Clinical Guidance

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.

Source: GeneReviews — "ALS2-Related Disorder"

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

Source: GeneReviews — "ALS2-Related Disorder"

Differential Diagnosis

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.

Source: GeneReviews — "ALS2-Related Disorder"

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

Source: GeneReviews — "ALS2-Related Disorder"

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.

Source: GeneReviews — "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 /

Educational issues

| Monitor developmental progress/educational needs.

Spine and hips

| Monitor to assure early detection of scoliosis /or hip dislocation.

Musculoskeletal/

ADL | PT OT to monitor gross motor fine motor skills therapy/equipment needs

Dysarthria

| Per speech language therapist

Dysphagia

| Monitor nutrition, safety of oral feeding in those w/o gastrostomy tube.

Bladder

dysfunction | Per treating urologist

Bowel

dysfunction | Per treating clinician

Family support/

resources | Use of local resources, coordination of care

ADL = activities of daily living; OT = occupational therapy; PT = physical therapy

Source: GeneReviews — "ALS2-Related Disorder"