Clinical Guidance

Variant locations. Reported phenotype correlations with variant locations to date include the following :

• Most reported SCA28-related pathogenic variants affect the proteolytic domain (exons 15 and 16).

• The five SPAX5-related pathogenic variants described to date are in the proteolytic domain (exons 15 and 16).

• SCAR-related pathogenic variants, identified in two individuals to date, are compound heterozygous variants – p.[Tyr616Cys];[p.Val723Met] and p.[Arg632Ter];p.[Val723Met] – located in the proteolytic domain (exons 15 and 16).

• OPA12-related pathogenic variants cluster in the ATPase domain (exons 9 to 12).

Source: GeneReviews — "AFG3L2-Related Neurologic Disorders"

Penetrance

SCA28. Based on studies published to date, penetrance appears to be complete . OPA12. Reduced penetrance or subclinical phenotypes are suggested by published data .

Source: GeneReviews — "AFG3L2-Related Neurologic Disorders"

Diagnostic Criteria

No consensus clinical diagnostic criteria for AFG3L2-related neurologic disorders have been published.

Suggestive Findings

The diagnosis of an AFG3L2-related neurologic disorder should be considered in probands with the following clinical and imaging findings and family history.

Clinical findings

Source: GeneReviews — "AFG3L2-Related Neurologic Disorders"

Differential Diagnosis

Spinocerebellar ataxia type 28 (SCA28). The ataxic gait of individuals with SCA28 is indistinguishable from that seen in other adult-onset inherited or acquired ataxias. When the family history suggests autosomal dominant inheritance, all other autosomal dominant cerebellar ataxias should be considered (see Hereditary Ataxia Overview). Spastic ataxia type 5 (SPAX5). The differential diagnosis of SPAX5 should include other spastic ataxias and complex ataxias. AFG3L2-related autosomal recessive spinocerebellar ataxia (AFG3L2-SCAR) presents with a clinical phenotype that closely resembles SCA28; therefore, the differential diagnosis is similar to that of SCA28. Optic atrophy type 12 (OPA12). Optic atrophy observed in individuals with OPA12 is clinically indistinguishable from that seen in other forms of optic atrophy. See for selected genes of interest in the differential diagnosis of AFG3L2-related neurologic disorders. Table 2. Genes of Interest in the Differential Diagnosis of AFG3L2-Related Neurologic Disorders

Management Guidelines

No clinical practice guidelines for AFG3L2-related neurologic disorders have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with an AFG3L2-related neurologic disorder, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

AFG3L2-Related Neurologic Disorders: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Cerebellar extracerebellar

| Neurologic exam to assess cerebellar motor dysfunction (gait postural ataxia, dysmetria, dysdiadochokinesis, tremor, dysarthria, nystagmus, saccades, smooth pursuit) | Use standardized scale to establish baseline for ataxia (SARA).1

Evaluate for UMN /or LMN dysfunction (weakness, spasticity, Babinski signs, hyperreflexia, amyotrophy, fasciculations). | • Brain MRI /or spinal cord MRI may be indicated to rule out coincident pathologies.

• Consider referral to neuromuscular clinic.

Evaluate for extrapyramidal features (e.g., dystonia, parkinsonism). | Consider referral to movement disorders clinic.

Consider referral to OT, PT, rehab specialist. | To assess gross motor fine motor skills, gait, ambulation, need for adaptive devices

Source: GeneReviews — "AFG3L2-Related Neurologic Disorders"

Clinical Guidance

Alcohol consumption and sedatives such as benzodiazepines may worsen gait ataxia and coordination difficulties. Carbamazepine and phenytoin may exacerbate myoclonus in spastic ataxia type 5 (SPAX5).

Source: GeneReviews — "AFG3L2-Related Neurologic Disorders"

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 — "AFG3L2-Related Neurologic Disorders"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended.

Table 5.

AFG3L2-Related Neurologic Disorders: Recommended Surveillance

System/Concern | Evaluation | Frequency

Neurologic

| • Neurologic assessment for progression of ataxia, UMN or LMN signs, dystonia parkinsonism, autonomic dysfunction

• Monitor ataxia progression w/standardized scale (SARA).1

| Annually or more often for an acute exacerbation

Physiatry OT/PT assessment of mobility self-help skills as they relate to ataxia, spasticity, weakness | Annually or more often for an acute exacerbation

EEG seizure history (in SPAX5) | Every 6 mos or annually; more often for an acute exacerbation

Dysarthria

| Assess need for alternative communication method or speech therapy. | Per disease progression

Dysphagia

| Assess aspiration risk feeding methods.

Weight/ Nutritional status

| • Monitor BMI.

• Consult nutritionist.

• High-calorie supplementation

| Annually

Ophthalmologic

involvement | • Assessment of nystagmus, ophthalmoparesis, ptosis.

• Assessment of visual acuity photophobia.

Cognitive/

neurobehavioral/

psychiatric manifestations | Evaluate mood, signs of psychosis, cognitive complaints, cognitive deterioration (e.g., using CCAS scale) to identify need for pharmacologic psychotherapeutic interventions. | Per disease progression development of psychiatric manifestations

Family/Community

| Assess family need for social work support (e.g., pall...

Source: GeneReviews — "AFG3L2-Related Neurologic Disorders"