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Table 2 Detailed clinical characteristics of patients with de novo p.Thr8Met SETX variants. NR: not reported

From: De novo pathogenic variant in SETX causes a rapidly progressive neurodegenerative disorder of early childhood-onset with severe axonal polyneuropathy

 

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