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.

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.

Although primary lateral sclerosis (PLS) is similar to amyotrophic lateral sclerosis (ALS; 105400), they are considered to be clinically distinct progressive paralytic neurodegenerative disorders. Following a period of diagnostic confusion, the clinical distinction between ALS and PLS became clear and diagnostic criteria were established (Pringle et al., 1992). PLS is characterized by degeneration of the upper motor neurons and the corticospinal and corticobulbar tracts, whereas ALS is a more severe disorder characterized by degeneration of both the upper and lower motor neurons. See 606353 for autosomal recessive juvenile-onset PLS, which is caused by mutations in the ALS2 gene (606352).

Spastic paraplegia-75 (SPG75) is an autosomal recessive, slowly progressive neurodegenerative disorder characterized by onset of spastic paraplegia and cognitive impairment in childhood (summary by Lossos et al., 2015). For a discussion of genetic heterogeneity of autosomal recessive SPG, see SPG5A (270800).