Als2-Related Disorders

Clinical 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 [JPLS]), to forms with lower motor neuron involvement (autosomal recessive juvenile amyotrophic lateral sclerosis [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 6.5 years), spasticity of facial muscles, uncontrolled laughter, spastic dysarthria, spastic gait, moderate muscle atrophy (variably present), bladder dysfunction, and sensory disturbances; some individuals are bedridden by age 12 to 50 years.

Diagnosis/testing.

Results of electrophysiology studies in ALS2-related disorders vary by phenotype; MRI shows brain changes in older individuals with IAHSP. Pathogenic variants in ALS2 have been found in four of 11 families with IAHSP; no other genes/loci are known to be associated with these disorders.

Management.

Treatment of manifestations: Physical and occupational therapy to promote mobility and independence and use of computer technologies and devices to facilitate writing and voice communication.

Prevention of secondary complications: Early detection and treatment of hip dislocation and/or spine deformities prevent further complications.

Surveillance: 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. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if both pathogenic variants have been identified in an affected family member.

Suggestive Findings

An ALS2-related disorder should be suspected in individuals with the following phenotypes, electrophysiologic findings, and neuroimaging findings:

Establishing the Diagnosis

The diagnosis of an ALS2-related disorder is established in a proband by identification of biallelic pathogenic variants in ALS2 on molecular genetic testing (see Table 1).

Molecular testing approaches can include single-gene testing and use of a multigene panel:

• Single-gene testing. Sequence analysis of ALS2 is performed first followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found. Note that while no ALS2 exon or whole-gene deletions/duplications have been reported to date, loss of ALS2 function due to these mechanisms would be expected to cause disease; thus, use of gene-targeted deletion/duplication analysis in this instance is a reasonable option.
• A multigene panel that includes ALS2 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

Pathogenic variants 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 have reached 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. Cognitive function 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. Survival is variable.

Intrafamilial variability can be considerable: in one family with two affected sibs with onset in early childhood, one began using a wheelchair at age two years (and was alive at age 42 years); the other began using a wheelchair at age 50 years (and was alive at age 55 years) [Mintchev et al 2009].

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. All affected 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, but another remained ambulatory until age 50 years.

Other. Two families with homozygous ALS2 pathogenic variants have been reported to demonstrate generalized dystonia and cerebellar signs [Sheerin et al 2014].

Genotype-Phenotype Correlations

Both IAHSP and JPLS have been associated with truncating ALS2 variants. Generally, the IAHSP and JPLS phenotypes are uniform within families (based on data regarding individuals from 9 families).

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)

For a detailed discussion of HSP and the differential diagnosis of HSP, see the Hereditary Spastic Paraplegia Overview.

The hereditary spastic paraplegias are clinically and genetically heterogeneous disorders characterized by insidiously progressive lower extremity weakness and spasticity. Hereditary spastic paraplegia may be transmitted in an autosomal dominant, autosomal recessive, X-linked, or maternally inherited (mitochondrial) manner.

Children with autosomal dominant HSP and with congenital onset of spasticity (SPG4, caused by pathogenic variants in SPAST encoding spastin and SPG3A, caused by pathogenic variants 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 pathogenic variants. Genetic heterogeneity has been demonstrated by Lesca et al [2003] by the fact of only four of 11 families with IAHSP have ALS2 pathogenic variants. No other genes/loci causing this phenotype have been identified.

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 pathogenic variants 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 pathogenic variants 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 pathogenic variant (c.499-1G>T) in ERLIN2 (OMIM 611225).

Amyotrophic Lateral Sclerosis (ALS)

For a detailed discussion of ALS and the differential diagnosis of 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. Approximately 25 genes are currently thought to be associated with ALS; of these, ALS2, SETX (ALS4), and SIGMAR1 (ALS16) are associated with juvenile onset [Marangi & Traynor 2015].

ALS4 is an autosomal dominant form of ALS, with signs and symptoms of both upper and lower motor neuron involvement and onset before age 25 years. This has also been described as a distal hereditary motor neuropathy with pyramidal signs. Individuals with ALS4 usually have onset before age 25 years, a slow rate of progression, and a normal life span [Chen et al 2004]. ALS4 is caused by mutation of SETX.

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 autosomal 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].

ALS16. Al-Saif et al [2011] reported a consanguineous family from Saudi Arabia with juvenile ALS (onset age 1-2 years, slowly progressing to use of a wheelchair by age 20 years) with a homozygous pathogenic missense variant (c.304G>C, p.Glu102Gln) in SIGMAR1 (OMIM 614373).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with an ALS2-related disorder, the following evaluations are recommended:

• Family history
• Neurologic examination, including assessment of eye movements, speech, fine motor and gross motor function, swallowing
• Detailed dietary and feeding assessment as needed
• Orthopedic and rehabilitation assessment as needed
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

The following are appropriate:

• Physical and occupational therapy to promote mobility and independence
• Aids for mobility and limb function
• Use of computer technologies and devices adapted to facilitate writing and voice communication

Surveillance

Routine monitoring:

• For feeding difficulties and assessment of diet to assure that the risk of aspiration is reduced
• For early detection and treatment of hip dislocation and/or spine deformities

Evaluation 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 in the US and EU Clinical Trials Register in Europe 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.