Table 1.
Clinical features and treatment details
| Clinical Features | Pre-Treatment Assessment | Metformin Treatment | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Pt | Age (y), Sex | Onset age (y) | Mutationa | Disease duration (y) | Concomitant AEDs | No. GTCS (last 28 days) | Myoclonusb | Disability scalec | Maximal dose (mg), adjusted dose (mg) | Outcome | Duration (months) | Adverse events |
| 1 | 17d, F | 13 | EPM2A: c.491 T > G (p.Ile164Ser), c.539 T > C (p.Leu180Pro) | 4 | VPA, ZNS, PB | 0e | +++ | 4 | 3000, 1500 | Mild improvement (see text) | 6 | Diarrhoea |
| 2 | 21, M | 16 | NHRLC1: c.436G > A (p.Asp146Asn), c.1133 T > C (p.Leu378Pro) | 4 | VPA, LEV, PERf, CNZ, CLB | 18 | + | 3 | 2000, 1000 | Seizure-freedom, improved cognition, lasted for 6 months | 9 | Diarrhoea |
| 3g | 25, F | 13 | EPM2A: c.243_246del (p.Asp82Argfs*7) | 10 | VPA, LEV, ZNS, PB, CNZ | 3 | +++ | 4 | 500, 500 | Disease progression | 12h | None |
| 4g | 19, F | 10 | NHLRC1: c.205C > G (p.Pro69Ala); c.826_829dup (p.Ala277Aspfs*23) | 7 | VPA, LEV, ZNS, CNZ | 6 | +++ | 4 | 1000, 500 | Disease progression | 24 | Asthenia |
| 5 | 17,F | 13 | NHLRC1: c.205C > G (p.Pro69Ala) | 3 | VPA, LEV, PER, CNZ | 8 | +++ | 4 | 2000, 2000 | Disease progression | 13 | None |
| 6 | 23, M | 14 | EPM2A: c.721C > T (p.Arg241*) | 7 | LEV, TPM, ZNS | 7 | +++ | 4 | 2000, 2000 | Disease progression | 9h | Elevated CPK, muscle cramps |
| 7 | 23, M | 10 | EPM2A: c.721C > T (p.Arg241*) | 11 | VPA, PB, PHT, PER, CNZ | 11 | +++ | 3 | 2000, 2000 | Disease progression | 28 | None |
| 8 | 18, M | 14 | NHLRC1: c.992del (p.Gly331Glufs*3) | 2 | VPA, LEV, PER | 2 | ++ | 2 | 1700, 500 | Disease progression | 26 | Diarrhoea |
| 9 | 22, F | 13 | NHLRC1: c.992del (p.Gly331Glufs*3) | 7 | VPA, ZNS, PER | 3 | +++ | 4 | 1700, 500 | Disease progression | 26 | Diarrhoea |
| 10 | 50, F | 18 | EPM2A: c.721C > T (p.Arg241*), c.835G > A (p.Gly279Ser) | 29 | VPA, LEV, ZNS, CNZ | 1 | +++ | 4 | 1000, 1000 | Mild improvement (see text) | 36 | None |
| 11 | 19, F | 11 | EPM2A: c.323G > T (p.Arg108Leu) | 7 | VPA, PB, PER, CNZ | 0.5 | +++ | 4 | 1000, 1000 | Disease progression | 12 | None |
| 12 | 18, M | 13 | NHLRC1: c.436G > A (p.Asp146Asn), c.1133 T > C (p.Leu378Pro) | 4 | VPA, LEV, ZNS, PB | 3 | ++ | 3 | 1500, 1500 | Disease progression | 12 | None |
Legend: AED antiepileptic drug, CLB clobazam, CNZ clonazepam, GTCS generalized tonic-clonic seizures, LD Lafora disease, LEV levetiracetam, PB phenobarbital, PER perampanel, PHT phenytoin, TPM topiramate, VPA valproate, ZNS zonisamide
aWhen only one variant is indicated, this is intended as homozygous. EPM2A RefSeq ID: NM_005670.4; NHLRC1 RefSeq: NM_198586.2
bMyoclonus severity: +, mild myoclonus, i.e. does not interfere with activities of daily living; ++, moderate myoclonus, i.e. interferes with activities of daily living but not with deambulation; +++, severe myoclonus, i.e. interferes with deambulation
cDisability scale developed by Franceschetti et al. [18]: 1, mild cognitive and motor impairment, preserved daily living activities, and social interaction; 2, moderate mental decline, limitations in motor activities and limited social interaction; 3, severe mental and motor impairment, needing help in walking and regular assistance in daily activity, and poor social interaction; 4, patient weelchair-bound or bedridden, and no significant daily living activities or social interaction
ddeceased
ethe patient did not present any GTCS but had 4 prolonged myoclonic seizures in 28 days requiring benzodiazepine rescue medications
fperampanel was introduced at the same time as metformin
gpreviously published in Ref. [19]
hsuspended