DiagnosisClinical DiagnosisALS2-related disorders involve retrograde degeneration of the upper motor neurons of the pyramidal tracts and comprise a clinical continuum from (1) infantile ascending hereditary spastic paraplegia (IAHSP)* to (2) juvenile forms without lower motor neuron involvement (juvenile primary lateral sclerosis or JPLS)* to (3) forms with lower motor neuron involvement (autosomal recessive juvenile amyotrophic lateral sclerosis or JALS). The different phenotypes reported in the literature are summarized.*Note: In some instances, the same entity may be called either juvenile primary lateral sclerosis or IAHSP.Infantile-onset ascending hereditary spastic paralysis (IAHSP) is characterized by the following features [Lesca et al 2003]: Onset of spasticity with increased reflexes and sustained clonus of the lower limbs within the first two years of life Progressive weakness and spasticity of the upper limbs by age seven to eight years Wheelchair dependence in the second decade, with progression toward severe spastic tetraparesis and a pseudobulbar syndrome Preservation of cognitive function Juvenile primary lateral sclerosis (JPLS) is characterized by the following features [Gascon et al 1995, Yang et al 2001]: Onset during the second year of life Loss of ability to walk in the second year of life Slowly progressive uncomplicated signs of upper motor neuron disease Wheelchair dependence by adolescence Later loss of motor speech production Preservation of cognitive function Autosomal recessive juvenile amyotrophic lateral sclerosis (JALS) (also known as ALS2) is characterized by the following features [Ben Hamida et al 1990]:Onset during childhood (mean age of onset 6.5 years; range 3-20 years) Spasticity of facial muscles with uncontrolled laughter and spastic dysarthria; spastic gait; in some individuals, mild atrophy of the legs and hands Inconstant and moderate muscle atrophy, absence of fasciculations, bladder dysfunction, and sensory disturbances Some individuals bedridden by age 12 to 50 years (no information is available on age of wheelchair dependence) Preservation of cognitive function not confirmedElectrophysiologic Studies Table 1 shows the results of various electrophysiologic studies in different phenotypes of ALS2-related disorders. Table 1. Electrophysiologic Studies in ALS2-Related Disorders by PhenotypeView in own windowStudy PhenotypeIAHSPJPLSJALSMEP 1 Severe dysfunction of the corticospinal tracts ² NA ³ Absent or reduced action potential, suggesting dysfunction of corticospinal tracts ⁴ SSEP 5 Normal in early stages; abnormal in later stagesPoorly configured; normal central conductionNA ^{3EMG 6 No signs of denervationNo signs of denervationSigns of denervationNCV 7 Normal NormalNormalVEP 8 NormalBAER 9 NormalTCMS 10 No motor evoked potentials1. Motor evoked potentials2. Primitive, pure degeneration of the upper motor neurons3. Not available4. Kress et al [2005]5. Somatosensory evoked potentials6. Electromyography7. Nerve conduction velocities8. Visual evoked potentials9. Brain stem auditory evoked potentials10. Transcranial magnetic stimulationNeuroimaging StudiesIAHSP. Magnetic resonance imaging (MRI) is normal in children. Older individuals have:Brain cortical atrophy predominant in the motor areasT₂-weighted bilateral punctate hyperintense signals in the corticospinal pathways of the posterior arms of the internal capsule and brain stem. In addition, it is common to find T₂- or FLAIR-weighted hyperintensities of periventricular areas and aspects of spinal cervical atrophy that are often seen in other hereditary spastic paraplegias (HSPs). JPLS. CT and MRI scans of brain and spinal cord are normal. JALS. MRI studies of brain and spinal cord are normal [Kress et al 2005, Shirakawa et al 2009].TestingDetection of the protein alsin using specific antibodies in protein extracts from skin biopsy fibroblasts and lymphoblastoid cells is possible. Molecular Genetic TestingGene. ALS2 (KIAA1563) is the only gene in which mutations are known to be associated with ALS2-related disorders. TestingSequence analysis of the ALS2 exons from genomic DNA extracted from lymphocytes detects mutations in all individuals with ALS2-related disorders. Deletion/duplication analysis. To date, no exonic or whole-gene deletions have been reported.Sequence analysis of alsin cDNA obtained from an RNA extract of lymphoblastoid cell lines and/or fibroblasts is possible.Table 2. Summary of Molecular Genetic Testing Used in ALS2-Related DisordersView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityALS2Sequence analysisSequence variants 2UnknownClinicalDeletion / duplication analysis 3Exonic or whole-gene deletionsUnknown1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. 3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo establish the diagnosis in a proband requires molecular genetic testing to identify a disease-causing mutation in ALS2. Note: Pre-screening with western blot analysis can be used to determine the presence or absence of the protein alsin before performing sequence analysis; however, fibroblasts or lymphoblastoid cells may not be available for such studies.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo phenotypes other than those discussed in this GeneReview are associated with mutations in ALS2.}

Natural HistoryMutations in ALS2 are responsible for a retrograde degeneration of the upper motor neurons of the pyramidal tracts, leading to a clinical continuum from infantile ascending hereditary spastic paraplegia to juvenile forms without lower motor neuron involvement (juvenile primary lateral sclerosis) or with lower motor neuron involvement (autosomal recessive juvenile amyotrophic lateral sclerosis).Infantile ascending hereditary spastic paraplegia (IAHSP). Spastic paraplegia begins during the first two years of life and extends to upper limbs within the next few years. Manifestations of the disease may start as early as the first year of life. During the first decade of life, the disease progresses to tetraplegia, anarthria, dysphagia, and slow eye movements. Feeding difficulties, especially in swallowing liquids, may manifest in the second decade; however, those few individuals with long-term follow-up who are now in their 30s have neither experienced recurrent bronchopneumonia nor required feeding gastrostomy. Some individuals are reported to require feeding by gastrostomy tube and to lose bladder and sphincter functions in the advanced state [Verschuuren-Bemelmans et al 2008]. Overall, IAHSP is compatible with long survival. Mental status is preserved.Juvenile primary lateral sclerosis (JPLS). Examination reveals upper motor neuron findings of pseudobulbar palsy and spastic quadriplegia without dementia or cerebellar, extrapyramidal, or sensory signs. In addition, affected individuals exhibit a diffuse conjugate saccadic gaze paresis, especially severe on downgaze. Some of these children are never able to walk independently, while others are delayed in walking and then lose the ability to walk independently by the first decade of life. Speech deterioration starts between ages two and ten years. No cognitive deterioration is reported. Autosomal recessive juvenile amyotrophic lateral sclerosis (JALS or ALS2) [Ben Hamida et al 1990, Hentati et al 1994]. Onset is between ages three and 20 years. Affected individuals constantly show a spastic pseudobulbar syndrome together with spastic paraplegia. Peroneal muscular atrophy is observed in some, but not all, individuals. Atrophy or fasciculation of the tongue does not occur. At the time of the description of clinical symptoms, three individuals from one family were bedridden by age 12, 20, and 50 years.

Genotype-Phenotype CorrelationsSo far, the IAHSP and JPLS phenotypes are uniform among individuals from nine families with truncating ALS2 mutations. Table 3 (pdf) summarizes the 15 mutations from 16 families classified as IAHSP or JPLS and from the sibs of the three families classified as JALS. Sixteen families with mutations in ALS2 show a uniform clinical course (except for existence of lower motor neuron involvement in some with JALS), while the Tunisian family with juvenile amyotrophic lateral sclerosis has a relatively milder phenotype.

Differential DiagnosisHereditary Spastic Paraplegia (HSP) See Hereditary Spastic Paraplegia Overview. Hereditary spastic paraplegia is characterized by insidiously progressive lower extremity weakness and spasticity. HSP is classified as "uncomplicated" or "pure" if neurologic impairment is limited to progressive lower extremity spastic weakness, hypertonic urinary bladder disturbance, mild diminution of lower extremity vibration sensation and, occasionally, of joint position sensation. HSP is classified as "complicated" ("complex") if the impairment present in uncomplicated HSP is accompanied by other system involvement or other neurologic findings such as seizures, dementia, amyotrophy, extrapyramidal disturbance, or peripheral neuropathy in the absence of other disorders such as diabetes mellitus. Hereditary spastic paraplegia may be transmitted in an autosomal dominant manner, an autosomal recessive manner, or an X-linked recessive manner. (The mode of inheritance is usually established by family history and rarely with molecular genetic testing.) In autosomal dominant hereditary spastic paraplegia (ADHSP) intrafamilial variability in age at onset is common. Progressive spasticity and motor disability involving the upper limbs, oculomotor function, and bulbar function are rarely observed in any of the different genetic forms of hereditary spastic paraplegia. Children with ADHSP and with congenital onset of spasticity (SPG4, caused by mutations in SPAST encoding spastin and SPG3A, caused by mutations in ATL1 encoding atlastin) have a non-progressive or very slowly progressive course, whereas in the most common presentation of HSP with onset of spasticity and weakness in adulthood, the course is clearly progressive.IAHSP without ALS2 mutations. Genetic heterogeneity has been demonstrated by Lesca et al [2003] by the fact of only four of 11 families with IAHSP have ALS2 mutations. No other genes/loci causing this phenotype have been identified to date.ARHSP. In general, in autosomal recessive hereditary spastic paraplegia (ARHSP) with onset during childhood, the progression is less severe and spasticity predominates over weakness. Pseudobulbar involvement in ALS2-related disorders clearly delineates it from all the other genetic forms of spastic paraparesis. In contrast, in ARHSP, muscle weakness predominates over spasticity, onset is clearly apparent during the first decade, and involvement of upper limbs and bulbar function is invariable. The role of ALS2 mutations in ARHSP has not yet been investigated. Normal brain white matter on MRI rules out the diagnosis of leukodystrophy.Metabolic investigations rule out other metabolic causes of progressive ARHSP (very long chain fatty acids (see X-linked adrenoleukodystrophy), arylsulfatase A Deficiency, mitochondrial dysfunction (see Mitochondrial Disorders Overview); however, decline in behavior or cognitive function is frequently observed in these conditions. Primary lateral sclerosis (PLS) is defined as the presence of slowly progressive, uncomplicated signs of upper motor neuron disease in persons in whom all other known causes of spasticity have been eliminated. PLS has been described in adults with an isolated degenerative process of the upper motor neurons, with sporadic occurrence [Pringle et al 1992]. No ALS2 mutations were identified in a study of 51 Dutch persons with adult-onset PLS [Brugman et al 2007].Al-Saif et al [2012] described a consanguineous family from Saudi Arabia having four sibs with infantile-onset PLS with severe progression requiring wheelchair by age 12 and associated with a homozygous splice junction mutation (c.499-1G>T) in ERLIN2. Amyotrophic Lateral Sclerosis (ALS) See Amyotrophic Lateral Sclerosis Overview. ALS is a progressive neurodegenerative disease involving both the upper motor neurons (UMN) and lower motor neurons (LMN). LMN signs include weakness, muscle wasting, muscle cramps, fasciculations, and eventually hyporeflexia. UMN signs include hyperreflexia, extensor plantar response, increased muscle tone, and weakness in a topographic representation. ALS1. Approximately 20% of individuals with familial ALS have ALS1 with an identified disease-causing mutation in SOD1. About 3% of affected individuals with no family history of ALS have SOD1 mutations. Inheritance of ALS1 is autosomal dominant. ALS5 (also known as type 1 autosomal recessive ALS) very closely resembles typical ALS of any age of onset and is the most prevalent form of recessive ALS, having been identified in several ethnic groups (North African, South Asian, and European). This form of recessive ALS was mapped to 15q by Hentati et al [1998]. The role of ALS2 mutations among the common adult forms of ALS was investigated by the following: Hand et al [2003], who screened for mutations in ALS2 from 95 unrelated individuals with familial ALS, 95 unrelated individuals with simplex ALS (i.e., only one individual affected in the family), and 11 individuals with early-onset amyotrophic lateral sclerosis. All 34 exons of ALS2 plus the 5' and 3' untranslated regions were sequenced and no disease-associated mutations were found. Each of the 23 variants identified was also analyzed among controls. No mutation of ALS2 has been identified as a cause of adult-onset familial or simplex ALS. Nagano et al [2003], who evaluated three Japanese individuals with autosomal recessive ALS. Although single-nucleotide polymorphisms (SNPs) were identified in non-coding regions of ALS2, no disease-causing mutations were identified. The possibility remains that the identified SNPs may predispose to ALS.Takahashi et al [2008] screened for ALS2 mutations in 45 persons with ALS (35 simplex [i.e., a single occurrence in a family] and 10 familial) and 238 controls. Two heterozygous missense mutations causing amino acid changes (p. Gln435Leu, p.Pro1016Thr) were identified. However, large-scale studies will be required to confirm the relevance of these mutations to ALS pathogenesis [Takahashi et al 2008]. Al-Saif et al [2011] reported a consanguineous family from Saudi Arabia with juvenile ALS (onset 1-2 years, slowly progressive to wheelchair by age 20) with a homozygous missense mutation (c.304G>C, p.Glu102Gln) in SIGMAR1.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).IAHSPJPLS

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with an ALS2-related disorder, the following evaluations are recommended:Family history Neurologic exam, including assessment of eye movements, speech, fine motor and gross motor function, swallowing Treatment of ManifestationsThe following are appropriate:Physical and occupational therapy to promote mobility and independence Use of computer technologies and devices adapted to facilitate writing and voice communication Prevention of Secondary ComplicationsEarly detection and treatment of hip dislocation and/or spine deformities is indicated.SurveillanceEvaluation for feeding difficulties and modification of diet to reduce risk of aspiration are indicated. Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.OtherIntrathecal baclofen in one person improved spasticity, facilitating care but not improving motor function [personal communication].

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. ALS2-Related Disorders: Genes and DatabasesView in own windowLocus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDALS2ALS22q33​.1Alsinalsod/ALS2 genetic mutations
ALS mutation database
ALS2 homepage - Mendelian genesALS2Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for ALS2-Related Disorders (View All in OMIM) View in own window 205100AMYOTROPHIC LATERAL SCLEROSIS 2, JUVENILE; ALS2 606352ALSIN 606353PRIMARY LATERAL SCLEROSIS, JUVENILE; PLSJ 607225SPASTIC PARALYSIS, INFANTILE-ONSET ASCENDING; IAHSPNormal allelic variants. ALS2 comprises 34 exons in a genomic region of 83 kb. Alternative splicing gives rise to a 184-kd full-length form of 1,657 amino acids and a smaller, alternatively spliced transcript of 396 amino acids. Pathologic allelic variants. Seventeen recessive homozygous mutations that result in a frameshift and predict a premature translation termination or a change of single amino acid (one mutation) have been published in individuals with ALS2-related disorders. See Table 3 (pdf) and Figure 1.FigureFigure 1. Schematic representation of the Alsin protein domain structure with reported amino acid changes indicated.
Alsin protein with RCC1 (regulator of chromatin condensation)-like domain (RLD), DH/PH (Dbl and pleckstrin homology), (more...)For more information, see Table A.Normal gene product. Sequence comparisons suggest that ALS2 encodes a protein containing three guanine nucleotide exchange factor (GEF) domains: RCC1(regulator of chromatin condensation)-like domain (RLD); the Dbl homology and pleckstrin homology (DH/PH); and the vacuolar protein sorting 9 (VPS9) (see Figure 1). GEF activates one or more small GTPases, facilitating the releasing of GDP and exchange for GTP. Alsin, the protein encoded by ALS2, has been shown to be capable of acting as a GEF for Rab5, a GTPase implicated in endosomal trafficking [Otomo et al 2003, Hadano et al 2007]. When highly expressed, alsin has also been shown to act on Rac1, a G protein involved in actin cytoskeleton remodeling [Topp et al 2004, Kanekura et al 2005]. Alsin has been demonstrated to interact with active Rac1 to be recruited to membrane ruffles and to be involved in Rac1-activated endocytosis [Kunita et al 2007]. Endogenous alsin is enriched in nervous tissue where it is peripherally bound to the cytoplasmic face of endosomal membranes. This association requires the amino-terminal "RCC1-like" GEF domain [Yamanaka et al 2003], but C-terminal sequences are also required [Otomo et al 2003, Kunita et al 2004, Topp et al 2004]. Alsin is also present in membrane ruffles and lamellipodia [Topp et al 2004], suggesting that alsin is involved in membrane transport events, potentially linking endocytic processes and actin cytoskeleton remodeling.Ectopically expressed alsin colocalizes with Rab5 and the early endosome antigen-1 (EEA1) onto early endosomal compartments and stimulates the enlargement of endosomes in cultured cortical neurons and non-neuronal cells in a Rab5-GEF activity-dependent manner [Otomo et al 2003]. Essentially, full-length ALS2 including the amino-terminal RLD domain is required for proper membrane targeting of alsin [Yamanaka et al 2003]. Exogenously-expressed ALS2 forms a homophilic oligomer through its C-terminal regions, which carries a VPS9 domain; oligomerization of ALS2 is apparently crucial for Rab5-GEF activity in vitro and ALS2-mediated endosome enlargement in cells [Kunita et al 2004].A gene homologous to ALS2, named ALS2 C-terminal like (ALS2CL), resides on chromosome 3p21 and encodes a 108-kd protein [Hadano et al 2004]. ALS2CL could be a novel factor modulating the Rab5-mediated endosome dynamics in the cells.The function of alsin in the nervous system has been tested in Als2-deficient mice and the primary neurons from them. Als2-deficient mice have been generated by several groups. Neuropathologic analysis exhibited mild axonal degeneration in the dorsolateral [Yamanaka et al 2006] or distal corticospinal tracts [Deng et al 2007, Gros-Louis et al 2008], or progressive loss of cerebellar Purkinje cells with decreased number of motor axons from lumbar spinal cord [Hadano et al 2006]. Modest behavioral abnormalities observed in Als2-deficient mice included motor slowness and/or decreased motor coordination measured by rotarod performance [Cai et al 2005, Deng et al 2007, Yamanaka et al 2006]. In summary, Als2-deficient mice have normal life span and a far milder phenotype than that observed in humans with ALS2 mutations. In contrast to mice models, als2a-knock down zebrafish exhibited severe developmental and motor abnormality [Gros-Louis et al 2008].Primary neuronal cells from Als2-deficient mice showed modest disturbance of endocytosis [Devon et al 2006], increased susceptibility to oxidative stress and glutamate excitotoxicity [Cai et al 2005, Lai et al 2006], or modest defect in axonal growth [Otomo et al 2008], although primary motor neurons with alsin knockdown showed reduced survival through Rac1-mediated signaling [Jacquier et al 2006].Abnormal gene product. Mutant alsin and a naturally truncated alsin isoform are rapidly degraded when expressed in cultured human cells, including lymphocytes and fibroblasts derived from individuals with ALS2 mutations. Thus, mutations in ALS2 linked to early-onset motor neuron disease uniformly produce loss of activity through decreased protein stability of this endosomal GEF [Yamanaka et al 2003]. A feature common to all reported ALS2 mutations causing motor neuron diseases is a loss of protein stability [Yamanaka et al 2003], which leads to reduction or loss of all three potential GEF domains. A current research focus is the role of alsin as a Rab5-GEF and its involvement in endosomal dynamics. It is premature to discount roles for the other GEF domains as well as corresponding GTPases in understanding the role of alsin in the death of upper motor neurons beginning in early postnatal life.