ALS2-Related Disorders

Summary

Disease characteristics.   ALS2-related disorders involve retrograde degeneration of the upper motor neurons of the pyramidal tracts and comprise a clinical continuum from infantile ascending hereditary spastic paraplegia (IAHSP) to juvenile forms without lower motor neuron involvement (juvenile primary lateral sclerosis or JPLS) to forms with lower motor neuron involvement (autosomal recessive juvenile amyotrophic lateral sclerosis or JALS). IAHSP is characterized by 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, and wheelchair dependence in the second decade with progression toward severe spastic tetraparesis and a pseudobulbar syndrome. JPLS is characterized by onset and loss of ability to walk during the second year of life, progressive signs of upper motor neuron disease, wheelchair dependence by adolescence, and later loss of motor speech production. JALS is characterized by onset during childhood (mean age of onset is 6.5 years), spasticity of facial muscles, uncontrolled laughter, spastic dysarthria, spastic gait, inconstant moderate muscle atrophy, bladder dysfunction, and sensory disturbances; some individuals are bedridden by age 12 to 50 years.

Diagnosis/testing.   Results of electrophysiologic studies in ALS2-related disorders vary by phenotype; MRI shows brain changes in older individuals with IAHSP. Mutations in the ALS2 gene have been found in four of 11 families with IAHSP; other genes/loci have not been identified. Molecular genetic testing of ALS2(KIAA1563), the only gene known to be associated with these disorders, detects mutations in all individuals with ALS2-related disorders and is available on a clinical basis.

Management.   Treatment of ALS2-related disorders includes physical and occupational therapy to promote mobility and independence and use of computer technologies and devices to facilitate writing and voice communication. In one person, intrathecal baclofen improved spasticity. Early detection and treatment of hip dislocation and/or spine deformities prevent further complications. Surveillance includes evaluation for feeding difficulties and modification of diet to reduce risk of aspiration.

Genetic counseling.   ALS2-related disorders are inherited in an autosomal recessive manner. 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. Carrier testing for at-risk family members is available on a clinical basis once the mutations have been identified in the proband. Prenatal diagnosis for pregnancies at increased risk is possible if both disease-causing alleles of an affected family member have been identified.

Diagnosis

Testing

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

Molecular Genetic Testing

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.—ED.

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

Other loci.  Mutations in the ALS2 gene have been found in only four of 11 families with IAHSP [Lesca et al 2003]; however, other genes/loci have not yet been identified.

Molecular genetic testing: Clinical uses

• Diagnostic testing

• Carrier testing

• Prenatal diagnosis

Molecular genetic testing: Clinical method

• Sequence analysis of the ALS2 exons from genomic DNA extracted from lymphocytes detects mutations in all individuals with ALS2-related disorders.

Note: Because ALS2-related disorders are defined by the presence of a mutation in ALS2, the mutation detection rate is 100%.

Molecular genetic testing: Research

• 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 summarizes molecular genetic testing for this disorder.

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

Test Method	Mutations Detected	Mutation Detection Rate	Test Availability
Sequence analysis	ALS2 truncating and nonsense mutations in the coding or splice site regions	100%  1	Clinical

1. Because ALS2-related disorders are defined by the presence of a mutation in ALS2, the mutation detection rate is 100%.

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

Clinical Description

Genotype-Phenotype Correlations

Table 3. Clinical Features of Individuals with ALS2 (more...)

Table 3. Clinical Features of Individuals with ALS2-Related Disorders by ALS2 Mutation

Mutation	A46fs	I336fs	T475fs	V491fs	L623fs	N846fs	R998st	M1207st	V1574fs
Length of Mutant Protein	49	339	545	492	645	857	997	1206	1616
Phenotype	JALS	IAHSP	JPLS	IAHSP	JPLS	IAHSP	IAHSP	IAHSP	IAHSP
Onset (years)	3-10	1.5	1.2	1.5	1-2	1.4	1	1	1.5
Loss of Walking (years)	12-50	4	NA  1	4	NA	5	NA	NA	Yes  2
Bulbar Symptoms (years)	Yes	13	4	8	2-10	12	3	13	<12
Upper/Lower Motor Neuron Involvement	Both  3	U  4	U	U	U	U	U	U	U

All reported disease-causing ALS2 mutations cause truncation of protein.
1. NA = walking never achieved
2. Age unknown
3. 50% of cases
4. Upper motor involvement

So far, the IAHSP and JPLS phenotypes are uniform among individuals from nine families with truncating ALS2 mutations. Table 3 summarizes the eight mutations from nine families classified as IAHSP or JPLS and some sibs of the tenth family classified as JALS. Nine out of ten families with mutations in ALS2 show a uniform clinical course, while the Tunisian family with juvenile amyotrophic lateral sclerosis has a relatively milder phenotype.

Differential Diagnosis

For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.

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, 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 the 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 (mutations in the genes encoding spastin and 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.

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, aryl sulphatase 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).  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]. However, the role of ALS2 mutations in adult- or adolescent-onset forms of primary lateral sclerosis has not been yet investigated.

Amyotrophic lateral sclerosis (ALS).  See Amyotrophic Lateral Sclerosis Overview.

ALS is a progressive neurodegenerative disease involving both the upper motor neuron (UMN) and lower motor neuron (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 topographical 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 might predispose to ALS.

Management

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.

Molecular Genetics

Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.

Normal 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: Nine recessive homozygous mutations provoking a frameshift mechanism and a pretermination codon in ALS2 have been published in individuals with ALS2-related disorders: 1-bp DEL, c.138delA [Hadano et al 2001, Yang et al 2001]; 2-bp DEL, c.1867_1868delCT [Yang et al 2001]; 2-bp DEL, c.1425_1426delAG [Hadano et al 2001]; 1-bp DEL, c.3619delA [Eymard-Pierre et al 2002]; 10-bp DEL, IVS5-1G> or c.1472_1481delTTTCCCCCAG [Eymard-Pierre et al 2002]; 2-bp DEL, c.2537_2538delAT [Eymard-Pierre et al 2002]; 2-bp DEL, c.1007_1008delTA [Eymard-Pierre et al 2002]; 1-bp DEL, c.4721delT [Gros-Louis et al 2003] and 1 homozygous stop codon mutation: c.2992→T [Devon et al 2003]. (For more information, see Genomic Databases table above.)

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)]. The activity of a 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]. When highly expressed, alsin has also been shown to act on Rac1, a G protein involved in actin cytoskeleton remodeling [Topp et al 2004].

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 co-localizes 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.

Abnormal gene product: Disease-causing mutations and a naturally truncated isoform of ALS2 are shown to be rapidly degraded when expressed in cultured human cells, including lymphocytes and fibroblasts derived from individuals with ALS2 mutations. Thus, mutations in the ALS2 gene 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. Most current work is focusing on the role of ALS2 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 ALS2 in the death of upper motor neurons beginning in early postnatal life.

Resources

GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select for the most up-to-date Resources information.—ED.

Amyotrophic Lateral Sclerosis Association (ALSA)
27001 Agoura Road, Suite 150
Calabasas Hills, CA 91301-5104
Phone: 800-782-4747 (patient hotline); 818-880-8007; 818-340-7573 (TDD)
Fax: 818-880-9006
Email: alsinfo@alsa-national.org
www.alsa.org

Amyotrophic Lateral Sclerosis Society of Canada
265 Yorkland Blvd, #300
Toronto, Ontario, Canada M2J 1S5
Phone: 888-267-4ALS (888-267-4257); 416-497-2267
Fax: 416-497-1256
Email: SI@als.ca
www.als.ca

National Ataxia Foundation
2600 Fernbrook Lane; Suite 119
Minneapolis, MN 55447
Phone: 763-553-0020
Fax: 763-553-0167
Email: naf@ataxia.org
www.ataxia.org

National Institute of Neurological Disorders and Stroke
Hereditary Spastic Paraplegia

Spastic Paraplegia Foundation, Inc.
209 Park Rd.
Chelmsford, MA 01824
Phone: 703-495-9261
Email: community@sp-foundation.org
sp-foundation.org

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.

Chapter Notes