Amyotrophic lateral sclerosis (ALS) is a progressive and generally fatal neurodegenerative disorder. Most cases are sporadic, but high familial incidence is observed occasionally. Amyotrophic lateral sclerosis 5 (ALS5) is one of many subtypes of familial ALS. It has been related to mutations in the SPG11 gene, a protein-coding gene whose product is possibly involved in the recognition and repair of DNA damage in neurons. ALS5 is a juvenile-onset form of ALS and is inherited in an autosomal recessive manner. ALS5 patients suffer from slowly progressive muscle weakness beginning in their limbs and spreading to the bulbar muscles. Pyramidal signs may be noted in advanced stages of the disease.
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.
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]:
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]:
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]:
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.