Table 2.

Detailed clinical characteristics of patients with de novo p.Thr8Met SETX variants. NR: not reported

	Current study	Current study	Individual described by Kitao et al., 2020
Patient	Patient 1	Patient 2	Proband
Age at last review	10 years	14 years	29 years
Gender	Male	Male	Male
Country of parental origin	Mother: Irish Father: Irish-Canadian	Mixed Northern European-Italian	Japan
Birth weight/gestational age	3.2 kg / 41 weeks	3.3 kg / 40 weeks	NR
Current height (centile)	< 1%ile	133 cm (< 1%ile)	130 cm (< 1%ile)
Current weight (centile)	19.5 kg (< 1%ile)	30 kg (< 1%ile)	21 kg (< 1%ile)
Feeding/swallowing difficulties	Failure to thrive from an early age	Failure to thrive and diarrhea (age 4)	NR
Respiratory function	Recurrent episodes of croup, recurrent pneumonias, moderate obstructive sleep apnea	Nocturnal CPAP, restrictive lung disease	Respiratory failure at age 20 requiring tracheostomy with positive-pressure ventilation (TPPV)
G-tube and age at dependency	No	Age 12	NR
Developmental/academic history	Grade 5, above average	Grade 9, grade A average	NR
Communication	Excellent vocabulary and spelling, severe dysarthria	Excellent written communication, severe dysarthria	No dysarthria
Gross motor	Sat 7–8 months, crawled 18 months, cruised 2 years, ambulated with walker until 9 years	Delays in rolling, sitting, crawling, standing, walked at 14 months, ambulated until 12 years	Walked at 2.5 years, ambulated until 12 years
Fine motor	No pincer grasp, severely limited by hand contractures	Severely limited by hand contractures	Difficult to assess due to muscle weakness and contractures
Functional status	Non-ambulatory (wheel-chair dependent), can use fork with assistance, fully dependent for most ADLs	Non-ambulatory (wheel-chair dependent), fully dependent for ADLs, required 24-h care	Non-ambulatory at 12 years
Facial weakness	Dysarthria, lower facial weakness	Myopathic facies, mild bilateral ptosis, dysarthric speech	Weakness of facial muscles
Tongue fasciculations	Yes	Yes (with associated atrophy)	No
Axial hypotonia	Significant (unable to sit unsupported for 20 s)	Significant (unstable when leaning forward in his chair)	Decreased tone
Appendicular hypertonia/spasticity	Moderate in legs bilaterally	Mild	NR
Muscle weakness	Generalized weakness, distal more than proximal	Generalized weakness, distal more than proximal	Distal muscle weakness
Muscle atrophy	Generalized atrophy, most notable of thenar and hypothenar eminences	Generalized atrophy, most notable in fingers	Generalized muscle atrophy
Sensory exam	Intact vibration, proprioception mildly decreased	Pain and temperature preserved, vibration and proprioception mildly decreased	Impairment in all modalities distally
Deep tendon reflexes	Absent throughout	1 + throughout	Absent throughout
Extensor plantar response	Bilaterally extensor	Bilaterally extensor	Absent
Scoliosis	Severe scoliosis with a Cobb angle of 75 degrees	Marked left-sided thoracic scoliosis	Severe scoliosis, Cobb angle of 71 degrees
Contractures	Bilateral club feet at birth, severe hand contractures	Severe finger, knee, ankle contractures	Hand contractures
Cardiac function	Echocardiogram (age 9): normal	Normal	NR
Other	CSF, CPK, serum neuromuscular antibody panel, PMP22, MPZ, ERG2, LITAF, PRX, NFL sequencing, chromosomal microarray, and mitochondrial DNA sequencing: negative	Karyotype, Fragile X, FISH and methylation studies for Prader-Willi and Angelman syndromes, CPK, sequencing of PRX, PMP22, EGR2, MPZ and GJB1: negative	Comprehensive gene analysis of hereditary peripheral neurological diseases by next-generation sequencing: negative
Brain MRI	Several non-specific tiny white matter hyperintensities in the centrum semiovale and peritrigonal regions bilaterally	Non-specific left peritrigonal increased T2 and FLAIR signal	Normal
Spine MRI	Normal	Normal	NR
EMG/NCS	Severe axonal loss and slowed conduction velocity (Table 1)	Severe axonal loss and slowed conduction velocity (Table 1)	Decreased compound muscle action potential amplitudes and reduced motor nerve conduction velocity with absent sensory nerve action potentials
SETX (NM_015046.5)	c.23C > T (de novo)	c.23C > T (de novo)	c.23C > T (de novo)
Genomic position (Hg19)	chr9:135224793G > A	chr9:135224793G > A	chr9:135224793G > A
Predicted effect on protein	p.Thr8Met	p.Thr8Met	p.Thr8Met
Type of mutation	Missense	Missense	Missense