Clinical Guidance

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 [, , , , , , , , , , , , , , , , , , , ]. The following description of the phenotypic features associated with this disorder is based on these reports. reviewed the clinical and genetic characteristics of 82 individuals described in the literature to July 2020.

Diagnostic Criteria

No consensus clinical diagnostic criteria for ALS2-related disorder have been published. ALS2-related disorder comprises a phenotypic continuum of three phenotypes previously thought to be distinct entities: infantile-onset ascending hereditary spastic paralysis (IAHSP), juvenile primary lateral sclerosis (JPLS), and juvenile amyotrophic lateral sclerosis (JALS). Suggestive Findings ALS2-related disorder should be suspected in individuals with the following clinical, electrophysiologic, and neuroimaging findings and family history. Clinical Findings • Childhood onset of progressive upper motor neuron involvement (spasticity affecting the legs and upper limbs) • Variably lower motor neuron involvement (muscle atrophy and sensory disturbances) • Later pseudobulbar involvement including speech • Preservation of cognitive function Electrophysiologic Findings shows the results of various electrophysiologic studies in the different phenotypes of ALS2-related disorders. Note that nerve conduction velocities, visual evoked potentials, and brain stem auditory evoked potentials are normal in all phenotypes. Table 1. Electrophysiologic Studies in ALS2-Related Disorder by Phenotype Study | Phenotype

Management Guidelines

No clinical practice guidelines specifically for ALS2-related disorder have been published. Management is similar to that of persons with the wider range of amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegia (HSP), and other neurodegenerative conditions. Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with ALS2-related disorder, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 3. Recommended Evaluations Following Initial Diagnosis in Individuals with ALS2-related Disorder

Surveillance Guidelines

Table 5.

Recommended Surveillance for Individuals with ALS2-related Disorder

System/Concern | Evaluation | Frequency

Neurologic

involvement | Neurologic exam to monitor progression of existing findings development of new findings | Annually or as needed

Development /