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 2 (ALS2) is one of many subtypes of familial ALS. It has been related to mutations in the ALS2 gene, a protein-coding gene whose product is required for the Rab5-dependent fusion of early endosomes. ALS2 is a juvenile-onset form of ALS and is inherited in an autosomal recessive manner. ALS2 patients suffer from a slowly progressive form of ALS. The clinical presentation may be dominated by spasticity or muscle weakness and atrophy.
ALS2 is clinically indistinguishable from other types of sporadic or familial ALS presenting as pure ALS, i.e., ALS2 is not associated with frontotemporal dementia, parkinsonism, or other neurodegenerative disorders. However, first symptoms manifest much earlier in life, generally in childhood or adolescence.
In the majority of patients, pyramidal signs may dominate over symptoms of lower motor neuron disease    . Increased stiffness in the lower limbs is a frequent presenting symptom and is related to spasticity. Such alterations in muscle tone don't remain restricted to the legs but spread to the muscles of arms, face, larynx, and pharynx. Bulbar involvement results in spastic dysarthria and dysphagia. Upper motor neuron dysfunction also causes hyperreflexia. Infantile-onset ALS2 may interfere with reaching motor milestones and speech acquisition  .
Besides those upper motor neuron signs, ALS patients usually show symptoms of lower motor neuron disease. Muscle weakness followed by atrophy and fasciculations are clinical hallmarks of ALS, and they have been observed in ALS2 patients. Indeed, there are ALS2 patients who primarily suffer from muscle weakness but present only mild spasticity in their limbs. Because this is in contrast to the above-cited reports that essentially describe ALS2 as a spastic motor paralysis with amyotrophy limited to the peroneal muscles, if detectable at all, Ben Hamida and colleagues suggested differentiating between the following ALS2 subtypes :
- Upper limb and sometimes bulbar amyotrophy with a bilateral pyramidal syndrome causing mild spasticity in all limbs
- Spastic paraplegia with peroneal muscle atrophy
- Spastic pseudobulbar form, amyotrophy possibly absent
Pseudobulbar symptoms seen in ALS2 patients comprise uncontrolled laughter and weeping.
Somatosensory deficits are not characteristic of ALS2.
Entire Body System
Eating problems People with ALS can develop malnutrition and dehydration from damage to the muscles that control swallowing. They are also at higher risk of getting food, liquids or saliva into the lungs, which can cause pneumonia. [mayoclinic.org]
In general, ALS2 patients are likely to develop spastic tetraparesis and pseudobulbar paralysis, to become wheelchair-bound and anarthric by age 12-50 years. Mean survival times of ALS2 patients have not yet been reported. [symptoma.com]
The clinical presentation may be dominated by spasticity or muscle weakness and atrophy. [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. [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]
weakness and wasting, in association with pyramidal signs, normal sensation, and absence of bulbar involvement, leading to degeneration of motor neurons in the brain and spinal cord. [orpha.net]
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]
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]
twitching, or fasciculations, and then progressively atrophies when the synapses connecting the muscles are lost.1 This tends to begin in the limbs and progresses to the eye and sphincter muscle neurons in the late stages.1 When the motor neurons of [ajmc.com]
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]
Stiffness of the Lower Limbs
Increased stiffness in the lower limbs is a frequent presenting symptom, and spasticity subsequently spreads to the muscles of arms, face, larynx, and pharynx. [symptoma.com]
1 ALS2 mutations: juvenile amyotrophic lateral sclerosis and generalized dystonia. 6 56 61 24562058 2014 2 Novel mutation in the ALS2 gene in juvenile amyotrophic lateral sclerosis. 56 6 Kress JA...Sperfeld AD 16240357 2005 3 The gene encoding alsin, [malacards.org]
[…] amyotrophic lateral sclerosis Full_Paper Panzeri 2006 The first ALS2 missense mutation associated with JPLS reveals new aspects of alsin biological function Full_Paper Sheerin 2014 ALS2 mutations: Juvenile amyotrophic lateral sclerosis and generalized dystonia [alsod.iop.kcl.ac.uk]
She also had jaw-opening dystonia, facial myokymia, and shoulder muscle fasciculations but did not have spasticity, muscle weakness, bradykinesia, rest tremor, or rigidity. Magnetic resonance imaging showed marked cerebellar atrophy. [jamanetwork.com]
ALS2 mutations: juvenile amyotrophic lateral sclerosis and generalized dystonia. Neurology. 2014 Mar 25;82(12):1065-7. doi: 10.1212/WNL.0000000000000254. Epub 2014 Feb 21. [ghr.nlm.nih.gov]
Dystonia MedGen UID: 3940 •Concept ID: C0013421 • Sign or Symptom An abnormally increased muscular tone that causes fixed abnormal postures. [ncbi.nlm.nih.gov]
Upper motor neuron dysfunction also causes hyperreflexia. Infantile-onset ALS2 may interfere with reaching motor milestones and speech acquisition. [symptoma.com]
[…] remission or relapse.8 Atypical presentation includes emotional lability, frontal lobe-type cognitive dysfunction, weight loss, and fasciculations and cramps without muscle weakness.8,14 Signs of UMN disease include muscle tone increase, slow movement, and hyperreflexia [ajmc.com]
He also had increased tone in all limbs, hyperreflexia, and a spastic gait. Sensory examination findings were normal. He also had a mild postural tremor, but there were no other clinical signs of cerebellar dysfunction. [jamanetwork.com]
Hyperreflexia MedGen UID: 57738 •Concept ID: C0151889 • Finding Autonomic nervous system overreaction to stimuli, most commonly after spinal cord injury at a T-5 level and above. [ncbi.nlm.nih.gov]
[…] age: 4th to 8th decade Fronto-Temporal Dementia (FTD) Dementia Language disorders Personality changes Behavioral disorders Amyotrophic lateral sclerosis syndrome (ALS) Bulbar dysfunction: Dysphagia Limb denervation Upper motor neuron signs in limbs Hyperreflexia [neuromuscular.wustl.edu]
JALS is characterized by onset during childhood (mean age of onset 6.5 years), spasticity of facial muscles, uncontrolled laughter, spastic dysarthria, spastic gait, moderate muscle atrophy (variably present), bladder dysfunction, and sensory disturbances [ncbi.nlm.nih.gov]
He also had increased tone in all limbs, hyperreflexia, and a spastic gait. Sensory examination findings were normal. He also had a mild postural tremor, but there were no other clinical signs of cerebellar dysfunction. [jamanetwork.com]
ALS2 (alsin; chromosome 2q33.1; ALS2): Autosomal recessive mutations in ALS2 lead to childhood-onset (average age of onset is 6.5 years) spastic paresis, spasticity of the facial musculature, uncontrollable laughing, spastic dysarthria, spastic gait, [mgz-muenchen.de]
Sign in Published on Sep 1, 2014 Key words: Amyotrophic lateral sclerosis Lou Gehrig Motor neuron disease Stephen Hawking Electromyography Riluzole Rilutek Superoxide dismutase SOD1 Clonus Upper motor neuron Lower motor neuron Fasciculation Babinski sign [youtube.com]
sign, or upward response of the plantar reflex, is also evidence of UMN dysfunction and is discovered in 30% to 50% of patients.8 Symptoms may be described as “limb onset” and “bulbar onset.” [ajmc.com]
Babinski sign MedGen UID: 19708 •Concept ID: C0034935 • Finding A reflex characterized by upward movement of the great toe and an outward movement of the rest of the toes, when the sole of the foot is stroked. [ncbi.nlm.nih.gov]
She had mild dysmetria on finger chase (1 point on SARA bilaterally), moderate intention tremor on nose-finger test (2 points on SARA bilaterally), and abnormal findings on the heel-shin slide test (2 points on SARA bilaterally). [jamanetwork.com]
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  . To date, mutations in the ALS2 gene have only been detected in patients suffering from juvenile-onset ALS and related entities, but not in individuals with adult-onset disease .
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 and may be considered here . Otherwise, only palliative treatment can be provided. In this context, ALS4 patients benefit from a multidisciplinary approach that aims at maintaining their mobility and their ability to cope with everyday life for as long as possible  :
- Spasticity and muscle cramps 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.
- 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.
- 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.
ALS2 has long since been considered a slowly progressive form of ALS with a disease duration of several decades . However, more rapid progression has also been described . In general, ALS2 patients are likely to develop spastic tetraparesis and pseudobulbar paralysis, to become wheelchair-bound and anarthric by age 12-50 years . Mean survival times of ALS2 patients have not yet been reported.
ALS2 is inherited in an autosomal recessive manner and has been mapped to chromosomal locus 2q33 . Subsequent studies allowed to relate ALS2 to the ALS2 gene, which encodes for alsin  . This protein comprises guanine nucleotide exchange factor domains and localizes with small GTPase Rab5 on early endosomes. It has therefore been speculated to function as a regulator of Rab5 activity and endosomal fusion. To date, more than a dozen pathogenic mutations of the ALS2 gene have been detected in patients that were homozygous or compound heterozygous for these mutations . Of note, mutations in the ALS2 gene have also been related to infantile-onset ascending hereditary spastic paralysis and juvenile primary lateral sclerosis, which are conditions associated with a phenotype very similar to the one seen in ALS2 patients . However, neurodegeneration is limited to upper motor neurons in both infantile-onset ascending hereditary spastic paralysis and juvenile primary lateral sclerosis, while upper and lower motor neuron disease underlies the development of ALS2  . It remains a matter of ongoing debate whether juvenile primary lateral sclerosis and ALS2 are truly separate entities, though, since most ALS2 patients present with predominantly upper motor neuron disease and little to no involvement of lower motor neurons .
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 this is not the case with ALS2, a juvenile-onset form of ALS. ALS2 patients' age at symptom onset ranges between 2-25 years  , their mean age at symptom onset being 6.5 years . Both men and women may develop ALS2. In recent years, ALS2 has mainly been diagnosed in families from Middle Eastern, Mediterranean, and European countries , but early case reports came from North America  .
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 ALS2, 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 . With regard to ALS2, failure of early endosome trafficking has been hypothesized to underlie neurodegeneration in patients suffering from this form of the disease, but it could not yet be clarified how - and if - it leads to the formation of intracellular protein aggregates as seen in sporadic ALS .
No recommendations can be given to prevent the onset of sporadic ALS, other than avoiding certain risk factors . By contrast, genealogical and 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 have not yet been reported for ALS2.
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 ALS2 gene, which encodes for alsin or ALS2 protein. While sporadic ALS typically manifests in adulthood, mutations in the ALS2 gene give rise to a juvenile-onset form of the disease. Therefore, ALS2 is sometimes simply referred to as juvenile ALS. The latter term has a potential for confusion, though, since juvenile-onset ALS may also be caused by mutations in genes SETX (amyotrophic lateral sclerosis 4), SPG11 (amyotrophic lateral sclerosis 5), and SIGMAR1 (amyotrophic lateral sclerosis 16), among others.
Early descriptions of ALS2 date from 1954 and 1971, when Refsum, Skillicorn, Gragg, and colleagues reported five children who developed ALS-like symptoms during their first decade of life  . The clinical presentation was predominated by upper motor neuron signs such as increased deep tendon reflexes and spasticity, but fasciculations, severe atrophy of distal muscles of arms and legs, and bulbar involvement were also noted. Less frequently, ALS2 manifests as upper limb and bulbar atrophy with only mild spasticity .
Diagnosis of ALS relies on well-defined diagnostic criteria and is mainly clinical, with the identification of ALS2 requiring additional genetic analyses. Effective treatment cannot be provided and therapy mainly aims at maintaining the patients' mobility and quality of life.
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 from Middle Eastern, Mediterranean, and European countries whose members present mutations in a gene called ALS2. Its designation has been chosen due to its association with amyotrophic lateral sclerosis 2 (ALS2).
Contrary to the more common sporadic form of ALS, ALS2 manifests in childhood or adolescence. Increased stiffness in the lower limbs is a frequent presenting symptom, and spasticity subsequently spreads to the muscles of arms, face, larynx, and pharynx. It progressively reduces the mobility of the patient and causes major problems with speaking and swallowing. Muscle weakness followed by atrophy is a clinical hallmark of sporadic ALS, but is less often observed in ALS2 patients.
With regards to diagnosis, treatment, and prognosis, ALS2 doesn't differ from classical ALS.
- Gragg GW, Fogelson MH, Zwirecki RJ. Juvenile amyotrophic lateral sclerosis in two brothers from an inbred community. Birth Defects Orig Artic Ser. 1971; 7(1):222-225.
- Kress JA, Kühnlein P, Winter P, et al. Novel mutation in the ALS2 gene in juvenile amyotrophic lateral sclerosis. Ann Neurol. 2005; 58(5):800-803.
- Refsum S, Skillicorn SA. Amyotrophic familial spastic paraplegia. Neurology. 1954; 4(1):40-47.
- Shirakawa K, Suzuki H, Ito M, et al. Novel compound heterozygous ALS2 mutations cause juvenile amyotrophic lateral sclerosis in Japan. Neurology. 2009; 73(24):2124-2126.
- Sheerin UM, Schneider SA, Carr L, et al. ALS2 mutations: juvenile amyotrophic lateral sclerosis and generalized dystonia. Neurology. 2014; 82(12):1065-1067.
- 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.
- 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.
- Hand CK, Devon RS, Gros-Louis F, et al. Mutation screening of the ALS2 gene in sporadic and familial amyotrophic lateral sclerosis. Arch Neurol. 2003; 60(12):1768-1771.
- 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.
- Hentati A, Bejaoui K, Pericak-Vance MA, et al. Linkage of recessive familial amyotrophic lateral sclerosis to chromosome 2q33-q35. Nat Genet. 1994; 7(3):425-428.
- Hadano S, Hand CK, Osuga H, et al. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat Genet. 2001; 29(2):166-173.
- Yang Y, Hentati A, Deng HX, et al. The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat Genet. 2001; 29(2):160-165.
- Orrell RW. ALS2-Related Disorders. 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.
- 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.
- Chandran J, Ding J, Cai H. Alsin and the molecular pathways of amyotrophic lateral sclerosis. Mol Neurobiol. 2007; 36(3):224-231.