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 [1] [2] [3] [4]. 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 [2] [5].

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 [6]:

• 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.

• Disability

  Degeneration of upper motor neurons often is responsible for spasticity and modest weakness, but degeneration of lower motor neurons causes more disabling weakness. As the motor neurons stop working, muscles also begin to atrophy. [youtube.com]

  Please enable JS and disable any ad blocker [cairn.info]

  A tool to write with eyes As a result of their disability, patients with ALS have difficulties to express themselves. [icm-institute.org]

  As a result, alsin is unstable and is broken down rapidly by the cell, or it is disabled and cannot function properly. It is unclear how the loss of functional alsin protein causes juvenile primary lateral sclerosis. [ghr.nlm.nih.gov]

  Living with ALS ALS will eventually lead to disability and death. Although your ability to move and breathe independently will be affected, your intelligence and ability to think is not. [hopkinsmedicine.org]

• Pain

  Pain relief A non-steroidal anti-inflammatory drug (NSAID), such as ibuprofen, will help with mild to moderate pain from muscle cramping as spasms. [medicalnewstoday.com]

  There's generally no pain in the early stages of ALS, and pain is uncommon in the later stages. ALS doesn't usually affect your bladder control or your senses. [mayoclinic.org]

  Please note that severe pain is not a typical symptom of ALS. Who is affected by ALS? Throughout the world, an average of 1 to 2 per 100,000 people are diagnosed with ALS every year. Men are affected more frequently than women. [my.clevelandclinic.org]

  Alistair Walpole Staff Specialist Department Anaesthesia & Pain Management Royal Melbourne Hospital Cost Costs are in Australian dollars and include GST Consultants and GPs $1,600 HMOs and registrars $1,200 Nurses and paramedics $820 Melbourne Health [thermh.org.au]

  Drugs are available to help individuals with pain, panic attacks, and depression Patients with ALS tend to lose weight. The illness itself increases the need for food and calories. [checkorphan.org]

• Inflammation

  People with amyotrophic lateral sclerosis are also at increased risk for acute inflammation of the lungs, caused by the inhalation of food or stomach contents (aspiration pneumonia). [rarediseases.org]

  RBM4514 p54nrb/NONO γ-Synuclein Autophagy: Autophagosomes & Autolysosomes in motor neuron cell bodies 38 Other spinal cord Pathology Corticospinal tracts: Loss of myelinated axons Posterior columns: Spared except in familial ALS Astroglial proliferation Inflammation [neuromuscular.wustl.edu]

  Increasing evidence also suggests that various types of glial support cells and inflammation cells of the nervous system may play an important role in the disease. [ninds.nih.gov]

  Mediat Inflamm. 2013;2013:360190. 94. Laird AS, Van Hoecke A, De Muynck L, Timmers M, Van Den Bosch L, Van Damme P, Robberecht W. Progranulin is neurotrophic in vivo and protects against a mutant TDP-43 induced axonopathy. [bmcmedicine.biomedcentral.com]

• Anemia

  Spinal muscular atrophy types 1-4 Centromeric SMN2 gene (survival of motor neuron 2; 5q13.2) deletions Spinal muscular atrophy type 3 COX1 (Complex IV, Cytochrome c Oxidase subunit I, MT-CO1) gene Leber optic atrophy, Acquired idiopathic sideroblastic anemia [scielo.br]

• Anorexia

  Bulik-Sullivan B, Finucane HK, Anttila V, Gusev A, Day FR, Loh P-R, ReproGen C, Psychiatric Genomics C, Genetic Consortium for Anorexia Nervosa of the Wellcome Trust Case Control C, Duncan L, et al. [bmcmedicine.biomedcentral.com]

• Pneumonia

  Another possibly fatal complication of ASL is pneumonia, or an infection of the lungs. [livescience.com]

  They are also at higher risk of getting food, liquids or saliva into the lungs, which can cause pneumonia. A feeding tube can reduce these risks and ensure proper hydration and nutrition. [mayoclinic.org]

  Affected individuals also face an increased risk of pneumonia during later stages of the disease. [ninds.nih.gov]

  People with amyotrophic lateral sclerosis are also at increased risk for acute inflammation of the lungs, caused by the inhalation of food or stomach contents (aspiration pneumonia). [rarediseases.org]

• Respiratory Insufficiency

  Most cases of ALS present with asymmetric focal apendicular weakness progressing with bulbar dysfunction, quadriparesis and respiratory insufficiency leading to death in about two to three years after onset1. [scielo.br]

• Diarrhea

  One of them presented also with typical systemic signs of CTX, including chronic diarrhea, juvenile bilateral cataracts and early-onset premenopausal osteopenia (unpublished data). [scielo.br]

• Abdominal Pain

  pain; increased aminotransferases Uncommon (0.1-1% frequency):[5] pancreatitis; interstitial lung disease Rare (<0.1% frequency):[5] neutropenia; allergic reaction (including angiooedema, anaphylactoid reaction) Overdose[edit] Symptoms of overdose include [en.wikipedia.org]

• Muscle Weakness

  Symptoms include: Difficulty breathing Difficulty swallowing Choking easily Drooling Gagging Head drop due to weakness of the neck muscles Muscle cramps Muscle contractions called fasciculations Muscle weakness that slowly gets worse Commonly involves [checkorphan.org]

  The clinical presentation may be dominated by spasticity or muscle weakness and atrophy. [symptoma.com]

  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]

  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]

• Muscular Atrophy

  muscular atrophy with diaphragm involvement. [pmj.bmj.com]

  Heterozygous mutations in CHCHD10 have also been described in a case of Jokela type spinal muscular atrophy (SMAJ) and in a family with autosomal dominant isolated mitochondrial myopathy. [mgz-muenchen.de]

  Progressive muscular atrophy (PMA) is a rare condition that affects the lower motor neurons in the spinal cord. It causes slow but progressive muscle wasting, especially in the arms, legs, and mouth. [medicalnewstoday.com]

  […] to ALS in most patients.30 Limb-onset ALS is also known as flail leg or flail arm (Vulpian Bernhardt) variants and cannot be diagnosed as ALS until a minimum of 2 body regions are involved.30 Similar to limb-onset syndrome, progressive muscular atrophy [ajmc.com]

  Lateral Sclerosis Benign Focal Amyotrophy of ALS Infantile Spinal Muscular Atrophy, ALS Juvenile Spinal Muscular Atrophy, Included Kugelberg-Welander Disease Primary Lateral Sclerosis Progressive Bulbar Palsy, Included Spinal Muscular Atrophy, Type ALS [rarediseases.org]

• Muscle Twitch

  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]

  1 Disruption of the lower motor neurons (LMNs) is first exhibited by spontaneous muscle 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 [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]

• Arthritis

  […] information targeting TissGene (DrugBank Version 5.0.6, 2017-04-01) DrugBank ID Drug name Drug activity Drug type Drug status Disease information associated with TissGene (DisGeNet, 2016-06-01) Disease ID Disease name # pubmeds Source umls:C0003873 Rheumatoid Arthritis [bioinfo.uth.edu]

  Using a shared set of ∼3,000 controls, case-control comparisons were used to successfully identify independent significant association signals in bipolar disorder, coronary artery disease, Crohn's disease, rheumatoid arthritis, type 1 diabetes, and type [journals.plos.org]

  Specifically, previous observational epidemiological studies have found that ALS patients tend to have less antecedent diseases (e.g., liver/lung/thyroid disease, diabetes, hypertension, hyperlipidemia, and arthritis) as compared to the general age/gender [bmcmedicine.biomedcentral.com]

• Dystonia

  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]

  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]

  PMID 26751646 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. Siddiqi S, et al. PLoS One, 2014. [ncbi.nlm.nih.gov]

  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]

• Hyperreflexia

  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]

• Spastic Gait

  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]

  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]

  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]

• Babinski Sign

  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]

  […] of UMN disease include muscle tone increase, slow movement, and hyperreflexia.8 The presence of the Babinski 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 [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]

• Seizure

  Subcortical atrophy Pathology Motor neuron loss: Upper & Lower Neuronal or Glial cytoplasmic inclusions TDP43 pathology GRN variant: Ceroid lipofuscinosis, neuronal, 11 (CLN11) Genetics: Recessive inheritance Clinical Retinal dystrophy: Visual loss Seizures [neuromuscular.wustl.edu]

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 [7] [8] [9]. Currently, revised El Escorial criteria are applied in most clinical trials. Those criteria are as follows [7]:

• 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 [7]:

• 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 [7].

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 [10] [11]. 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 [12].

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 [13]. 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 [14]. 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 [14] [15]:

• 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 [16]. However, more rapid progression has also been described [2]. In general, ALS2 patients are likely to develop spastic tetraparesis and pseudobulbar paralysis, to become wheelchair-bound and anarthric by age 12-50 years [15]. 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 [16]. Subsequent studies allowed to relate ALS2 to the ALS2 gene, which encodes for alsin [17] [18]. 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 [4]. 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 [19]. 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 [5] [18]. 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 [15].

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 [20]. 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 [4] [6], their mean age at symptom onset being 6.5 years [15]. Both men and women may develop ALS2. In recent years, ALS2 has mainly been diagnosed in families from Middle Eastern, Mediterranean, and European countries [4], but early case reports came from North America [1] [3].

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 [21]. 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 [22].

No recommendations can be given to prevent the onset of sporadic ALS, other than avoiding certain risk factors [20]. By contrast, genealogical and genetic analyses may facilitate the identification of carriers and as-of-yet asymptomatic patients in families affected by familial ALS [10]. 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 [1] [3]. 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 [6].

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.

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