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]

  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]

  Spasticity is usually accompanied by HYPERREFLEXIA and variable degrees of MUSCLE WEAKNESS. [ncbi.nlm.nih.gov]

• Difficulty Walking

  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]

  walking Distal muscle weakness And another 10 symptoms. [mendelian.co]

  Early reports highlight the diagnostic difficulty in children and the distance from our current genetically defined understanding of such disorders ( Gordon and Delicati, 1928 ; Lelong et al., 1932 ). [academic.oup.com]

  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]

  The earliest symptoms may include twitching, cramping, or stiffness of muscles; muscle weakness affecting an arm or a leg; slurred and nasal speech; or difficulty chewing or swallowing. [anmjournal.com]

• Asymptomatic

  Interestingly, 22% (11/49) of the patients had unambiguous upper and lower motor neuron signs but were asymptomatic at the time of initial evaluation. [academic.oup.com]

  The patient was asymptomatic until the bulbar dysfunction appeared, and then clinical signs of upper and lower motor neuron deficits in the cervical, thoracic, and lumbar regions developed. [journals.lww.com]

  By contrast, genealogical and genetic analyses may facilitate the identification of carriers and as-of-yet asymptomatic patients in families affected by familial ALS. [symptoma.com]

• Swelling

  Swellings were prominent around motor neurons, probably representing changes in presynaptic terminals. [jhu.pure.elsevier.com]

  Axonal swellings in the corticospinal tracts in amyotrophic lateral sclerosis. Acta Neuropathol 1990;80:222-6. 8. Ben Hamida M, Hentati F, Ben Hamida C. Hereditary motor system diseases (chronic juvenile amyotrophic lateral sclerosis). [pediatricneurosciences.com]

  In January 2002, complaining on this occasion of right lower leg swelling and pain, the patient was readmitted with an ANC of zero. [kundoc.com]

  Neuropathological remarks include neurofilamentous swelling of proximal axons with reduced calibre of distal axons and axonal wallerian degeneration, accumulation of neurofilament and peripherin in axons and perikarium, reactive glyosis, Lewy body-like [scielo.br]

• Amyloidosis

  An autosomal dominant inherited form of amyloidosis. [icd10data.com]

  Erythrokeratodermie GJB4, LOR Erythromelalgie SCN9A Escobar syndrome, Multiple pterygium syndrome, lethal type CHRNG Exudative vitreoretinopathy FZD4, NDP, TSPAN12 Facio-scapulo-humerale Dystrophie FSHD Factor XIII deficiency F13A1, F13B Familial Transthyretin Amyloidosis [meduniwien.ac.at]

  Rousseau F, Schymkowitz J, Serrano L (2006) Protein aggregation and amyloidosis: confusion of the kinds? Current Opinion in Structural Biology 16, 118–126: View Article Google Scholar 27. [journals.plos.org]

• Pneumonia

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

  Bilateral lobectomy is done for Aspergillus fumigatus pneumonia and Rx with IV amphotericin for 4 months. [kundoc.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]

  […] islet autotransplantation Acute pancreatitis: Acute peritonitis Macroamylasemia Macrolipasemia Malabsorption syndromes/processes Perforated viscus Chronic pancreatitis: Ampullary carcinoma Cholangitis Cholecystitis Chronic gastritis Community-acquired pneumonia [centogene.com]

  Because they do not have the strength to cough or clear their throats, people with advanced ALS are prone to aspiration pneumonia. In fact, most people with ALS will ultimately pass away due to aspiration or respiratory failure. [verywell.com]

• Dysphagia

  Affected individuals may develop slurred speech (dysarthria) and, later, difficulty chewing or swallowing (dysphagia). [ncbi.nlm.nih.gov]

  Lateral Sclerosis Type 5 29 SPG11 MalaCards organs/tissues related to Amyotrophic Lateral Sclerosis Type 5: 40 Spinal Cord Articles related to Amyotrophic Lateral Sclerosis Type 5: # Title Authors PMID Year 1 Pharyngeal residue in neurogenic oropharyngeal dysphagia [malacards.org]

  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 have difficulty swallowing (dysphagia), and speech may be slowed. [rarediseases.org]

• Muscle Weakness

  As the disease progresses, muscle weakness spreads to the tongue, to pharyngeal and laryngeal muscles. ALS5 patients then develop dysarthria and dysphagia. [symptoma.com]

  Spasticity is usually accompanied by HYPERREFLEXIA and variable degrees of MUSCLE WEAKNESS. [ncbi.nlm.nih.gov]

  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]

  Orlacchio Published in Brain : a journal of neurology 2016 DOI: 10.1093/brain/awv320 Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot [semanticscholar.org]

• Muscular Atrophy

  […] lateral sclerosis G12.24 Familial motor neuron disease G12.25 Progressive spinal muscle atrophy G12.29 Other motor neuron disease G12.8 Other spinal muscular atrophies and related syndromes G12.9 Spinal muscular atrophy, unspecified G13 Systemic atrophies [icd10data.com]

  […] 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]

  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]

  Impaired BMP/TGF-β signaling was found in some neurodegenerative diseases including ALS, Huntington disease, hereditary spastic paraplegias, spinal muscular atrophy, spinobulbar muscular atrophy, and Alzheimer disease.23 Familial ALS and sporadic ALS [journals.lww.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]

• Muscle Twitch

  Fasciculations may be visualized as a muscle twitch or dimpling under the skin, but usually do not generate sufficient force to move a limb. [ncbi.nlm.nih.gov]

  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). [icdlist.com]

  Lower motor neuron signs include muscle wasting (atrophy), weakness, and muscle twitches. [5] Facial spasticity, slurred speech ( dysarthria ), and a spastic gait are common. [rarediseases.info.nih.gov]

  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]

• Leg Cramp

  Leg cramps may occur during the night, most frequently in the calf and/or thigh muscles. Gradually, additional muscles become involved. Amyotrophic lateral sclerosis may progress quickly or slowly. [rarediseases.org]

• Dysarthria

  Lower motor neuron signs include muscle wasting (atrophy), weakness, and muscle twitches. [5] Facial spasticity, slurred speech ( dysarthria ), and a spastic gait are common. [rarediseases.info.nih.gov]

  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]

  Most patients present as limb-onset ALS (70%), and the remaining ones present as bulbar-onset ALS, which usually manifests with dysarthria and/or dysphagia. [journals.lww.com]

  This review discusses the characteristics of dysarthria and symptom management for these conditions. [jkslp.org]

  Affected individuals may develop slurred speech (dysarthria) and, later, difficulty chewing or swallowing (dysphagia). [ncbi.nlm.nih.gov]

• Tremor

  Signs of parkinsonism include unusually slow movements (bradykinesia), stiffness, and tremors. Affected members of the same family can have different combinations of signs and symptoms. [ Read More ] [icdlist.com]

  Diagnosis The diagnosis of ALS is primarily based on the symptoms and signs Weakness, often beginning in one area Muscle tremors, spasms, twitching, or loss of muscle tissue Twitching of the tongue (common) Abnormal reflexes Stiff or clumsy walk Increased [checkorphan.org]

  Signs of parkinsonism include unusually slow movements (bradykinesia), stiffness, and tremors. [ncbi.nlm.nih.gov]

  The physical exam may show: Weakness, often beginning in one area Muscle tremors, spasms, twitching, or loss of muscle tissue Twitching of the tongue (common) Abnormal reflexes Stiff or clumsy walk Decreased or increased reflexes at the joints Difficulty [medlineplus.gov]

  There may be muscle tremors, spasms, twitching, or muscle atrophy (loss of tissue). Atrophy and twitching of the tongue are common. Usually, there is no significant change in sensation. The gait may be stiff or clumsy. [healthengine.com.au]

• 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]

  […] develop symptoms of both upper and lower motor dysfunction, but the symptoms, rate of progression, and severity varies from person to person. [5] Signs of upper motor neuron dysfunction include the Babinski sign, muscle spasms, and overactive reflexes (hyperreflexia [rarediseases.info.nih.gov]

  Spasticity is usually accompanied by HYPERREFLEXIA and variable degrees of MUSCLE WEAKNESS. [ncbi.nlm.nih.gov]

  Clinical Features Top most frequent phenotypes and symptoms related to Amyotrophic Lateral Sclerosis 5, Juvenile; Als5 Muscle weakness Spasticity Cognitive impairment Hyperreflexia Dysarthria Skeletal muscle atrophy Hypoplasia of the corpus callosum Babinski [mendelian.co]

• Slurred Speech

  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]

  Affected individuals may develop slurred speech (dysarthria) and, later, difficulty chewing or swallowing (dysphagia). [icdlist.com]

  Sometimes the initial problem can be one of slurred speech or difficulty swallowing. As ALS progresses, though, more and more symptoms are noticed. The following are the most common symptoms of ALS. [columbianeurology.org]

  Damage to the medulla can cause: slurred speech hoarseness difficulty swallowing emotional lability, which is characterized by excessive emotional reactions such as laughing or crying a loss of tongue muscle contour, or tongue atrophy excess saliva difficulty [healthline.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]

  Lower motor neuron signs include muscle wasting (atrophy), weakness, and muscle twitches. [5] Facial spasticity, slurred speech ( dysarthria ), and a spastic gait are common. [rarediseases.info.nih.gov]

  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]

  gait, diffuse fasciculations, then bilateral arm wasting Warner (1926) 40 (female) Both legs spastic and weak, later both arms finally bulbar Wechsler et al. (1929) 48 (male) Right foot drop, then both legs, diffuse fasciculations, then bulbar Wechsler [academic.oup.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 [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].

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.

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

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].

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].

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.

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.

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].

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.

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