ALS2-Related Disorder

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:

1. 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

2. 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

3. 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.