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. 2017 Oct 27;140(11):2838–2850. doi: 10.1093/brain/awx249

Table 1.

Clinical details of affected patients

Family 1 Family 2 Family 3
Pedigree ID Patient IV:1 Patient V:1 Patient V:3 Patient III:5
Mutation NM_021815.2 c.282 T>A; p.Ser94Arg NM_021815.2 c.335T>A; p.Val112Glu NM_021815.2 c.335T>A; p.Val112Glu NM_021815.2 c.629 C>T; Pro210Leu
Gender Female Female Male Female
Ethnicity Turkish Hispanic Hispanic Somalian
Age of latest exam, years 2.5 Deceased at 11 months Deceased age 6 months 3.5
Birth gestation, birth weight, OFC 32 w, 1676 g (50th centile), 30 cm (60th centile) 40 w, 2760 g (10th centile) 38 w, 2985 g (75th centile) 37 w, 2515 g (10-25th centile), 33 cm (50th centile)
Presentation at birth Floppy infant, lack of respiratory effort, ventilator dependent, swallowing difficulties Floppy infant, lack of respiratory effort, ventilator dependent, swallowing difficulties Floppy infant, lack of respiratory effort, ventilator dependent, swallowing difficulties Floppy infant, respiratory insufficiency, ventilated, swallowing difficulties
Neurological features

  • Severe global developmental delay

  • Motor reaction to sensory stimuli without orientation

  • Severe muscular hypotonia

  • Generalized muscle atrophy

  • Minimal spontaneous and non-purposeful antigravity movements

  • Bulbar insufficiency

  • Severe global developmental delay

  • Severe muscular hypotonia

  • Bulbar insufficiency

  • Seizures

  • Severe global developmental delay

  • Severe muscular hypotonia

  • Severe muscular hypotonia

  • Fatigability, independent sitting

  • Global developmental delay

  • Myoclonic jerks with EEG features
Respiratory features Continuous ventilation via tracheostomy Continuous ventilation via endotracheal intubation Continuous ventilation via tracheostomy Continuous ventilation via tracheostomy
Gastrointestinal features Gastrostomy Bowel perforations (recurrent) Bowel perforations (recurrent) Gastrointestinal reflux, Recurrent diarrhoea, Gastrostomy for swallowing difficulties
Ocular features Ophthalmoplegia, ptosis Not available/not reported Not available/not reported Ophthalmoplegia, ptosis
Neuroimaging Generalized atrophy of the brain (brain MRI, 2.5 years) Normal (cranial U/S at birth) Normal (brain MRI) Subcortical cysts (brain MRI, 2 months)
Nerve conduction studies/ EMG Repetitive stimulation revealed no responses from both median and tibialis nerves Not available Widespread fibrillation in limb and trunk muscles with no voluntary motor unit activity. The motor CMAP were severely reduced with relatively preserved conduction velocities Repetitive stimulation at 2 months of age of N. ulnaris, M. abductor digiti minimi dx. At rest, nerve stimulation (3 Hz) × 10 times resulted in 84% decrement. A marked reduction in decrement was noted after administration of high dose edrophonium, resulting in 17% decrement.
Muscle histology Myopathic changes, loss of fibre typing, atrophic fibres, targetoid areas on electron microscopy (muscle biopsy at 5 month of age) Generalized muscle atrophy Myofibres seem to vary little in shape; scattered myofibres showing segmental granularity with loss of cross sections; electron microscopy of the skeletal muscle fibres showed changes compatible with targetoid fibres: focal loss of Z-bands, unsynchronized contractile elements, and jumbled contractile elements Not performed
EEG Reduced activity and few spikes Left occipital and temporal epileptiform discharges with occasional right temporal lobe discharges In neonatal period, frequent spikes and sharp waves from the right temporal region at times clustering in a semi-rhythmic fashion up to 10 s. Some sharp wave activity was independently observed in the right central (C4) and over the central vertex (CZ) areas Epileptiform activity, (normalized at age 2 years on levetiracetam treatment)
Treatment and response In neonatal period no response to 3 days of pyridostigmine trial Not available/not reported Not available/not reported Positive test result: edrophonium (Tensilon®), pyridostigmine: improved tone and muscle function, with increased spontaneous movements of limbs and decrease in ophthalmologic symptoms Addition of 3,4-diaminopyridine: no effect and was terminated Ephedrine: positive effect on spontaneous motor activity in limbs and on respiratory function, additional to that of pyridostigmine

CMAP = compound muscle action potential; dx = dextra; EEG = electroencephalogram; OFC = occipitofrontal circumference; U/S = ultrasound; w = weeks.