GARS1-Associated Axonal Neuropathy

Clinical characteristics: The phenotypic spectrum of GARS1-associated axonal neuropathy ranges from GARS1 infantile-onset SMA (GARS1-iSMA) to GARS1 adolescent- or early adult-onset hereditary motor/sensory neuropathy (GARS1-HMSN).

1. GARS1-iSMA. Age of onset ranges from the neonatal period to the toddler years. Initial manifestations are typically respiratory distress, poor feeding, and muscle weakness (distal greater than proximal). Weakness is slowly progressive, ultimately requiring mechanical ventilation and feeding via gastrostomy tube.

2. GARS1-HMSN. Age of onset is most commonly during the second decade (range eight to 36 years). Initial manifestations are typically muscle weakness in the hands sometimes with sensory deficits. Lower limb involvement (seen in ~50% of individuals) ranges from weakness and atrophy of the extensor digitorum brevis and weakness of toe dorsiflexors to classic peroneal muscular atrophy with foot drop and a high steppage gait.

Diagnosis/testing: The diagnosis of GARS1-associated axonal neuropathy is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in GARS1 identified by molecular genetic testing.

Management: Treatment of manifestations:

1. GARS1-iSMA. Supportive treatment should be tailored to the needs of the affected individual and his/her current functional status (non-sitter, sitter, or walker). A multidisciplinary team to include a neurologist, pulmonologist, physiatrist, and medical geneticist is recommended.

2. GARS1-HMSN. Symptomatic treatment includes facilitating activities of daily living and addressing of mobility needs by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists.

Surveillance:

1. GARS1-iSMA. Routine monitoring of: growth, nutritional status, safety of oral feeding vs gastric tube feeding, respiratory status, need for assistive devices for activities of daily living and mobility, developmental progress and educational needs, and family need for social work support.

2. GARS1-HMSN. Routine monitoring of neurologic findings, physical therapy and occupational therapy needs, and skin for pressure ulcers or sores and skin breakdown (particularly the feet, hips, and other pressure points).

Agents/circumstances to avoid: Medications that are toxic or potentially toxic to persons with HMSN.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an individual with GARS1-HMSN in order to identify as early as possible those who would benefit from prompt initiation of symptomatic management and awareness of agents/circumstances to avoid.

Genetic counseling: GARS1-associated axonal neuropathy is an autosomal dominant disorder.

1. GARS1-iSMA. All probands reported to date with the GARS1-iSMA phenotype whose parents have undergone molecular genetic testing have the disorder as a result of a de novo GARS1 pathogenic variant. If the GARS1 pathogenic variant cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism.

2. GARS1-HMSN. Most individuals diagnosed with the GARS1-HMSN phenotype have an affected parent. Each child of an individual with GARS1-HMSN is at a 50% risk of inheriting the GARS1 pathogenic variant.

Once the GARS1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.