With regards to the specific presentation of ALS11, few general statements can be derived from the low number of case descriptions available. The youngest patient reported so far presented at age of 40, the oldest at the age of 77 [1] [2]. ALS initially manifests as limb muscle weakness or dysarthria and dysphagia, with the latter being characteristic of bulbar palsy. Both ALS11 patients who have been diagnosed with definite ALS suffered from bulbar-onset disease, while another two individuals with probable and possible ALS, respectively, claimed upper limb weakness [1] [2]. It has been stated that ALS11 patients show asymmetric disease progression, although further details have not been revealed. In general, ALS progression causes affected individuals to lose muscle strength in all four limbs and to develop bulbar palsy, if that didn't occur during early stages of the disease. Muscle weakness is followed by atrophy, and fasciculations are very common, too [3]. Fasciculations of the tongue are often observed and patients may eventually show tongue amyotrophy. The patients' sensibility is usually unaltered, although minor sensory impairment has been reported [1].

Besides those lower motor neuron signs, ALS patients may show distinct symptoms of upper motor neuron disease. Indeed, a striking prominence of corticospinal findings is assumed to be characteristic of ALS11 [1]. Hyperreflexia and an increase of muscle tone are most typical 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 [3].

ALS11 has not yet been reported to be associated with neurodegenerative disorders such as frontotemporal dementia or parkinsonism. Chow et al. claimed "the absence of dementia" to be a characteristic feature of ALS11, although one of their patients had experienced "subtle personality changes" for two years previous to their death [1]. Additionally, a possibly pathogenic FIG4 mutation has been identified in a single ALS patient who did suffer from frontotemporal dementia [4].

• Respiratory Insufficiency

  Progressive weakness leads to increasing disability and respiratory insufficiency, resulting in death. [jamanetwork.com]

  One study (Pinto 1999) was a controlled study of exercise in ALS patients with respiratory insufficiency. One study (Sivak 1982) was an anecdotal study. [cochranelibrary.com]

  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]

  Safety and efficacy of diaphragm pacing in patients with respiratory insufficiency due to amyotrophic lateral sclerosis (DiPALS): a multicentre, open-label, randomised controlled trial. [mayoclinicproceedings.org]

• Hypophonia

  Hoarseness, hypophonia, short phonation time, nonproductive cough, stridor, sudden laryngeal spasms, choking, or paroxysmal dyspnea should raise suspicion and justify prompt referral to an otolaryngologist. [jamanetwork.com]

• Stridor

  Symptoms of vocal cord dysfunction range from hoarseness, hypophonia, and short phonation time to nocturnal nonproductive cough and attacks of inspiratory stridor and dyspnea.3-6Inspiratory stridor is defined as a harsh, strained sound with a higher pitch [jamanetwork.com]

• Dysphagia

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

  ALS initially manifests as limb muscle weakness or dysarthria and dysphagia, with the latter being characteristic of bulbar palsy. [symptoma.com]

  Patients with bulbar onset ALS usually present with dysarthria and dysphagia for solids or liquids. Limb symptoms can develop almost simultaneously with bulbar symptoms, and in the vast majority of cases will occur within 1-2 years. [orpha.net]

  A 69-year-old man was referred to our neurology department with progressive dysarthria, dysphagia, and pseudobulbar affect present for 1.5 years. [jamanetwork.com]

• Tongue Atrophy

  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]

  There was no spontaneous activity in the tongue and rectus abdominal muscle. [journals.lww.com]

• Muscle Weakness

  Spasticity and muscle cramps may be resolved by muscle relaxants like quinine, levetiracetam, baclofen, or dantrolene. Weakness of the respiratory muscles requires ventilatory assistance. [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]

  It refers to a group of progressive, neurological diseases that cause dysfunction in the nerves that control muscle movement. This leads to muscle weakness and changes in how the body works. [medicalnewstoday.com]

  Degeneration here can cause: limp muscles, or flaccid weakness muscle wasting twitching breathing problems caused by weakness in the diaphragm and other respiratory muscles Early signs of ALS may include problems performing everyday tasks. [healthline.com]

• Muscular Atrophy

  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]

  Very early-onset (generally before 6 years up to adolescence) with prominent distal muscular atrophy and eventually cerebellar ataxia are clues to diagnosis, mimicking spinal muscular atrophy with pyramidal signs and some forms of hereditary distal motor [scielo.br]

  […] 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]

  atrophy Pseudobulbar paralysis Flail arm Multisystem disorders ALS + PNL + EOM & Extrapyramidal Δ Fronto-Temporal Dementia Multiple system atrophy Polyglucosan body disease Western Pacific ALS ALS-PD1 ALS-PD2 MRI: FLAIR Motor Neuron Disease (Late) Cerebral [neuromuscular.wustl.edu]

• Muscle Twitch

  The earliest symptoms include muscle twitching, cramping, stiffness, or weakness. Affected individuals may develop slurred speech (dysarthria) and, later, difficulty chewing or swallowing (dysphagia). [ncbi.nlm.nih.gov]

  in some cases, genetic cause.[2] Early symptoms may include muscle twitching, cramping, stiffness, or weakness, slurred speech, and/or difficulty chewing or swallowing. [rarediseases.info.nih.gov]

• Suggestibility

  Limited and Suggestive Evidence of an Association This category would indicate that evidence is suggestive of an association between military service and ALS in humans, but the body of evidence is limited by the inability to rule out chance and bias, [nap.edu]

  suggested that PP may be of use in cryoglobulinemic polyneuropathy. [nbscience.com]

  Millecamps S et al. [43] suggested that FUS patients had a shorter lifespan, more rapid disease, younger onset than other mutations. 5. [intechopen.com]

• Abnormal Behavior

  As already mentioned, abnormal behaviors are found in ALS patients along the FTD spectrum. [frontiersin.org]

• Dysarthria

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

  ALS initially manifests as limb muscle weakness or dysarthria and dysphagia, with the latter being characteristic of bulbar palsy. [symptoma.com]

  Patients with bulbar onset ALS usually present with dysarthria and dysphagia for solids or liquids. Limb symptoms can develop almost simultaneously with bulbar symptoms, and in the vast majority of cases will occur within 1-2 years. [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]

• Paresis

  Vocal cord abductor paresis and laryngospasm in ALS are rarely described in the neurological literature. [jamanetwork.com]

  Spastic paresis could be present at the beginning or in the fully developed stage of the disease. [intechopen.com]

  Disease with Ophthalmoplegia & Extrapyramidal Disorders 4 Clinical Onset 4th to 7th decade Often bulbar dysfunction: Dysarthria Motor Weakness: Bulbar, Arms & Legs Upper motor neuron signs Variably present Tendon reflexes: Brisk or Normal Ocular Gaze paresis [neuromuscular.wustl.edu]

  The D90A-homozygous mutation is associated with slowly progressive paresis in the legs that gradually spreads up to the arms, thoracic and bulbar musculature, with atypical non-motor features such as ataxia, neuralgic, aching pain, heat sensations, and [translationalneurodegeneration.biomedcentral.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]

• Hyperreflexia

  Additionally, ALS causes hyperreflexia and an increase of muscle tone. Those so-called pyramidal signs may predominate the clinical picture in case of ALS11. Unfortunately, there is no cure for ALS. [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]

  Disease progression comprised atrophic tetraplegia and dysarthria, with hyperreflexia in the limbs but only lower motor neuron signs in the bulbar region. [jamanetwork.com]

  […] 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]

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 [5] [6] [7]. Currently, revised El Escorial criteria are applied in most clinical trials. Those criteria are as follows [6]:

• 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 [6]:

• 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 [6]. However, FIG4 mutations have also been detected in patients suffering from sporadic ALS, primary lateral sclerosis, and Charcot-Marie-Tooth disease type 4J, among others [2]. This fact highlights the importance of genetic studies and the necessity of interpreting their results in the context of anamnestic and clinical data.

Even though molecular biological analyses are not required for the diagnosis of ALS, they are necessary to determine the subtype. Indeed, the identification of sequence anomalies may accelerate the diagnostic process: If FIG4 mutations are known to cause ALS in a determined family, a more targeted approach to diagnosis becomes feasible. By contrast, the identification of FIG4 mutations in patients suffering from sporadic ALS may improve the understanding of the pathophysiology of the disease. Additionally, ALS patients known to carry mutations that possibly predispose for frontotemporal dementia or parkinsonism - as is the case with FIG4 mutations - may be referred for neuropsychological tests. In conclusion, genetic analyses provide both physicians and scientists with an appropriate tool to identify carriers and family members at risk, and to promote research [8] [9].

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 [10]. The application of α-tocopherol has been proposed as a complementary measure to slow down disease progression in milder cases [11]. 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 [3] [11]:

• 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.

If ALS11 patients suffer from associated neurodegenerative disorders such as dementia or parkinsonism, these should be treated according to the respective guidelines. Unfortunately though, they can neither be cured at this moment.

Progressive muscle weakness and atrophy eventually leads to respiratory paralysis and death. ALS11 has once been considered a rapidly progressive variant of ALS, with mean survival times of less than two years [1]. However, ALS11 has later been characterized as a slowly progressive form of ALS, with the possibility of long-term survival [2]. For comparison only: Total mean survival times of ALS patients were estimated to be three to four years [12].

In 2009, Chow and colleagues reported three unrelated patients who suffered from familial ALS and who carried mutations in the FIG4 gene [1]. This gene has previously been implicated in the pathogenesis of Charcot-Marie-Tooth disease type 4J and encodes for phosphatidylinositol 3,5-bisphosphate 5-phosphatase, an enzyme that is likely to affect a myriad of intracellular signaling cascades [13] [14]. It is best known, though, for its role in vesicle trafficking: Deficiencies cause defective vesicle fission and subsequent vesicle enlargement, which results in an impairment of vesicle transport. In detail, loss-of-function mutations of the FIG4 gene entail a reduction of intracellular phosphatidylinositol 3,5-bisphosphate levels [15].

Besides genetic factors, environmental influences are assumed to play a major role in ALS pathogenesis [1]. With regards to such environmental influences, the following have been identified and confirmed as risk factors for ALS [12]:

• Exposure to metals like lead and mercury
• Glutamate toxicity
• Exposure to pesticides
• Smoking
• Military service

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 [12]. This is in agreement with data published regarding ALS11. Individuals aged 40 to 77 years presented with first symptoms of ALS [1] [2] [4]. 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 [12]. About 10% of all those cases are familial, but FIG4 mutations have only ever been related to ALS in a handful of cases: Chow and colleagues have been the first ones to relate FIG4 mutations to ALS and detected such mutations in three patients of European ancestry [1]. In 2017, Osmanovic et al. identified FIG4 mutations in distinct members of a European family affected by ALS [2]. And only recently, targeted genetic analyses allowed for the identification of FIG4 mutations in ALS patients by yet another research group [4]. Nevertheless, the pathogenetic relevance of FIG4 mutations remains a matter of debate [4]. Familial ALS is generally inherited in an autosomal dominant manner; autosomal dominant inheritance with incomplete penetrance has been reported for ALS11 [2].

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 misfolded proteins. Sequence anomalies, e.g., of genes like FIG4, 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 [16].

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 [8]. Prenatal diagnoses may become feasible if the disease can be related to well-defined DNA sequence anomalies, but this does not yet apply to ALS11.

ALS is the most common motor neuron disease. 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 FIG4 gene, which encodes for protein the enzyme pphosphatidylinositol 3,5-bisphosphate 5-phosphatase. ALS linked to mutations in the FIG4 gene has been designated ALS11 [3] [17].

Few cases of ALS11 have been reported to date [1] [2]. Affected individuals suffer from ALS with prominent pyramidal signs, and both spinal and bulbar onset have been described [1]. ALS11 has been described as a rapidly progressive variant of ALS, but prolonged survival has also been reported [1] [2]. Contradictory data exist regarding the association of ALS11 with other neurodegenerative disorders [1] [4].

Diagnosis of ALS relies on well-defined diagnostic criteria and is mainly clinical, with the identification of ALS11 requiring additional genetic analyses. Data regarding mean survival times range between less than two years and several decades [1] [2]. In any case, 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 are several families of different origin whose members present mutations in a gene called FIG4. This particular condition has later been designated amyotrophic lateral sclerosis 11 (ALS11).

Only a handful of ALS11 cases have been reported to date. In general, ALS patients are known to primarily experience muscle weakness, which may initially be limited to a single arm or leg, or to the laryngeal and pharyngeal muscles. Eventually though, affected individuals lose muscle strength in all four limbs and many develop dysarthria and dysphagia as a result of bulbar involvement. Additionally, ALS causes hyperreflexia and an increase of muscle tone. Those so-called pyramidal signs may predominate the clinical picture in case of ALS11.

Unfortunately, there is no cure for ALS. ALS11 follows a progressive course and eventually leads to respiratory paralysis and death.

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