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 3 (ALS3) is one of many subtypes of familial ALS. It has been related to chromosomal locus 18q21 and is inherited in an autosomal dominant manner. ALS3 patients suffer from typical ALS, usually with lower limb onset. First symptoms manifest in adulthood.
ALS3 is clinically indistinguishable from other types of sporadic or familial ALS presenting as pure ALS, i.e., ALS3 is not associated with frontotemporal dementia, parkinsonism, or other neurodegenerative disorders. First symptoms manifest in adulthood, at a mean age of 45 years . Affected individuals claim muscle weakness, which may initially be limited to the lower limbs, causing them to stumble. As the disease progresses, they lose muscle strength in all four limbs and develop bulbar palsy. Occasionally, though, bulbar palsy may be present early in the course of the disease .
- In the long term, muscle weakness is followed by atrophy, but fasciculations are very common, too . With regards to bulbar palsy, this condition is characterized by dysarthria and dysphagia. Fasciculations of the tongue are often observed and patients may eventually show tongue amyotrophy.
- Besides those lower motor neuron signs, ALS patients may show distinct symptoms of upper motor neuron disease. Hyperreflexia and an increase of muscle tone are most characteristic and may be detected in muscles of face, larynx and pharynx (bulbar region), neck, arms, and diaphragm (cervical region), abdomen and back (thoracic region), and legs (lumbosacral region). The fact that hyperreflexia may be detected in regions of muscle atrophy is considered to be highly indicative of ALS .
Atypical features such as pain, sensory signs, and cerebellar degeneration have not been described in ALS3 patients .
Entire Body System
Signs and symptoms might include: Difficulty walking or doing normal daily activities Tripping and falling Weakness in your leg, feet or ankles Hand weakness or clumsiness Slurred speech or trouble swallowing Muscle cramps and twitching in your arms, [mayoclinic.org]
Those with limb-onset ALS may rely on a cane, walker, or wheelchair due to difficulties walking and maintaining balance. In most cases of ALS, cognitive function is not affected. [als.net]
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]
Progressive muscle weakness and atrophy leads to respiratory paralysis and death within five years of symptom onset. [symptoma.com]
ALS is a degenerative disorder characterized by the death of motor neurons in the cortex, brainstem, and spinal cord, resulting in progressive muscle weakness and atrophy and death from respiratory failure usually within 3 to 5 years of symptom onset [ncbi.nlm.nih.gov]
Patients generally die 3-5 years after the diagnosis is made because of progressive motor neuron loss and voluntary muscle weakness. The primary cause... Main content Source Citation Source Citation Genç, Deniz, et al. [go.gale.com]
However, muscle weakness can quickly progress to the arms and legs, making it difficult to distinguish between spinal and bulbar ALS. Bulbar ALS is slightly more common in women, and people over age 70. [alsnewstoday.com]
또는 본 임상시험에 참여하는 동안 파트너가 임신하는 것을 막기 위하여 적절한 피임방법을 사용하는데 동의하지 않는 남성 환자 14) 운동신경원질환중 상위운동신경원징후만 나타나는 PLS(primary lateral sclerosis)나 하위운동신경원징후만 나타나는 PMA(progressive muscular atrophy)환자 15) 출혈성 경향이 있는 자 16) 악성종양이 있는 자 17) 인공호흡기 또는 기관절개술 및 위루술을 시행된 환자 18 [cris.nih.go.kr]
[…] 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]
의료진 채종희, 임병찬, 서동인 관련 질환명 루게릭병(Lou Gehrig’s Disease),게릭병(Gehrig’s Disease),운동계질환(Motor System Disease(Focal and Slow)),근위축성 측상경화증(ALS),근육위축가쪽경화증-폴리클루코산 체(Amyotrophic Lateral Sclerosis-Polyglucosan Bodies),아랑-뒤시엔느 근육 위축증(Aran-Duchenne Muscular Atrophy) [raredisease.snuh.org]
atrophies and related syndromes V123 의료비(급여부분) 간병비 호흡보조기 또는 기침유발기 보장구 구입비 [enif.kr]
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]
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). [malacards.org]
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 early signs and symptoms of ALS include: muscle cramps and muscle twitching weakness in hands, legs, feet or ankles difficulty speaking or swallowing The senses, including hearing, sight, smell, taste, and touch, are not affected by ALS. [als.net]
Over the course of the disease, they develop muscle weakness and atrophy in all four limbs, and probably bulbar palsy associated with dysarthria and dysphagia. [symptoma.com]
This review discusses the characteristics of dysarthria and symptom management for these conditions. [jkslp.org]
ALS is a disease of middle and late onset and its common incipient symptoms are gait disturbance, limb weakness, dysarthria or dysphagia. Death usually occurs with in 3 years from onset. No medical therapy leads the duration of illness. [ci.nii.ac.jp]
[…] perish, the ventral roots thin and the limb, tongue, and oropharynx muscles become amyotrophic.1 However, one-third of patients experience bulbar disease, manifesting as challenges with speaking, chewing, or swallowing.1 Signs of bulbar disease include dysarthria [ajmc.com]
Affected individuals may develop slurred speech (dysarthria) and, later, difficulty chewing or swallowing (dysphagia). [malacards.org]
The fact that hyperreflexia may be detected in regions of muscle atrophy is considered to be highly indicative of ALS. Atypical features such as pain, sensory signs, and cerebellar degeneration have not been described in ALS3 patients. [symptoma.com]
Hyperreflexia and spasticity appears as upper motor neuron signs and weakness, atrophy and fasciculations as lower motor neuron signs. [medeniyetmedicaljournal.org]
[…] 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]
Spastic paresis could be present at the beginning or in the fully developed stage of the disease. [intechopen.com]
ALS HNRNPA1 (Heterogeneous Nuclear Ribonucleoprotein A1; 12q13.13) – 2013 AD ALS20, IBM with early-onset Paget disease without FTD type 3 DCTN1 (Dynactin 1; 2p13.1) – 2003 AD ALS, Perry syndrome, Distal hereditary motor neuronopathy with vocal paresis [scielo.br]
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  .
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 . 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  :
- 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.
In 2002, Hand and colleagues studied a French family 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 have found highly significant linkage of the disease to a determined locus on chromosome 18. The respective locus was flanked by markers D18S846 and D18S1109, comprised 8 Mbp and had not been associated with ALS before . It would later be defined as the genetic hallmark of ALS3 .
Data regarding the role of locus 18q21 in ALS3 pathogenesis are not available. Low penetrance has been reported for ALS3  and in this context, it turns out increasingly difficult to evaluate the influence of genetic and environmental factors on the development of ALS3: Family members may carry the respective sequence anomalies, but may not develop the disease because of low gene expression or because they have not been exposed to triggering environmental factors. With regards to such environmental influences, the following have been identified and confirmed as risk factors for ALS :
ALS is the most common motor neuron disease in adults; it affects both men and women. ALS patients' mean age at symptom onset is 60 years . By contrast, members of the French family affected by ALS3 were reported to manifest first symptoms at a mean age of 45 years . 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, as is the case with ALS3. Penetrance, however, varies largely: Hand and colleagues described "incomplete and age-dependent penetrance" for ALS3. By contrast, expressivity seems to be relatively stable, as can be deduced from the uniformity of clinical presentation of ALS3 patients .
Despite extensive research, the pathophysiology of ALS remains poorly understood. The death of motor neurons is the hallmark of the disease and entails muscle weakness and atrophy, but its causes could not yet be clarified. Neuronal death has been speculated to be due to the accumulation of protein aggregates which, in turn, consist of abnormal proteins. Sequence anomalies, e.g., of regulatory or protein-coding genes on chromosomal locus 18q21, 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 .
No recommendations can be given to prevent the onset of sporadic ALS, other than avoiding the risk factors mentioned above. By contrast, genetic analyses may facilitate the identification of carriers and as-of-yet asymptomatic patients in families affected by familial ALS . Prenatal diagnoses may become feasible if the disease can be related to well-defined DNA sequence anomalies, but this does not yet apply to ALS3. Further research is required to identify those genes on chromosomal locus 18q21 that predispose for the development of this type of ALS.
ALS is the most common motor neuron disease. ALS patients may be genetically predisposed to develop the disease, and distinct chromosomal loci have been associated with its familial form. While studying the background of ALS in a large French family, Hand et al. found the disease to be linked to chromosomal locus 18q21 . Later on, ALS linked to locus 18q21 has been designated ALS3 . Presumably, mutations of genes in this locus confer susceptibility to environmental risk factors that eventually trigger disease onset in adulthood . But even though much has been speculated, very little is actually known about the etiology and pathogenesis of ALS3 and other types of ALS, other than that it is characterized by the death of motor neurons in the cortex, brain stem, and spinal cord. The disease follows a progressive course and ultimately leads to death by respiratory failure.
Familial ALS may be associated with frontotemporal dementia, but this does not apply to ALS3. The clinical presentation of ALS3 is that of "pure ALS", i.e., in early stages of the disease, patients experience muscle weakness, particularly in their legs. Over the course of the disease, they develop muscle weakness and atrophy in all four limbs, and probably bulbar palsy associated with dysarthria and dysphagia. Besides these lower motor neuron signs, upper motor neuron signs are characteristic of ALS: ALS patients suffer from hyperreflexia and present with an increased muscle tone, and while those complaints are initially limited to certain body regions, they spread in a similar manner as amyotrophy. As for ALS3, the intrafamilial variability of clinical presentation is low .
Diagnosis of ALS relies on well-defined diagnostic criteria and is mainly clinical, with the identification of ALS3 requiring additional genetic analyses. Mean survival times don't exceed five years and patients should be treated by a multidisciplinary team to preserve life quality for as long as possible, despite the fact that there is no cure for this disease.
Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease that typically manifests in adulthood. Little is known about the causes of ALS, but at least a minor proportion of ALS patients seems to be genetically predisposed. This condition is reflected in an increased familial incidence, i.e., relatives of an ALS patient carrying certain gene defects are much more likely to develop the disease than the general population. In this context, ALS has been associated with distinct chromosome and gene anomalies. For instance, there is a large European family whose members present sequence anomalies on the long arm of chromosome 18. This particular condition has later been designated amyotrophic lateral sclerosis 3 (ALS3).
With regards to clinical presentation, diagnosis, treatment, and prognosis, ALS3 doesn't differ from classical ALS.
- Hand CK, Khoris J, Salachas F, et al. A novel locus for familial amyotrophic lateral sclerosis, on chromosome 18q. Am J Hum Genet. 2002; 70(1):251-256.
- 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.
- 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.
- 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.
- Talbott EO, Malek AM, Lacomis D. The epidemiology of amyotrophic lateral sclerosis. Handb Clin Neurol. 2016; 138:225-238.
- Gros-Louis F, Gaspar C, Rouleau GA. Genetics of familial and sporadic amyotrophic lateral sclerosis. Biochim Biophys Acta. 2006; 1762(11-12):956-972.
- 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.