Clinical characteristics.

ALS2-related disorder involves retrograde degeneration of the upper motor neurons of the pyramidal tracts and comprises a clinical continuum of the following three phenotypes:

• Infantile ascending hereditary spastic paraplegia (IAHSP), 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 caused by progressive cranial nerve involvement
• Juvenile primary lateral sclerosis (JPLS), characterized by upper motor neuron findings of pseudobulbar palsy and spastic quadriplegia without dementia or cerebellar, extrapyramidal, or sensory signs
• Juvenile amyotrophic lateral sclerosis (JALS or ALS2), characterized by onset between ages three and 20 years. All affected individuals show a spastic pseudobulbar syndrome (spasticity of speech and swallowing) together with spastic paraplegia. Some individuals are bedridden by age 12 to 50 years.

Diagnosis/testing.

The diagnosis of ALS2-related disorder is established in a proband with suggestive findings and biallelic pathogenic variants in ALS2 identified on molecular genetic testing.

Management.

Treatment of manifestations: Management by multidisciplinary specialists including neurology, orthopedics, physical therapy, occupational therapy, speech and language therapy, and feeding specialists (gastroenterology, nutrition) is recommended. Physical and occupational therapy promote mobility and independence; use of computer technologies and devices can facilitate writing and voice communication. Early detection and treatment of hip dislocation and/or spine deformities can prevent further complications.

Surveillance: Routine reevaluation by the multidisciplinary care providers to monitor progression of existing findings and development of new findings.

Genetic counseling.

ALS2-related disorder is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an ALS2 pathogenic variant, each sib of an affected individual has at conception 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 both ALS2 pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.

Suggestive Findings

ALS2-related disorder should be suspected in individuals with the following clinical, electrophysiologic, and neuroimaging findings and family history.

Establishing the Diagnosis

The diagnosis of ALS2-related disorder is established in a proband with suggestive findings and biallelic pathogenic variants in ALS2 identified on molecular genetic testing (see Table 2).

Note: Identification of biallelic ALS2 variants of uncertain significance – or identification of one known ALS2 pathogenic variant and one ALS2 variant of uncertain significance – does not establish or rule out a diagnosis of this disorder.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of ALS2-related disorder has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Pathogenic variants in ALS2 are responsible for a retrograde degeneration of the upper motor neurons of the pyramidal tracts, leading to phenotypes on a clinical continuum ranging from infantile ascending hereditary spastic paraplegia (IAHSP) to juvenile forms without lower motor neuron involvement (juvenile primary lateral sclerosis [JPLS]) or with lower motor neuron involvement (juvenile amyotrophic lateral sclerosis [JALS]).

An increasing number of individuals have been identified with biallelic pathogenic variants in ALS2 [Hadano et a 2001, Yang et al 2001, Eymard-Pierre et al 2002, Devon et al 2003, Gros-Louis et al 2003, Kress et al 2005, Eymard-Pierre et al 2006, Panzeri et al 2006, Sztriha et al 2008, Verschuuren-Bemelmans et al 2008, Herzfeld et al 2009, Mintchev et al 2009, Shirakawa et al 2009, Sheerin et al 2014, Simone et al 2018, Borg et al 2021, Lin et al 2021, Nogueira et al 2021, Shepheard et al 2021, Sprute et al 2021]. The following description of the phenotypic features associated with this disorder is based on these reports. Sprute et al [2021] reviewed the clinical and genetic characteristics of 82 individuals described in the literature to July 2020. There may be intra- as well as interfamilial phenotypic variability in ALS2-related disorder [Nogueira et al 2021].

Infantile ascending hereditary spastic paraplegia (IAHSP). Spasticity with increased reflexes and sustained clonus of the lower limbs begins during the first two years of life (and often in the first year) and extends to upper limbs by age seven to eight years. 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 in the advanced stage of disease are reported to require feeding by gastrostomy tube and to lose bladder and sphincter functions [Verschuuren-Bemelmans et al 2008].

Overall, IAHSP is compatible with long survival. Cognitive function is preserved.

Juvenile primary lateral sclerosis (JPLS) is characterized by 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].

Juvenile amyotrophic lateral sclerosis (JALS or ALS2). Onset is between ages three and 20 years. All affected show a spastic pseudobulbar syndrome (spasticity of speech and swallowing) together with spastic paraplegia. Peroneal muscular atrophy is observed in some (not all) individuals. At the time of the description of clinical manifestations, three individuals from one family were bedridden by ages 12, 20, and 50 years; another individual remained ambulatory until age 50 years [Ben Hamida et al 1990, Hentati et al 1994].

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

Genotype-Phenotype Correlations

Sprute et al [2021] identified significant clinical heterogeneity, and no correlation between disease severity and affected domain or type of variant. Both IAHSP and JPLS have been associated with truncating ALS2 variants.

Nomenclature

In some instances, the same entity may be referred to as either juvenile primary lateral sclerosis (JPLS) or infantile ascending hereditary spastic paraplegia (IAHSP).

JALS may also be referred to as JALS/ALS2.

Prevalence

No data on prevalence are available; however, ALS2-related disorder is probably currently underdiagnosed.

ALS2-related disorder has 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 that only four of 11 families with IAHSP have ALS2 pathogenic variants. No other genes/loci causing this phenotype have been identified.

Autosomal recessive hereditary spastic paraplegia (ARHSP). In general in ARHSP with onset during the first decade, the progression is less severe and may appear non-progressive, and spasticity predominates over weakness. In later-onset ARHSP there may be progressive worsening of gait. Pseudobulbar involvement in ALS2-related disorder delineates it from other genetic forms of spastic paraparesis.

ARHSP caused by pathogenic variants in ERLIN2 (SPG18; see Hereditary Spastic Paraplegia Overview) has been described in a consanguineous family from Saudi Arabia having four sibs with infantile-onset primary lateral sclerosis (PLS) with severe progression requiring wheelchair by age 12 years and associated with a homozygous splice junction pathogenic variant (c.499-1G>T).

Metabolic causes of progressive HSP include X-linked adrenoleukodystrophy, arylsulfatase A deficiency, and mitochondrial dysfunction (see Mitochondrial Disorders Overview); however, decline in behavior or cognitive function is frequently observed in these conditions.

Note: PLS, 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, has been reported in adults with an isolated degenerative process of the upper motor neurons. Phenotypic overlap has not been described between PLS and ALS2-related disorder [Brugman et al 2007].

Amyotrophic Lateral Sclerosis (ALS)

For a detailed discussion of ALS and the differential diagnosis of ALS, see Amyotrophic Lateral Sclerosis Overview.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ALS2-related disorder, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Management by multidisciplinary specialists, including neurology, orthopedics, physical therapy, occupational therapy, speech and language therapy, and feeding specialists (gastroenterology, nutrition) is recommended.

Surveillance

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.

Mode of Inheritance

ALS2-related disorder is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one ALS2 pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an ALS2 pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent, the following possibilities should be considered:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for an ALS2 pathogenic variant, each sib of an affected individual has at conception 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.
• Intrafamilial variability is recognized. For example, Mintchev et al [2009] describe two sibs with juvenile primary lateral sclerosis and homozygous ALS2 c.2980-2A>G pathogenic variants; one sib required a wheelchair at age two years while the other sib required a wheelchair at age 50 years.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Individuals with ALS2-related disorder 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 of an ALS2 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the ALS2 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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 carriers or are at risk of being carriers.

Prenatal Testing and Preimplantation Genetic Testing

Once the ALS2 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Biallelic pathogenic variants of ALS2, the gene encoding alsin Rho guanine nucleotide exchange factor, cause an early-onset progressive neurodegeneration, predominantly of upper motor neurons. This manifests clinically as ALS2-related disorder comprising the spectrum of IAHSP (infantile-onset ascending hereditary spastic paralysis), JALS (juvenile amyotrophic lateral sclerosis), and JPLS (juvenile primary lateral sclerosis). Alsin has multiple cellular functions including modulation of endosome and mitochondrial trafficking, and endocytosis.

Mechanism of disease causation. Nonsense, frameshift, missense, and splice site ALS2 variants cause loss of function or dysfunction of the cellular processes.

Author Notes

Dr Orrell is Associate Professor in Clinical Neurosciences at UCL Queen Square Institute of Neurology, and Consultant Neurologist at Royal Free London Hospital and National Hospital for Neurology and Neurosurgery, London. He has longstanding research and clinical interests in the genetics, pathogenesis, experimental therapeutics, and management of patients with motor neuron diseases, including ALS.

Acknowledgments

Dr Orrell acknowledges support from the Motor Neurone Disease Association.

Author History

Enrico S Bertini, MD; Ospedale Bambino Gesu, Rome (2005-2016)
Odile Boespflug-Tanguy, MD, PhD; Institut National de la Santé et de la Recherche Médicale, Clermont-Ferrand (2005-2016)
Don W Cleveland, PhD, University of California San Diego (2005-2016)
Eleonore Eymard-Pierre, PhD; Institut National de la Santé et de la Recherche Médicale, Clermont-Ferrand (2005-2016)
Richard W Orrell, BSc, MD, FRCP (2016-present)
Koji Yamanaka, MD, PhD; RIKEN Brain Science Institute, Wako (2005-2016)

Revision History

• 13 May 2021 (bp) Comprehensive update posted live
• 28 January 2016 (me) Comprehensive update posted live
• 18 April 2013 (tb) Revision: information on mutations in ERLIN2 and SIGMAR1 added to Differential Diagnosis
• 10 February 2011 (me) Comprehensive update posted live
• 21 October 2005 (me) Review posted live
• 16 December 2004 (esb) Original submission

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