Allen Supplemental Data pg 3
Allen Supplemental Data pg 3
table e-3. Progressive Myoclonus EpilepsiesDisease (genes) / Inheritance / Age of onset / Cognition / Other Clues/Investigations
Neuronal ceroid lipofuscinosis
(PPT1, TPP1, CLN3, DJAJC5, CLN5, CLN6, MFSD8, CLN8, CTSD, GRN, ATP13A2, CTSF, KCTD7) / AR / rare AD late onset forms / Early childhood, but several clinical and gene variants. / Early progressive decline / Visual deterioration common (except Kuf’s/adult form). Age, neurophysiology (EEG, VER, ERG helpful), skin biopsy, enzyme analysis, and MRI help delineate phenotype
Lafora’s Disease (EPM2A/ EPM2B or NHLRC1) / AR / 12-15 years, or earlier onset forms. / Early decline common / May mimic genetically generalized epilepsy (formerly IGE) at onset, seizures can be occipital, visual hallucinations. Ataxia. Skin biopsy (complete sweat gland duct visualisation) for Lafora bodies
Unverricht-Lundborg Disease (CSTB) / AR / 5 to 15 years / None/ mild/ late decline / Overall one of most common causes of PME, mild ataxia, other generalised seizures
North-Sea PME (GOSR2)
[Disorder of Golgi Qb-SNARE complex (vesicle trafficking)] / AR / Age < 2 years with ataxia, PME > 5 years / Slow or no decline / GTCS, absences and drop attacks. Progressive physical deterioration, scoliosis, syndactyly, pes cavus, hyperCKemia
Myoclonus Epilepsy and Ataxia due to potassium channel (K+) mutation “MEAK” (KCNC1) / AD / 6 to 14 years / Mild later decline / Resembles Unverricht-Lundborg in early stages but more progressive later course
PRICKLE1-related PME with Ataxia (PRICKLE1). [PRICKLE proteins are involved in cell polarity signalling in embryogenesis] / AR / 5 to 10 years / Usually preserved / Ataxia, myoclonus can affect bulbar/facial muscles
Action Myoclonus Renal Failure
(SCARB2/LIMP2) / AR / 2nd decade on / Usually preserved / Ataxia, dysarthria, with or without renal failure. French population.
Sialidosis (NEU1)
Type 1 (cherry red spot myoclonus syndrome).
Type 2 (Galactosialidosis) / AR / Type 1: juvenile to adult.
Type 2: infantile to early childhood / Type 1: usually normal
Type 2: usually impaired / Type 1: Visual disturbance, ataxia
Type 2: Signs of storage disorder (corneal clouding, coarse features, etc).
Urine sialyloligosaccharide may be elevated
Gaucher disease type 3 (GBA)
(non-infantile neuronopathic form) / AR / Usually 2 years / Decline in later stages / White cell enzyme analysis (B-glucocerebrosidase), bulbar, pyramidal, oculomotor signs
Myoclonus epilepsy with ragged red fibres/MERRF (MT-TK) / Mitochondrial / Usually childhood but any age / Decline (variable, can be mild) / Muscle biopsy, often multisystem (myopathy, optic atrophy, short stature, deafness)
CARS2 mutation (CARS2 encodes mitochondrial cysteinyl-tRNA synthetase) / AR / 5 to 10 years / Decline / Novel MERFF-like syndrome; tetraparesis, visual, hearing decline
Dentatorubral-pallidoluysian atrophy/ DRPLA (DRPLA) / AD / “PME” usually < 20 years / Decline / Ataxia, myoclonus, seizures, atrophy of related structures (e.g. cerebellum). More common in Japan.
Neuroserpinopathy (SERPINI1) / AD / Childhood to adulthood / Decline / Later dementia presentation also, frontal syndrome, brain biopsy (Collin’s bodies)
KCTD7 mutation (encodes Potassium Channel Tetramerisation Domain-Containing 7) / AR / < 2 years / Rapid decline / Rapid motor deterioration, other seizure types
CERS1 mutation (encodes ceramide synthase 1) / AR / 6 to 16 years / Decline / GTCS
AFG3L2 mutation (encodes the catalytic subunit of an ATP proteolytic complex of the inner mitochondrial membrane) / AR / Childhood / Mildly affected / Ataxia, or spastic ataxia with PME
Other known disorders associated with PME: Neurodegeneration with brain iron accumulation (NBIA-related disorders), GM2 gangliosidosis (Tay-Sachs disease), celiac disease, Alzheimer’s disease.
Other novel genes associated with PME (single cases or families): 5,10-methylenetetrahydrofolate reductase deficiency (MTHFR mutation, treatable): ASAH1 mutation, PRNP mutation, SACS mutation, TBC1D24 mutation, LMNB2 mutation.
Abbreviations: GTCS: generalized tonic clonic seizures; AR: autosomal recessive; AD: autosomal dominant.
Allen Supplemental Data pg 3
table e-4. Neuroserpinopathy families by mutation, age of onset and severitySERPINI1 Mutation (protein) / Onset (years), inheritance (dominant) / Clinical Features / Histopathology / MRI / Ref
Gly392Glu (G392E) / 10y,
de novo / PME with dementia (cognitive regression), myoclonus, occasional GTCS, still alive / No histopathology / Cerebellar atrophy / Allen et al, this case
Gly392Glu (G392E) / 13y,
(Family 3) / PME with dementia, status epilepticus, dysarthria, death at 19y (status epilepticus). Father cognitive decline, uncle died at 18y (epilepsy) / Autopsy: widespread inclusions more than S52R and S49P, also in cerebellum / Not reported / Davis et al, 2002
Gly392Arg (G392R) / 8y,
de novo / Severe dementia, epilepsy; CSWS, “psychic” seizures, eyelid myoclonus, alive at publication / Biopsy (inclusions) / Not reported / Coutelier et al, 2008
His338Arg (H338R) / 15y,
single case (Case 5) / PME with dementia, tremor, dysarthria, death at 23y / Biopsy (inclusions) / Not reported / Davis et al, 2002
Ser52Arg (S52R) / 2nd or 3rd decade,
2 generation family / Epilepsy and cognitive decline / Biopsy (inclusions) / Diffuse cortical atrophy in older subjects / Davis et al, 1999/
Yerby et al, 1986
Ser52Arg (S52R) / 24y,
2 brothers / PME with dementia, death 43y (status epilepticus and pneumonia) / Autopsy (19 years into illness: widespread inclusions but less than G392E case) / NA / Takao et al, 2000
SerS52Arg (S52R) / 18y,
2 generation family / PME with dementia. Photosensitive. Seizures first, later dementia, frontal syndrome, cerebellar syndrome. Death: mother age 59y similar symptoms; sibling 2 at 33y pneumonia. / Autopsy (Sibling 2): widespread inclusions / Cortical and subcortical atrophy / Gourfinkel-An et al, 2007
Leu47Pro (L47P) / 24y,
de novo / Dementia and PME. GTCS, photosensitive. Gait disturbance, paratonia, cerebellar signs. Death 34y sepsis/pneumonia / Autopsy: widespread inclusions / Mild atrophy & PVWM lesions (also likely had MS) / Hagen et al, 2011
Ser49Pro (S49P) / 5th decade,
4 generation family / Dementia, tremor, rare seizures, Death 57y / Autopsy :(Inclusions but less than G392E and S52R) / Cortical atrophy (later in disease) / Davis et al, 1999
Abbreviations: MS: multiple sclerosis; y: years; CSWS: continuous spike during slow wave sleep; PME: progressive myoclonus epilepsy; MRI: magnetic resonance imaging of the brain; EEG: electroencephalogram; PVWM: periventricular white matter; GTCS: generalized tonic clonic seizures; NA: not available; inclusions means neurosperpin inclusions or Collin’s bodies
Allen Supplemental Data pg 3
e-References (Neuroserpinopathy)
Davis RL, Holohan PD, Shrimpton AE, Tatum AH, Daucher J, Collins GH, et al. Familial encephalopathy with neuroserpin inclusion bodies. Am J Pathol 1999; 155:1901–1913.
Davis RL, Shrimpton AE, Holohan PD, Bradshaw C, Feiglin D, Collins GH, et al. Familial dementia caused by polymerization of mutant neuroserpin. Nature 1999; 401:376–379.
Davis RL, Shrimpton AE, Carrell RW, Lomas DA, Gerhard L, Baumann B et al. Association between conformational mutations in neuroserpin and onset and severity of dementia. Lancet 2002; 359: 2242–2247.
Gourfinkel-An I, Duyckaerts C, Camuzat A, Meyrignac C, Sonderegger P, Baulac M, Brice A. Clinical and neuropathologic study of a French family with a mutation in the neuroserpin gene. Neurology 2007; 69:79–83.
Takao M, Benson MD, Murrell JR, Yazaki M, Piccardo P, Unverzagt FW, et al. Neuroserpin mutation S52R causes neuroserpin accumulation in neurons and is associated with progressive myoclonus epilepsy. J Neuropathol Exp Neurol 2000; 59:1070–1086.
Hagen MC, Murrell JR, Delisle MB, Andermann E, Andermann F, Guiot MC, Ghetti B. Encephalopathy with neuroserpin inclusion bodies presenting as progressive myoclonus epilepsy and associated with a novel mutation in the Proteinase Inhibitor 12 gene. Brain Pathol 2011; 21: 575-82.
Yerby MS, Shaw C-M, Watson JMD. Progressive dementia and epilepsy in a young adult: unusual intraneuronal inclusions. Neurology 1986, 36:68–71.
Coutelier M, Andries S, Ghariani S, Dan B, Duyckaerts C, van Rijckevorsel K, et al. Neuroserpin mutation causes electrical status epilepticus of slow-wave sleep. Neurology 2008; 71: 64-66.
e-References (Progressive Myoclonus Epilepsy)
Bassuk AG, Wallace RH, Buhr A, Buller AR, Afawi Z, Shimojo M, et al. A homozygous mutation in human PRICKLE1 causes an autosomal-recessive progressive myoclonus epilepsy-ataxia syndrome. Am J Hum Genet 2008;83:572–81.
Berkovic SF, Dibbens LM, Oshlack A, Silver JD, Katerelos M, Vears DF, et al. Array-based gene discovery with three unrelated subjects shows SCARB2/LIMP-2 deficiency causes myoclonus epilepsy and glomerulosclerosis. Am J Hum Genet 2008;82:673–84.
Boissé Lomax L, Bayly MA, Hjalgrim H, Møller RS, Vlaar AM, Aaberg KM, et al. 'North Sea' progressive myoclonus epilepsy: phenotype of subjects with GOSR2 mutation. Brain 2013;136(Pt 4):1146–54.
Corbett MA, Schwake M, Bahlo M, Dibbens LM, Lin M, Gandolfo LC, et al. Am J Hum Genet 2011;88:657–63: 21549339.
Muona M, Berkovic SF, Dibbens LM, Oliver KL, Maljevic S, Bayly MA, et al. A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy. Nat Genet 2015;47:39–46.
Shahwan A, Farrell M, Delanty N. Progressive myoclonic epilepsies: a review of genetic and therapeutic aspects. Lancet Neurol 2005;4:239–48.
Mosbech MB, Olsen AS, Neess D, Ben-David O, Klitten LL, Larsen J, et al. Reduced ceramide synthase 2 activity causes progressive myoclonic epilepsy. Ann Clin Transl Neurol 2014;1(2):88-98.
Kousi M, Anttila V, Schulz A, Calafato S, Jakkula E, Riesch E, et al. Novel mutations consolidate KCTD7 as a progressive myoclonus epilepsy gene. J Med Genet 2012;49(6):391-9.
Hallmann K, Zsurka G, Moskau-Hartmann S, Kirschner J, Korinthenberg R, Ruppert AK, et al. A homozygous splice-site mutation in CARS2 is associated with progressive myoclonic epilepsy. Neurology 2014;83(23):2183-7.
Damiano JA, Afawi Z, Bahlo M, Mauermann M, Misk A, Arsov T, et al. Mutation of the nuclear lamin gene LMNB2 in progressive myoclonus epilepsy with early ataxia. Hum Mol Genet 2015 May 7 [Epub ahead of print].