Clinical Guidance

GARS1-iSMA. GARS1 pathogenic variants in the catalytic or anticodon binding domain are associated with this phenotype: , , , and .

GARS1 adolescent- or early adult-onset HMSN

• GARS1 variants associated exclusively with distal spinal muscular atrophy V (dSMA-V): and .

• GARS1 variants associated with Charcot-Marie-Tooth neuropathy type 2D (CMT2D): , , and .

• GARS1 variants associated with both dSMA-V and CMT2D: , , and

Source: GeneReviews — "GARS1-Associated Axonal Neuropathy"

Penetrance

To the authors' knowledge, reduced penetrance has not been described for GARS1-iSMA. For adolescent- or adult-onset GARS1-HMSN, variable expressivity is described and at least one example of non-penetrance has been reported .

Source: GeneReviews — "GARS1-Associated Axonal Neuropathy"

Diagnostic Criteria

No consensus clinical diagnostic criteria for GARS1-associated axonal neuropathy have been published.

Suggestive Findings

GARS1-associated axonal neuropathy should be suspected in individuals with the following clinical findings; findings on EMG and neuroimaging; and family history.

Clinical Findings

GARS1 infantile-onset spinal muscular atrophy (GARS1-iSMA)

• Typically, infantile onset of respiratory distress, poor feeding, and muscle weakness, with distal weakness greater than proximal; however, some children may present with features similar to toddlers.

• Absence of molecular genetic findings of spinal muscular atrophy (SMA) (i.e., either biallelic SMN1 deletions or compound heterozygosity for an SMN1 deletion and an SMN1 sequence variant)

Source: GeneReviews — "GARS1-Associated Axonal Neuropathy"

Differential Diagnosis

Infantile-Onset Spinal Muscular Atrophy

Table 3.

Hereditary Disorders with Hypotonia in the Differential Diagnosis of GARS1 Infantile-Onset Spinal Muscular Atrophy (GARS1-iSMA)

Gene(s) or Region | DiffDx Disorder | MOI | Additional Features Overlapping w/GARS1-iSMA | Features of DiffDx Disorder Not Associated w/GARS1-iSMA

15q11.2-q131 | Prader-Willi syndrome | See footnote 1. | Feeding difficulties | Rarely assoc w/poor respiratory effort

CHATCHRNECOLQDOK7GFPT1RAPSN2 | Congenital myasthenic syndromes | ARAD | Hypotonia | Ophthalmoplegia, ptosis, episodic respiratory failure

Source: GeneReviews — "GARS1-Associated Axonal Neuropathy"

Management Guidelines

No clinical practice guidelines for GARS1-associated axonal neuropathy have been published. Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with GARS1-associated axonal neuropathy, the evaluations summarized in and (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 4. Recommended Evaluations Following Initial Diagnosis in Individuals with GARS1-Associated Axonal Neuropathy: Infantile-Onset Spinal Muscular Atrophy (GARS1-iSMA)

Source: GeneReviews — "GARS1-Associated Axonal Neuropathy"

Clinical Guidance

Medications that are toxic or potentially toxic to persons with HMSN comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association website (pdf) for an up-to-date list. Chemotherapy for cancer that includes vincristine may be especially damaging to peripheral nerves and may severely worsen HMSN . Given the relatively few individuals reported with GARS1-iSMA and limited longitudinal follow up, avoidance of neurotoxic (and potentially neurotoxic) medications would be appropriate despite the current lack of data.

Source: GeneReviews — "GARS1-Associated Axonal Neuropathy"

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 — "GARS1-Associated Axonal Neuropathy"

Surveillance Guidelines

Table 7.

Recommended Surveillance for Individuals with GARS1-Associated Axonal Neuropathy: Infantile-Onset Spinal Muscular Atrophy

System/Concern | Evaluation | Frequency

Growth

| Plot growth parameters on standard growth chart. | At each visit or more often depending on severity of disease /or need for additional intervention

Gastrointestinal/

Feeding

| Oral feeders: aspiration risk, nutritional status, time to complete a feed

Gastric tube: nutritional status; constipation

Respiratory

| Non-ventilator dependent: work on breathing, oxygenation, ability to manage secretions.

Ventilator dependent: ventilation, oxygenation, secretions

Musculoskeletal

| OT, PT assessment of gross motor skills, mobility, need for assistive devices, activities of daily living

Orthopedist eval for kyphoscoliosis, contractures, hip dislocation

Development

| Monitor developmental progress educational needs.

Family support

resources | Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources) care coordination.

OT = occupational therapist; PT = physical therapist

Table 8.

Recommended Surveillance for Individuals with GARS1-Associated Axonal Neuropathy: Adolescent-/Adult-Onset Hereditary Motor/Sensory Neuropathy

System/Concern | Evaluation | Frequency

Neurologic

|

• Screening neurologic exam w/focus on progression of limb weakness

• Eval for pain

| Annually or more often depending on disease progression patient needs

Musculoskeletal,

activities of daily

living mobility |

Source: GeneReviews — "GARS1-Associated Axonal Neuropathy"