A number sign (#) is used with this entry because of evidence that the James type of infantile spinal muscular atrophy (SMAJI) is caused by heterozygous mutations in the GARS1 gene (600287) on chromosome 7p15.

Heterozygous mutation in the GARS1 gene can also cause CMT2D (601472) and HMND5 (600794), which have similar but less severe features.

The James type of infantile spinal muscular atrophy (SMAJI) is a severe neuromuscular disorder with onset of hypotonia in the first weeks or months of life. Some patients may have normal early motor development prior to the onset of symptoms, but all show delayed motor milestones with loss of previous motor skills in the first year of life. There is muscle weakness and atrophy, primarily affecting distal muscles, resulting in the inability to walk independently and causing impairment of fine motor skills of the hands. The disorder is slowly progressive: additional features may include feeding difficulties with failure to thrive, foot deformities, hyperlordosis, scoliosis, vocal cord weakness, and respiratory insufficiency, which may require intervention. Laboratory studies are most consistent with a motor neuronopathy, although skeletal muscle biopsy may also show myopathic features. This disorder is considered to be at the most severe end of the phenotypic spectrum of disorders caused by mutations in the GARS1 gene. The disorder is phenotypically similar to SMA1 (253300) (summary by Eskuri et al., 2012; Markovitz et al., 2020).

James et al. (2006) reported a 7-year-old girl, born of unrelated parents (family 1), who presented at 6 months of age with lower extremity weakness and 'floppy feet.' She had normal early motor development until that time, but thereafter showed motor difficulties and never achieved independent ambulation. The disorder was progressive, and physical examination showed distal muscle weakness and atrophy with areflexia, particularly of the lower limbs, but also eventually affecting the hands. She developed mild weakness of eye closure, weak cough, decreased voice volume, and mild respiratory insufficiency with use of accessory muscles and forced vital capacity at 80% of predicted values. Skeletal features included hip flexion contractures, foot deformities, marked lumbar lordosis, and scoliosis. EMG and muscle biopsy were consistent with denervation due to anterior horn cell degeneration. Motor and sensory nerve conduction velocities were normal.

Eskuri et al. (2012) reported a pair of monozygotic twin girls who had severe hypotonia with no spontaneous movement of the toes or feet by 6 months of age. At 16 months, they had delayed motor milestones and loss of motor skills, with lack of pincer grasp and inability to walk independently. Additional features included poor overall growth (less than first percentile for height and weight), flat feet, diminished or absent reflexes, hand muscle wasting, hyperlordosis, scoliosis, and vocal cord dysfunction with inspiratory stridor. Muscle biopsy in one twin showed fiber type variation and type I fiber predominance, consistent with a congenital myopathy, whereas electrophysiologic studies in the other twin showed decreased nerve amplitudes and fibrillations, consistent with a motor neuronopathy. Neither had apparent sensory abnormalities.

Forrester et al. (2020) reported a 12-month-old infant with SMAJI who presented at about 3 months of age with a neurogenic disorder characterized by severe muscle weakness and failure to thrive. The weakness was more severe in the lower limbs and distally, although the child was ventilator-dependent from age 7 months and required a feeding tube. EMG and nerve conduction studies suggested neurogenic abnormalities with a severe reduction in compound muscle action potential (CMAP) and slowed motor conduction; sensory values were normal.

Markovitz et al. (2020) reported 3 unrelated infants with SMAJI. The patients, who ranged from 6 to 39 months of age, presented at birth (patient 3) or in the first weeks of life (patients 1 and 2) with severe muscle weakness, poor feeding, and weak cry with respiratory distress. They had hypotonia, hyporeflexia, and respiratory insufficiency with stridor, necessitating tracheostomy or mechanical ventilation. The muscle weakness was more prominent in the lower limbs; there was both distal and proximal weakness. All had poor feeding and were gastrostomy-tube dependent. The 2 patients with slightly later onset had regression of motor skills. Additional features observed in 1 or 2 patients included tongue fasciculations, muscle atrophy, contractures, claw-like hands, pes cavus, and kyphoscoliosis. Nerve conduction studies showed decreased CMAP, EMG showed poor muscle recruitment, and muscle biopsy showed variation in fiber size, denervation atrophy, and fascicular atrophy. The findings were most consistent with a chronic active axonal sensorimotor peripheral neuropathy, although motor features were more severe. Only 1 had overt sensory impairment, although all had poor sural nerve sensory responses on EMG/NCV studies.

The heterozygous mutations in the GARS1 gene that were identified in patients with SMAJI by James et al. (2006) and Markovitz et al. (2020) occurred de novo.

In a 7-year-old girl with SMAJI, James et al. (2006) identified a de novo heterozygous missense mutation in the GARS1 gene (G598A; 600287.0007). Functional studies of the variant were not performed, but the mutation affected a residue in the anticodon binding domain; the authors postulated a dominant-negative effect.

In a pair of monozygotic twin girls with SMAJI, Eskuri et al. (2012) identified a de novo heterozygous missense mutation in the GARS1 gene (G652A; 600287.0007), which the authors stated was the same mutation as that reported by James et al. (2006). Functional studies of the variant were not performed.

In a 14-month-old infant with SMAJI, Forrester et al. (2020) identified a heterozygous missense mutation in the GARS1 gene (E125K; 600287.0009). Functional studies of the variant were not performed. There was no mention of family history, segregation of the mutation, or genetic testing of the parents.

In 3 unrelated children with SMAJI, Markovitz et al. (2020) identified de novo heterozygous missense mutations in the GARS1 gene (I334N, 600287.0010 and G652R, 600287.0011). The mutations, which were found by trio-based exome sequencing, were not present in the gnomAD database. In vitro functional complementation studies showed that the I334N variant was unable to rescue the growth defect phenotype in yeast, consistent with a loss-of-function effect. Functional studies of the G652R variant were not performed.