ALS9 is clinically indistinguishable from other types of sporadic or familial ALS, although it is occasionally associated with frontotemporal dementia or parkinsonism [1]. First symptoms manifest in adulthood. Progressive lower and upper motor neuron loss results in bulbar palsy, muscle weakness followed by atrophy, hyperreflexia and an increase of muscle tone. Presenting symptoms vary and while bulbar-onset has been described as a common feature of ALS9 [2], this assessment could not be confirmed in later studies [3].

In case of limb-onset ALS, patients may initially claim difficulties with writing or walking. Muscle weakness subsequently spreads from distal regions to the proximal musculature, eventually causing tetraplegia [4]. Bulbar palsy is a common complication of limb-onset ALS9, but may also precede the impairment of hand and feet function. Bulbar involvement is associated with dysarthria and dysphagia. Additional symptoms typical of ALS, such as fasciculations, spasticity, and hyperreflexia, have also been described in ALS9 patients [3] [5].

• Weakness

  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. [symptoma.com]

  Facioscapulohumeral childhood to early adults Symptoms include facial muscle weakness and weakness with some wasting of shoulders and upper arms; progression is slow with periods of rapid deterioration; life span may be many decades after onset. [urmc.rochester.edu]

  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]

• 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]

• Fever

  Febrile neutropenia (ANC<1000/mm3 and fever ≥38.5°C). Grade 4 thrombocytopenia >48 hour duration or with bleeding requiring platelet transfusion. [bmjopen.bmj.com]

• Respiratory Insufficiency

  insufficiency R 1..1 Indent82953-1 Total score [ALSFRS-R] R {score} Fully-Specified Name Component Amyotrophic lateral sclerosis functional rating scale - revised (ALSFRS-R) Property - Time Pt System ^Patient Scale - Method ALSFRS-R Basic Attributes [loinc.org]

  Grade 4: Need assistance in everyday life; presence of respiratory insufficiency, difficulty in coughing out sputum or dysphagia. Grade 5: Bedridden and full life support equipment required. [bmjopen.bmj.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]

• Dysphagia

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

  Her husband was 73 years old when he noted dysphagia in 1999. Deep tendon reflexes were brisk in the 4 limbs with diffuse fasciculations and amyotrophy. [jamanetwork.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]

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

• Muscular Atrophy

  Spinal muscular atrophies: Amyotrophic lateral sclerosis (ALS), or motor neuron disease Infantile progressive spinal muscular atrophy Intermediate spinal muscular atrophy Juvenile spinal muscular atrophy Adult spinal muscular atrophy Inflammatory myopathies [urmc.rochester.edu]

  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]

  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]

  Progressive Muscular Atrophy (PMA) - a progressive neurological disease in which the lower motor neurons (nerve cells) deteriorate. [hopkinsmedicine.org]

• 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]

  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]

  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]

• Muscle Spasticity

  DO ID DOID:332 Description A motor neuron disease that is characterized by muscle spasticity, rapidly progressive weakness due to muscle atrophy, difficulty in speaking, swallowing, and breathing. [yeastgenome.org]

  spasticity and stiffness, and modest muscle atrophy.1 PLS cannot be diagnosed as ALS until there is evidence of LMN dysfunction of at least 1 limb or region and it progresses to ALS in most patients.30 Limb-onset ALS is also known as flail leg or flail [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]

• Arm Weakness

  Common symptoms include: difficulty carrying out daily activities, including walking increased clumsiness weakness in the feet, hands, legs, and ankles cramping and twitching in the arms, shoulders, or tongue difficulty maintaining good posture and holding [medicalnewstoday.com]

• Dysarthria

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

  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]

  Bulbar involvement was present with dysarthria, dysphagia, emotional lability, and amyotrophy of the tongue. The patient died after 20 months of disease. His wife had died of ALS in 1984 at age 67 years. [jamanetwork.com]

  Bulbar involvement is associated with dysarthria and dysphagia. Additional symptoms typical of ALS, such as fasciculations, spasticity, and hyperreflexia, have also been described in ALS9 patients. [symptoma.com]

• Hyperreflexia

  Additional symptoms typical of ALS, such as fasciculations, spasticity, and hyperreflexia, have also been described in ALS9 patients. [symptoma.com]

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

  […] 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]

  In 1977, there were diffuse fasciculations with generalized hyperreflexia and amyotrophy of the arms and the left leg. Myography showed diffuse denervation in the 4 limbs. The disease progressed with tetraplegia and bulbar involvement. [jamanetwork.com]

• Limb Weakness

  ALS damages the corticospinal tract and causes spastic limb weakness. The anterior horn is the front part of the spinal cord. [healthline.com]

  […] of limbs (60-80%), bulbar symptoms (20%), respiratory muscle weakness (1-3%), generalized weakness in limbs and bulbar muscles (1-9%), axial onset with muscle weakness, muscle atrophy and fasciculations.[7,8] Muscle cramping with pain presents in 7-12% [nnjournal.net]

  The beginning of symptoms was weakness in upper limbs, without involvement of lower limbs or bulbar functions. [intechopen.com]

• Paresis

  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]

• Facial Muscle Weakness

  Facioscapulohumeral childhood to early adults Symptoms include facial muscle weakness and weakness with some wasting of shoulders and upper arms; progression is slow with periods of rapid deterioration; life span may be many decades after onset. [urmc.rochester.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 [6] [7] [8]. 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, ANG mutations have been detected in patients suffering from apparently sporadic ALS [2] [9]. However, ANG mutations have been detected in patients suffering from ALS clinically different from ALS8 [10].

This fact highlights the importance of genetic studies. 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: If VAPB mutations are known to cause ALS in a determined family, a more targeted approach to diagnosis becomes feasible. Thus, genetic analyses provide both physicians and scientists with an appropriate tool to identify carriers and family members at risk, and to promote research [11] [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 [14]. The administration of neurotrophic factors such as angiogenin and vascular endothelial growth factor may compensate for inherited deficiencies and has recently been discussed as an approach to ALS therapy, but clinical trials have yet to be carried out [15].

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 [10] [14]:

• 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 ALS9 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.

ALS9 has been reported to follow a rapidly progressive course. Still, it remains unclear if ANG mutations are the sole drivers of ALS progression in patients carrying pathogenic alleles. The identification of additional risk factors would facilitate the establishment of a scoring system that could possibly be used to make a more reliable prognosis: Patients may survive over ten years but ALS9 may also lead to death from respiratory failure within less than three years [4].

ALS9 is inherited in an autosomal dominant manner and has been related to the ANG gene, which encodes for angiogenin. Angiogenin is a potent enhancer of blood vessel formation. To date, few families are known to be affected by ALS9, and it the establishment of genotype-phenotype correlations is difficult because data are scarce. It should be noted, though, that specific ANG mutations have been identified in patients suffering from rapidly progressive ALS and healthy individuals [10]. This raises the question if ANG mutations are indeed the sole cause of ALS9, or if they should rather be considered a risk factor for a multifactorial disease [3].

ALS is the most common motor neuron disease in adults. 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 [16]. About 10% of all those cases are familial. Familial ALS is generally inherited in an autosomal dominant manner, as is the case with ALS9. Penetrance, however, varies largely between distinct types of ALS. For ALS9, incomplete penetrance has been postulated because a 75-year-old carrier of a pathogenic ANG mutation had not yet developed any symptoms [1]. Both men and women may develop ALS9. ALS patients' mean age at symptom onset is 60 years [16]. This is in agreement with data published regarding ALS9 [1] [3]. ALS9 has mainly been diagnosed in families from Central and Northern Europe, but ANG mutations have also been associated with North American ALS cases [10].

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 ANG, 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 [17].

Mutations in genes ANG and VEGF, both of which are involved in the regulation of angiogenesis, have been considered risk factors for ALS even before they were identified in any patient. For ANG mutations, this hypothesis has been confirmed when Greenway and colleagues associated a single nucleotide polymorphism of ANG with an increased risk for ALS [9]. With regard to VEGF mutations, such evidence has been provided some years later [18]. Both angiogenin and vascular endothelial growth factor, the products of ANG and VEGF, are potent enhancers of angiogenesis. Thus, loss-of-function mutations in ANG and VEGF interfere with angiogenesis and may lead to chronic neuronal ischemia. It has also been speculated that the absence of trophic effects otherwise exerted by these mediators may be implicated in the pathogenesis of ALS [19] [20] [21]. Further research is required to prove or refute these hypotheses, and to clarify how - and if - reduced angiogenesis leads to the formation of intracellular protein aggregates as described above [5].

No recommendations can be given to prevent the onset of sporadic ALS, other than avoiding certain risk factors [16]. By contrast, genealogical and genetic analyses may facilitate the identification of carriers and as-of-yet asymptomatic patients in families affected by familial ALS [11]. Prenatal diagnoses may become feasible if the disease can be related to well-defined DNA sequence anomalies, but have not yet been reported for ALS9 [3].

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 ANG gene, which encodes for angiogenin. ALS linked to mutations in the ANG gene has been designated ALS9. Interestingly, linkage of ALS to ANG has been postulated years before the first case report of an affected family has been published [1] [9].

The clinical presentation of ALS9 doesn't differ from that of classical sporadic ALS. Bulbar onset is common but ALS9 patients also suffer from limb muscle weakness and show pyramidal signs [10]. Familial ALS may be associated with frontotemporal dementia or parkinsonism, as has been reported in isolated cases of ALS9 [1].

Diagnosis of ALS relies on well-defined diagnostic criteria and is mainly clinical, with the identification of ALS9 requiring additional genetic analyses. ALS9 has been reported to follow a rapidly progressive course, but data regarding disease progression and outcome are scarce [4]. 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 neurodegenerative disorder 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 Central and Northern European as well as North American families whose members present mutations in a gene called ANG. This particular condition has later been designated amyotrophic lateral sclerosis 9 (ALS9).

With regards to clinical presentation, diagnosis, treatment, and prognosis, ALS9 doesn't differ from classical ALS.

1. van Es MA, Diekstra FP, Veldink JH, et al. A case of ALS-FTD in a large FALS pedigree with a K17I ANG mutation. Neurology. 2009; 72(3):287-288.
2. Greenway MJ, Andersen PM, Russ C, et al. ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis. Nat Genet. 2006; 38(4):411-413.
3. Gellera C, Colombrita C, Ticozzi N, et al. Identification of new ANG gene mutations in a large cohort of Italian patients with amyotrophic lateral sclerosis. Neurogenetics. 2008; 9(1):33-40.
4. Paubel A, Violette J, Amy M, et al. Mutations of the ANG gene in French patients with sporadic amyotrophic lateral sclerosis. Arch Neurol. 2008; 65(10):1333-1336.
5. Kirby J, Highley JR, Cox L, et al. Lack of unique neuropathology in amyotrophic lateral sclerosis associated with p.K54E angiogenin (ANG) mutation. Neuropathol Appl Neurobiol. 2013; 39(5):562-571.
6. 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.
7. 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.
8. de Carvalho M, Dengler R, Eisen A, et al. Electrodiagnostic criteria for diagnosis of ALS. Clin Neurophysiol. 2008; 119(3):497-503.
9. Greenway MJ, Alexander MD, Ennis S, et al. A novel candidate region for ALS on chromosome 14q11.2. Neurology. 2004; 63(10):1936-1938.
10. 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.
11. 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.
12. 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.
13. 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.
14. Soriani MH, Desnuelle C. Care management in amyotrophic lateral sclerosis. Rev Neurol (Paris). 2017; 173(5):288-299.
15. Yacila G, Sari Y. Potential therapeutic drugs and methods for the treatment of amyotrophic lateral sclerosis. Curr Med Chem. 2014; 21(31):3583-3593.
16. Talbott EO, Malek AM, Lacomis D. The epidemiology of amyotrophic lateral sclerosis. Handb Clin Neurol. 2016; 138:225-238.
17. 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.
18. Lambrechts D, Storkebaum E, Morimoto M, et al. VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nat Genet. 2003; 34(4):383-394.
19. Bradshaw WJ, Rehman S, Pham TT, et al. Structural insights into human angiogenin variants implicated in Parkinson's disease and Amyotrophic Lateral Sclerosis. Sci Rep. 2017; 7:41996.
20. Gros-Louis F, Gaspar C, Rouleau GA. Genetics of familial and sporadic amyotrophic lateral sclerosis. Biochim Biophys Acta. 2006; 1762(11-12):956-972.
21. Wu D, Yu W, Kishikawa H, et al. Angiogenin loss-of-function mutations in amyotrophic lateral sclerosis. Ann Neurol. 2007; 62(6):609-617.