Clinical Description
Individuals with GARS1-associated axonal neuropathy can present across the life span (infancy through adulthood). Although in utero presentation of a fetus with a GARS pathogenic variant has not been reported to date, it is possible (if not likely) given reports of in utero presentations of spinal muscular atrophy [MacLeod et al 1999, Kong et al 2021]. GARS1 infantile-onset SMA presents with respiratory distress, poor feeding, and muscle weakness that is distal greater than proximal. GARS1 adolescent- or early adult-onset hereditary motor/sensory neuropathy presents from childhood to adulthood, most commonly with muscle weakness in the hands and sometimes with sensory deficits in a stocking and (less often) glove pattern.
GARS1 Infantile-Onset Spinal Muscular Atrophy (GARS1-iSMA)
Age of onset ranges from the neonatal period to the toddler years. The presenting manifestations are typically respiratory distress, poor feeding, and muscle weakness (distal weakness greater than proximal).
Neonates present emergently with respiratory distress (stridor, weak cry, and respiratory insufficiency), poor feeding, and severe hypotonia, ultimately requiring mechanical ventilation and early placement of a gastrostomy tube. In neonates, the neurologic examination is notable for hypotonia, hyporeflexia, and tongue fasciculations in some.
Infants typically have delayed motor milestones with subsequent motor milestone regression. They do not achieve independent walking [James et al 2006, Eskuri et al 2012, Liao et al 2015]. Toddlers present with delayed walking and lack of stability progressing to loss of ambulation [Liao et al 2015]. Infant and toddler examinations are notable for hypotonia, absent or diminished reflexes, and stridor in some.
Nerve/muscle biopsy. Hematoxylin and eosin stain of quadriceps muscle of an infant show marked variation in fiber size with small group and fascicular atrophy typical of spinal muscular atrophy (see ).
Hematoxylin and eosin stain of quadriceps muscle of an infant with GARS1-iSMA at 4X (A) and 10X (B) magnification showing findings typical of spinal muscular atrophy A. Low power magnification demonstrates small atrophied fibers with marked variation (more...)
GARS1 Adolescent- or Early Adult-Onset Hereditary Motor/Sensory Neuropathy (GARS1-HMSN)
Age of onset ranges from eight to 36 years, with most individuals (75%) developing manifestations during the second decade of life [Sivakumar et al 2005, James et al 2006].
The presenting manifestation is typically muscle weakness, often initially evident as transient cramping and pain in the hands on exposure to cold and cramping in calf muscles on exertion. Progressive weakness and atrophy of the thenar and first dorsal interosseus muscles are the major complaints (). The hypothenar eminence is spared until later in the disease course.
The lower limbs are involved in about 50% of affected individuals. Lower-extremity involvement 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. Peroneal muscles are affected earlier and more severely than the calf muscles. Peroneal muscular atrophy is associated with pes cavus and moderate sensory abnormalities. Reflexes at the ankles are diminished or absent in individuals with leg muscle weakness and sensory deficits.
Proximal limb muscle weakness is not observed in the upper or lower extremities.
Sensory examination is either normal or shows mild-to-moderate impairment of vibration sense in the hands and feet and reduction of pinprick, temperature, touch, and vibration perception in a stocking and (less often) glove pattern.
A minority of individuals show upper motor neuron signs (mild pyramidal signs and spasticity) [Christodoulou et al 1995, Sivakumar et al 2005, Dubourg et al 2006]. The occurrence of upper motor neuron signs may be attributed to relative preservation of sensory nerves and involvement of central motor pathways.
While progression of manifestations is often slow, extending over decades, some individuals may have a more rapid evolution of lower extremity involvement, which may more often be seen in the setting of both motor and sensory changes [Dubourg et al 2006].
Nomenclature
GARS1 infantile-onset spinal muscular atrophy (GARS1-iSMA). In this GeneReview,
GARS1-iSMA is used to denote early-onset SMA (from the neonatal period to toddler age, presenting with respiratory insufficiency, poor feeding, hypotonia and areflexia).
GARS1 adolescent- or early adult-onset hereditary motor/sensory neuropathy (GARS1-HMSN)