), among others, are also known to trigger early-onset ALS [1].

ALS5 is characterized by slowly progressive muscle weakness starting in the distal limbs and spreading to the tongue and bulbar muscles. Pyramidal signs such as hyperreflexia and spasticity are observed in advanced-stage ALS5 only [1]. Diagnosis of ALS relies on well-defined diagnostic criteria and is mainly clinical, with the identification of ALS5 requiring additional genetic analyses. Effective treatment cannot be provided and therapy mainly aims at maintaining the patients' mobility and quality of life. Their degree of disability from the disease at a given point in time depends on the severity of ALS5 and varies from case to case. ALS5 patients generally survive over several decades [3].

Patient Information

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. 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 SPG11. Its designation has been chosen due to its association with amyotrophic lateral sclerosis 5 (ALS5).

Contrary to the more common sporadic form of ALS, ALS5 manifests in childhood or adolescence, and follows a slowly progressive course. Affected children suffer from increasing muscle weakness in their hands and feet, which causes problems with writing and walking. Weakness subsequently spreads to the tongue, to pharyngeal and laryngeal muscles, thereby provoking speech and swallowing disorder. In advanced stages of the disease, an increased muscle tone and spasticity may become more pronounced.

With regards to diagnosis, treatment, and prognosis, ALS5 doesn't differ from classical ALS.

References

Article

  1. Orban P, Devon RS, Hayden MR, Leavitt BR. Chapter 15 Juvenile amyotrophic lateral sclerosis. Handb Clin Neurol. 2007; 82:301-312.
  2. Hentati A, Ouahchi K, Pericak-Vance MA, et al. Linkage of a commoner form of recessive amyotrophic lateral sclerosis to chromosome 15q15-q22 markers. Neurogenetics. 1998; 2(1):55-60.
  3. Orlacchio A, Babalini C, Borreca A, et al. SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis. Brain. 2010; 133(Pt 2):591-598.
  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. Ben Hamida M, Hentati F, Ben Hamida C. Hereditary motor system diseases (chronic juvenile amyotrophic lateral sclerosis). Conditions combining a bilateral pyramidal syndrome with limb and bulbar amyotrophy. Brain. 1990; 113 ( Pt 2):347-363.
  8. Hirano M, Quinzii CM, Mitsumoto H, et al. Senataxin mutations and amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2011; 12(3):223-227.
  9. 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.
  10. 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.
  11. 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.
  12. Soriani MH, Desnuelle C. Care management in amyotrophic lateral sclerosis. Rev Neurol (Paris). 2017; 173(5):288-299.
  13. 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.
  14. Su XW, Broach JR, Connor JR, Gerhard GS, Simmons Z. Genetic heterogeneity of amyotrophic lateral sclerosis: implications for clinical practice and research. Muscle Nerve. 2014; 49(6):786-803.
  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.
  17. van Welsem ME, Hogenhuis JA, Meininger V, Metsaars WP, Hauw JJ, Seilhean D. The relationship between Bunina bodies, skein-like inclusions and neuronal loss in amyotrophic lateral sclerosis. Acta Neuropathol. 2002; 103(6):583-589.

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Last updated: 2018-06-21 18:20