Table 1.
Summary of clinical and instrumental features of published patients affected by pre-synaptic CMS
| Gene Chromosome Inheritance | Frequency | Onset | Phenotype | Brain MRI | RNS/SFEMG | Muscle biopsy | Genotype | Drugs | Ref. |
| SLC5A7 2q12.3 AD | 14 pts | con | Hypotonia, apneas, swallowing difficulties, developmental delay, ptosis, ophtalmoplegia, muscle atrophy (rare: hydramnios, arthrogriposis, facial dysmorphism, seizures) | brain atrophy (rare: intraventricular and putamen hemorrage) | decremental response to RNS | Myopathic changes, atrophic fibres, targetoid areas | c.282T>A/c.282T>A (p.Ser94Arg/Ser94Arg) c.335T>A/c.335T>A (p.Val112Glu/Val112Glu) c.629 C>T/c.629 C>T (p.Pro210Leu/Pro210Leu) c.194 G>A/c.313 C>T ((p.Gly65Glu/Pro105Ser) | some response to pyridostigmine and ephedrine; no response to 3,4-DAP and salbutamol | [8, 9, 18–21] |
| CHAT 10q11.23 AR | 52 pts | con or early infancy | reduced fetal movements, hypotonia, apneas, swallowing and feeding difficulties, developmental delay, fluctuated ptosis, ophthalmoparesis, muscle fatigability | (rare: mild delay in myelination of the centrum semiovale, and corpus callosum atrophy) | decremental response to RNS after prolonged high frequency; increased jitter and blocking at SFEMG | unspecific myopathic changes, type 1 fibre predominance | c.1007T>C/c.1007T>C (p.Ile336Thr/Ile336Thr) c.629T>C/ 631 C>G (p.Leu210Pro/Pro211Ala) c.678_684delTGGCACC/2078T>G (p.*/Ile693Ser) c.1078 G.A/1078 G.A (p.Gly360Arg/Gly360Arg) | variable response to pyridostigmine and 3,4-DAP | [11, 30–41] |
| SLC18A3 10q11.23 AR | 4 pts | con | hypotonia, cyanosis, feeding difficulties, global developmental disability, ptosis, ophthalmoplegia, fatigable weakness (rare: arthrogryposis, severe necrotizing enterocolitis) | brain atrophy, demyelination (rare: small hemorrhages in the frontal and parietal lobes) | decremental response to RNS | n.p. | c.557 G>C/557 G>C (p.Gly186Ala/Gly186Ala)+10q11.22-q11.23del c.1192 G>C/1192 G>C (p.Asp398His/Asp398His) c.1078 G.A/1078 G.A (p.Gly360Arg/Gly360Arg) | slight response to pyridostigmine, and 3,4- DAP, distigmine and ephedrine | [10, 47–51] |
| SNAP25 20p12.12 AD | 2 pt | con | fetal hypomotility, cyanosis, fluctuating ptosis, dysarthria, ataxia, fatigable weakness, arthrogryposis and fatal respiratory failure (1 pt) | normal (1 pt), n.p. (1 pt) | decremental response to RNS (1 pt), n.p. (1 pt) | normal (1 pt), mild fibres size variation (1 pt) | c.200T>A (p.Ile67Asn) c.529 C>T (p.Gln177X) | no response to pyridostigmine; slight response to 3,4-DAP | [74] |
| VAMP1/ SYB1 12p13.21 AR | 9 pts | con | hypotonia, feeding difficulties, delayed motor development, ophthalmoparesis, facial and bulbar muscle weakness, generalized muscle weakness, joint contractures | n.p | decremental response to RNS | myopathic features and borderline low complex IV activity, type 2 fibres atrophy | c.200T>A/200T>A (p.Ile67Asn/Ile67Asn) c.146 G>C/146 G>C (p.Arg49Pro/Arg49Pro) c.51_64delAGGTGGGG GTCCCC/ c.51_64delAGGTGGGG GTCCCC (p.Gly18TrpfsTer5*/Gly18TrpfsTer5*) c.340delA/340delA (p.Ile114SerfrsTer72 for isoform A, p.Ser114ValfsTer32 for isoform D) | slight response to pyridostigmine and salbutamol | [67–70] |
| SYT2 1q32.1 AD | 10 pts | childhood | ptosis, ophthalmoparesis, limb weakness, muscle fatigue, gait difficulties, foot deformities, reduced or absent deep tendon reflexes | n.p | decremental response to RNS | n.p | c.920A>C (p.Asp307Ala) c.923 C>T (p.Pro308Leu) | no response to pyridostigmine; slight response to 3,4-DAP | [81–87] |
| UNC13A 19 AR | 1 pt | con | premature birth, hypotonia, ventilator dependent, facial dysmorphism, ptosis | thin corpus callosum | decrement response to RNS | marked type 2 fibres atrophy | c.304 C>T/304 C>T (p.Gln102*/Gln102*) | no response to pyridostigmine; modest response to 3,4-DAP | [94] |
| MYO9A 15q23 AR | 3 pts | con | fetal hypomotility, swallowing difficulties, apneas, delayed cognitive functions, ptosis, ophthalmoplegia, muscle weakness | normal | decremental response to RNS; abnormal jitter at SFEMG | n.p. | p.Arg1517His/Arg2283His p.Asp1698Gly/Asp1698Gly | good response to pyridostigmine and 3,4-DAP | [15] |
| PREPL 2p21 AR | 11 pts | con | hypotonia, feeding difficulties, respiratory distress, cognitive impairment, ptosis, bulbar signs, muscle weakness, short stature (rare: absence of uterus and ovaries, microcephaly) | normal | normal response to RNS (rare: decremental response) | irregular intracellular vacuoles and perimysium fibrosis | c.616 + 1 G>T/616 + 1 G>T (p.Glu206Glyfs*22/Glu206Glyfs*22) c.1528 C>T/2094 G>T (p.Arg510*/Lys698Asn) c.1529 + 1 G>A/c.1784delinsAA (p.?/Thr595Lysfs * 19) c.1282_1285delTTTG/c.1282_1285delTTTG (p.Phe428Argfs*18/Phe428Argfs*18) c.342delA/342delA (p.Val115Leufs*39/Val115Leufs*39) | slight response to pyridostigmine | [103–109] |
| LAMA5 20q13.33 AR | 1 pt | con | hypotonia, respiratory failure, scoliosis, chronic inflammatory bowel disease, ptosis, ophthalmoplegia, muscles weakness, dysmorphic features, myopia, tics | mild cerebral atrophy | decremental response to RNS | type I fibres predominance; EM: increased postsynaptic folding, moderate reduction of SVs | p.Arg2659Trp/Arg2659Trp | response to pyridostigmine and 3,4-DAP | [14, 112] |
| RPH3A 12q24.13 AR/AD? | 1 pt | childhood | limb weakness, fatigability, hand tremors, hands incoordination, postural imbalance, nasal speech, learning disabilities | normal | Incremental response to high frequency RNS; abnormal jitter at SFEMG | type I fibres predominance; EM: reduction of SVs, degenerative lamellar bodies | c.806 G>A/ c.1390 G>T (p.Arg269Gln/p.Val464Leu) | response to albuterol sulfate | [119] |
| SLC25A1 22q11.21 AR | 19 pts | childhood | ptosis, ophthalmoplegia, some dysmorphisms, dysarthria, chewing difficulties, generalized weakness, mild intellectual disability | normal | decremental response to RNS; abnormal jitter and blockings at SFEMG | non-specific myopathic features; enlarged mitochondria and increased in number on EM | c.205 G>T/c.205 G>T (p.Asp69Tyr/p.Asp69Tyr) c.740 G>A/c.740 G>A (p.Arg247Gln/p.Arg247Gln) c.628 C>T/c.145 G>A (p.Arg210X/p.Val49Met) | partial response to pyridostigmine and 3,4-DAP | [122–126] |
MRI: magnetic resonance imaging; RNS: repetitive nerve stimulation, SFEMG: single fiber electromyography; AD: autosomal dominant, AR: autosomal recessive; 3,4-DAP: 3,4-diaminopyridine; SVs: synaptic vescicles: con: congenital: pts: patients; n.p.: not performed; ?: inheritance pattern not clear.