Clinical Diagnosis

ALS2-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 confirmed

Neuroimaging Studies

IAHSP. Magnetic resonance imaging (MRI) is normal in children.

Older individuals have:

• Brain cortical atrophy predominant in the motor areas

• T₂-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].

Testing

Detection of the protein alsin using specific antibodies in protein extracts from skin biopsy fibroblasts and lymphoblastoid cells is available on a research basis only.

Molecular Genetic Testing

Gene. ALS2 (KIAA1563) is the only gene in which mutations are known to be associated with ALS2-related disorders.

Clinical testing

• Sequence 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.

Research testing

• Sequence analysis of alsin cDNA obtained from an RNA extract of lymphoblastoid cell lines and/or fibroblasts is performed on a research basis only.

Table 2. Summary of Molecular Genetic Testing Used in ALS2-Related Disorders

View in own window

Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
ALS2	Sequence analysis	Sequence variants 2	Unknown	Clinical
	Deletion/duplication analysis 3	Exonic or whole-gene deletions	Unknown

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To 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, such testing is available on a research basis only. Furthermore, 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 to develop the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No phenotypes other than those discussed in this GeneReview are associated with mutations in ALS2.

Natural History

Mutations 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 Correlations

So 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.

Penetrance

All individuals who are homozygous or compound heterozygous for ALS2 mutations manifest the disease.

Anticipation

Anticipation has not been observed.

Nomenclature

See Amyotrophic Lateral Sclerosis Overview.

Prevalence

No data on prevalence are available, but ALS2-related disorders are probably currently underdiagnosed.

ALS2-related disorders have been described in individuals from a variety of ethnic backgrounds.

Hereditary 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].

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].

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).

• IAHSP

• JPLS

Evaluations Following Initial Diagnosis

To 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 Manifestations

The 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 Complications

Early detection and treatment of hip dislocation and/or spine deformities is indicated.

Surveillance

Evaluation for feeding difficulties and modification of diet to reduce risk of aspiration are indicated.

Testing of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search 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.

Other

Intrathecal baclofen in one person improved spasticity, facilitating care but not improving motor function [personal communication].

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

ALS2-related disorders are inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.

• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. Individuals with ALS2-related disorders have marked motor disability and have not been known to reproduce.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations have been identified in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. Both disease-causing alleles must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

1. Ben Hamida M, Hentati F, Ben Hamida C. Hereditary motor system diseases (chronic juvenile amyotrophic lateral sclerosis). Conditions combining a bilateral pyramidal syndrome with limb and bulbar amyotrophy. Brain. 1990;113(Pt 2):347–63. [PubMed: 2328408]
2. Brugman F, Eymard-Pierre E, van den Berg LH, Wokke JH, Gauthier-Barichard F, Boespflug-Tanguy O. Adult-onset primary lateral sclerosis is not associated with mutations in the ALS2 gene. Neurology. 2007;69(7):702–4. [PubMed: 17698795]
3. Cai H, Lin X, Xie C, Laird FM, Lai C, Wen H, Chiang HC, Shim H, Farah MH, Hoke A, Price DL, Wong PC. Loss of ALS2 function is insufficient to trigger motor neuron degeneration in knock-out mice but predisposes neurons to oxidative stress. J Neurosci. 2005;25(33):7567–74. [PMC free article: PMC2364727] [PubMed: 16107644]
4. Deng HX, Zhai H, Fu R, Shi Y, Gorrie GH, Yang Y, Liu E, Dal Canto MC, Mugnaini E, Siddique T. Distal axonopathy in an alsin-deficient mouse model. Hum Mol Genet. 2007;16(23):2911–20. [PubMed: 17855450]
5. Devon RS, Orban PC, Gerrow K, Barbieri MA, Schwab C, Cao LP, Helm JR, Bissada N, Cruz-Aguado R, Davidson TL, Witmer J, Metzler M, Lam CK, Tetzlaff W, Simpson EM, McCaffery JM, El-Husseini AE, Leavitt BR, Hayden MR. Als2-deficient mice exhibit disturbances in endosome trafficking associated with motor behavioral abnormalities. Proc Natl Acad Sci U S A. 2006;103(25):9595–600. [PMC free article: PMC1480452] [PubMed: 16769894]
6. Gascon GG, Chavis P, Yaghmour A, Stigsby B, Shums A, Ozand P, Siddique T. Familial childhood primary lateral sclerosis with associated gaze paresis. Neuropediatrics. 1995;26:313–9. [PubMed: 8719747]
7. Gros-Louis F, Kriz J, Kabashi E, McDearmid J, Millecamps S, Urushitani M, Lin L, Dion P, Zhu Q, Drapeau P, Julien JP, Rouleau GA. Als2 mRNA splicing variants detected in KO mice rescue severe motor dysfunction phenotype in Als2 knock-down zebrafish. Hum Mol Genet. 2008;17(17):2691–702. [PubMed: 18558633]
8. Hadano S, Benn SC, Kakuta S, Otomo A, Sudo K, Kunita R, Suzuki-Utsunomiya K, Mizumura H, Shefner JM, Cox GA, Iwakura Y, Brown RH, Ikeda JE. Mice deficient in the Rab5 guanine nucleotide exchange factor ALS2/alsin exhibit age-dependent neurological deficits and altered endosome trafficking. Hum Mol Genet. 2006;15(2):233–50. [PubMed: 16321985]
9. Hadano S, Kunita R, Otomo A, Suzuki-Utsunomiya K, Ikeda JE. Molecular and cellular function of ALS2/alsin: implication of membrane dynamics in neuronal development and degeneration. Neurochem Int. 2007;51(2-4):74–84. [PubMed: 17566607]
10. Hadano S, Otomo A, Suzuki-Utsunomiya K, Kunita R, Yanagisawa Y, Showguchi-Miyata J, Mizumura H, Ikeda JE. ALS2CL, the novel protein highly homologous to the carboxy-terminal half of ALS2, binds to Rab5 and modulates endosome dynamics. FEBS Lett. 2004;575:64–70. [PubMed: 15388334]
11. Hand CK, Devon RS, Gros-Louis F, Rochefort D, Khoris J, Meininger V, Bouchard JP, Camu W, Hayden MR, Rouleau GA. Mutation screening of the ALS2 gene in sporadic and familial amyotrophic lateral sclerosis. Arch Neurol. 2003;60:1768–71. [PubMed: 14676054]
12. Hentati A, Bejaoui K, Pericak-Vance MA, Hentati F, Speer MC, Hung WY, Figlewicz DA, Haines J, Rimmler J, Ben Hamida C. et al. Linkage of recessive familial amyotrophic lateral sclerosis to chromosome 2q33-q35. Nat Genet. 1994;7(3):425–8. [PubMed: 7920663]
13. Hentati A, Ouahchi K, Pericak-Vance MA, Nijhawan D, Ahmad A, Yang Y, Rimmler J, Hung W, Schlotter B, Ahmed A, Ben Hamida M, Hentati F, Siddique T. Linkage of a commoner form of recessive amyotrophic lateral sclerosis to chromosome 15q15-q22 markers. Neurogenetics. 1998;2:55–60. [PubMed: 9933301]
14. Jacquier A, Buhler E, Schäfer MK, Bohl D, Blanchard S, Beclin C, Haase G. Alsin/Rac1 signaling controls survival and growth of spinal motoneurons. Ann Neurol. 2006;60(1):105–17. [PubMed: 16802292]
15. Kanekura K, Hashimoto Y, Kita Y, Sasabe J, Aiso S, Nishimoto I, Matsuoka M. A Rac1/phosphatidylinositol 3-kinase/Akt3 anti-apoptotic pathway, triggered by AlsinLF, the product of the ALS2 gene, antagonizes Cu/Zn-superoxide dismutase (SOD1) mutant-induced motoneuronal cell death. J Biol Chem. 2005;280:4532–43. [PubMed: 15579468]
16. Kress JA, Kühnlein P, Winter P, Ludolph AC, Kassubek J, Müller U, Sperfeld AD. Novel mutation in the ALS2 gene in juvenile amyotrophic lateral sclerosis. Ann Neurol. 2005;58(5):800–3. [PubMed: 16240357]
17. Kunita R, Otomo A, Mizumura H, Suzuki K, Showguchi-Miyata J, Yanagisawa Y, Hadano S, Ikeda JE. Homo-oligomerization of ALS2 through its unique carboxyl-terminal regions is essential for the ALS2-associated Rab5 guanine nucleotide exchange activity and its regulatory function on endosome trafficking. J Biol Chem. 2004;279:38626–35. [PubMed: 15247254]
18. Kunita R, Otomo A, Mizumura H, Suzuki-Utsunomiya K, Hadano S, Ikeda JE. The Rab5 activator ALS2/alsin acts as a novel Rac1 effector through Rac1-activated endocytosis. J Biol Chem. 2007;282(22):16599–611. [PubMed: 17409386]
19. Lai C, Xie C, McCormack SG, Chiang HC, Michalak MK, Lin X, Chandran J, Shim H, Shimoji M, Cookson MR, Huganir RL, Rothstein JD, Price DL, Wong PC, Martin LJ, Zhu JJ, Cai H. Amyotrophic lateral sclerosis 2-deficiency leads to neuronal degeneration in amyotrophic lateral sclerosis through altered AMPA receptor trafficking. J Neurosci. 2006;26(45):11798–806. [PMC free article: PMC2556290] [PubMed: 17093100]
20. Lesca G, Eymard-Pierre E, Santorelli FM, Cusmai R, Di Capua M, Valente EM, Attia-Sobol J, Plauchu H, Leuzzi V, Ponzone A, Boespflug-Tanguy O, Bertini E. Infantile ascending hereditary spastic paralysis (IAHSP): clinical features in 11 families. Neurology. 2003;60:674–82. [PubMed: 12601111]
21. Nagano I, Murakami T, Shiote M, Manabe Y, Hadano S, Yanagisawa Y, Ikeda JE, Abe K. Single-nucleotide polymorphisms in uncoding regions of ALS2 gene of Japanese patients with autosomal-recessive amyotrophic lateral sclerosis. Neurol Res. 2003;25:505–9. [PubMed: 12866199]
22. Otomo A, Hadano S, Okada T, Mizumura H, Kunita R, Nishijima H, Showguchi-Miyata J, Yanagisawa Y, Kohiki E, Suga E, Yasuda M, Osuga H, Nishimoto T, Narumiya S, Ikeda JE. ALS2, a novel guanine nucleotide exchange factor for the small GTPase Rab5, is implicated in endosomal dynamics. Hum Mol Genet. 2003;12:1671–87. [PubMed: 12837691]
23. Otomo A, Kunita R, Suzuki-Utsunomiya K, Mizumura H, Onoe K, Osuga H, Hadano S, Ikeda JE. ALS2/alsin deficiency in neurons leads to mild defects in macropinocytosis and axonal growth. Biochem Biophys Res Commun. 2008;370(1):87–92. [PubMed: 18358238]
24. Pringle CE, Hudson AJ, Munoz DG, Kiernan JA, Brown WF, Ebers GC. Primary lateral sclerosis. Clinical features, neuropathology and diagnostic criteria. Brain. 1992;115(Pt 2):495–520. [PubMed: 1606479]
25. Shirakawa K, Suzuki H, Ito M, Kono S, Uchiyama T, Ohashi T, Miyajima H. Novel compound heterozygous ALS2 mutations cause juvenile amyotrophic lateral sclerosis in Japan. Neurology. 2009;73(24):2124–6. [PubMed: 20018642]
26. Takahashi Y, Seki N, Ishiura H, Mitsui J, Matsukawa T, Kishino A, Onodera O, Aoki M, Shimozawa N, Murayama S, Itoyama Y, Suzuki Y, Sobue G, Nishizawa M, Goto J, Tsuji S. Development of a high-throughput microarray-based resequencing system for neurological disorders and its application to molecular genetics of amyotrophic lateral sclerosis. Arch Neurol. 2008;65(10):1326–32. [PubMed: 18852346]
27. Topp JD, Gray NW, Gerard RD, Horazdovsky BF. Alsin is a Rab5 and Rac1 guanine nucleotide exchange factor. J Biol Chem. 2004;279:24612–23. [PubMed: 15033976]
28. Verschuuren-Bemelmans CC, Winter P, Sival DA, Elting JW, Brouwer OF, Müller U. Novel homozygous ALS2 nonsense mutation (p.Gln715X) in sibs with infantile-onset ascending spastic paralysis: the first cases from northwestern Europe. Eur J Hum Genet. 2008;16(11):1407–11. [PubMed: 18523452]
29. Yamanaka K, Miller TM, McAlonis-Downes M, Chun SJ, Cleveland DW. Progressive spinal axonal degeneration and slowness in ALS2-deficient mice. Ann Neurol. 2006;60(1):95–104. [PubMed: 16802286]
30. Yamanaka K, Vande Velde C, Eymard-Pierre E, Bertini E, Boespflug-Tanguy O, Cleveland DW. Unstable mutants in the peripheral endosomal membrane component ALS2 cause early-onset motor neuron disease. Proc Natl Acad Sci U S A. 2003;100:16041–6. [PMC free article: PMC307689] [PubMed: 14668431]
31. Yang Y, Hentati A, Deng HX, Dabbagh O, Sasaki T, Hirano M, Hung WY, Ouahchi K, Yan J, Azim AC, Cole N, Gascon G, Yagmour A, Ben-Hamida M, Pericak-Vance M, Hentati F, Siddique T. The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat Genet. 2001;29:160–5. [PubMed: 11586297]

Suggested Reading

1. Dion PA, Daoud H, Rouleau GA. Genetics of motor neuron disorders: new insights into pathogenic mechanisms. Nat Rev Genet. 2009;10:769–782. [PubMed: 19823194]
2. Singer MA, Statland JM, Wolfe GI, Barohn RJ. Primary lateral sclerosis. Muscle Nerve. 2007;35(3):291–302. [PubMed: 17212349]

Revision History

• 10 February 2011 (me ) Comprehensive update posted live

• 21 October 2005 (me) Review posted to live Web site

• 16 December 2004 (esb) Original submission