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| table e-3. Progressive Myoclonus Epilepsies |

|Disease (genes) |Inheritance |Age of onset |Cognition |Other Clues/Investigations |

|Neuronal ceroid lipofuscinosis |AR / rare AD |Early childhood, but |Early progressive |Visual deterioration common (except Kuf’s/adult |

|(PPT1, TPP1, CLN3, DJAJC5, CLN5, |late onset forms|several clinical and gene |decline |form). Age, neurophysiology (EEG, VER, ERG helpful),|

|CLN6, MFSD8, CLN8, CTSD, GRN, | |variants. | |skin biopsy, enzyme analysis, and MRI help delineate|

|ATP13A2, CTSF, KCTD7) | | | |phenotype |

|Lafora’s Disease (EPM2A/ EPM2B or |AR |12-15 years, or earlier |Early decline common |May mimic genetically generalized epilepsy (formerly|

|NHLRC1) | |onset forms. | |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 |Overall one of most common causes of PME, mild |

| | | |decline |ataxia, other generalised seizures |

|North-Sea PME (GOSR2) |AR |Age < 2 years with ataxia,|Slow or no decline |GTCS, absences and drop attacks. Progressive |

|[Disorder of Golgi Qb-SNARE complex | |PME > 5 years | |physical deterioration, scoliosis, syndactyly, pes |

|(vesicle trafficking)] | | | |cavus, hyperCKemia |

|Myoclonus Epilepsy and Ataxia due to |AD |6 to 14 years |Mild later decline |Resembles Unverricht-Lundborg in early stages but |

|potassium channel (K+) mutation | | | |more progressive later course |

|“MEAK” (KCNC1) | | | | |

|PRICKLE1-related PME with Ataxia |AR |5 to 10 years |Usually preserved |Ataxia, myoclonus can affect bulbar/facial muscles |

|(PRICKLE1). [PRICKLE proteins are | | | | |

|involved in cell polarity signalling | | | | |

|in embryogenesis] | | | | |

|Action Myoclonus Renal Failure |AR |2nd decade on |Usually preserved |Ataxia, dysarthria, with or without renal failure. |

|(SCARB2/LIMP2) | | | |French population. |

|Sialidosis (NEU1) |AR |Type 1: juvenile to adult.|Type 1: usually normal|Type 1: Visual disturbance, ataxia |

|Type 1 (cherry red spot myoclonus | |Type 2: infantile to early|Type 2: usually |Type 2: Signs of storage disorder (corneal clouding,|

|syndrome). | |childhood |impaired |coarse features, etc). |

|Type 2 (Galactosialidosis) | | | |Urine sialyloligosaccharide may be elevated |

|Gaucher disease type 3 (GBA) |AR |Usually > 2 years |Decline in later |White cell enzyme analysis (B-glucocerebrosidase), |

|(non-infantile neuronopathic form) | | |stages |bulbar, pyramidal, oculomotor signs |

|Myoclonus epilepsy with ragged red |Mitochondrial |Usually childhood but any |Decline (variable, can|Muscle biopsy, often multisystem (myopathy, optic |

|fibres/MERRF (MT-TK) | |age |be mild) |atrophy, short stature, deafness) |

|CARS2 mutation (CARS2 encodes |AR |5 to 10 years |Decline |Novel MERFF-like syndrome; tetraparesis, visual, |

|mitochondrial cysteinyl-tRNA | | | |hearing decline |

|synthetase) | | | | |

|Dentatorubral-pallidoluysian atrophy/|AD |“PME” usually < 20 years |Decline |Ataxia, myoclonus, seizures, atrophy of related |

|DRPLA (DRPLA) | | | |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 |AR |< 2 years |Rapid decline |Rapid motor deterioration, other seizure types |

|Channel Tetramerisation | | | | |

|Domain-Containing 7) | | | | |

|CERS1 mutation (encodes ceramide |AR |6 to 16 years |Decline |GTCS |

|synthase 1) | | | | |

|AFG3L2 mutation (encodes the |AR |Childhood |Mildly affected |Ataxia, or spastic ataxia with PME |

|catalytic subunit of an ATP | | | | |

|proteolytic complex of the inner | | | | |

|mitochondrial membrane) | | | | |

|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. |

| table e-4. Neuroserpinopathy families by mutation, age of onset and severity |

|SERPINI1 Mutation |Onset (years), inheritance |Clinical Features |Histopathology |MRI |Ref |

|(protein) |(dominant) | | | | |

|Gly392Glu (G392E) |10y, |PME with dementia (cognitive regression), myoclonus, |No histopathology |Cerebellar atrophy |Allen et al, this case |

| |de novo |occasional GTCS, still alive | | | |

|Gly392Glu (G392E) |13y, |PME with dementia, status epilepticus, dysarthria, death at |Autopsy: widespread inclusions |Not reported |Davis et al, 2002 |

| |(Family 3) |19y (status epilepticus). Father cognitive decline, uncle |more than S52R and S49P, also in | | |

| | |died at 18y (epilepsy) |cerebellum | | |

|Gly392Arg (G392R) |8y, |Severe dementia, epilepsy; CSWS, “psychic” seizures, eyelid|Biopsy (inclusions) |Not reported |Coutelier et al, 2008 |

| |de novo |myoclonus, alive at publication | | | |

|His338Arg (H338R) |15y, |PME with dementia, tremor, dysarthria, death at 23y |Biopsy (inclusions) |Not reported |Davis et al, 2002 |

| |single case (Case 5) | | | | |

|Ser52Arg (S52R) |2nd or 3rd decade, |Epilepsy and cognitive decline |Biopsy (inclusions) |Diffuse cortical atrophy in |Davis et al, 1999/ |

| |2 generation family | | |older subjects |Yerby et al, 1986 |

|Ser52Arg (S52R) |24y, |PME with dementia, death 43y (status epilepticus and |Autopsy (19 years into illness: |NA |Takao et al, 2000 |

| |2 brothers |pneumonia) |widespread inclusions but less | | |

| | | |than G392E case) | | |

|SerS52Arg (S52R) |18y, |PME with dementia. Photosensitive. Seizures first, later |Autopsy (Sibling 2): widespread |Cortical and subcortical |Gourfinkel-An et al, 2007 |

| |2 generation family |dementia, frontal syndrome, cerebellar syndrome. Death: |inclusions |atrophy | |

| | |mother age 59y similar symptoms; sibling 2 at 33y pneumonia.| | | |

|Leu47Pro (L47P) |24y, |Dementia and PME. GTCS, photosensitive. Gait disturbance, |Autopsy: widespread inclusions |Mild atrophy & PVWM lesions |Hagen et al, 2011 |

| |de novo |paratonia, cerebellar signs. Death 34y sepsis/pneumonia | |(also likely had MS) | |

|Ser49Pro (S49P) |5th decade, |Dementia, tremor, rare seizures, Death 57y |Autopsy :(Inclusions but less |Cortical atrophy (later in |Davis et al, 1999 |

| |4 generation family | |than G392E and S52R) |disease) | |

|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 |

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].

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|table e-2. Initial metabolic and further investigations performed in this case (all normal) |

|Initial investigations included: |

|Baseline chemistry (electrolytes, renal, liver, bone profiles), creatine kinase, thyroid function tests, celiac|

|antibodies, full blood count/blood smear, B12, folate |

|Metabolic: including serum lactate, ammonia, amino-acids (including free and total homocysteine), very long |

|chain fatty acids, lysosomal enzymes, urine organic acids, urine mucopolysaccharides and oligosaccharides/ |

|sialic acid and screen for Wilson’s disease (serum ceruloplasmin, copper, 24-hour urinary copper excretion). |

|Considering the underlying nature of the presentation i.e. unexplained neurodevelopmental (significant |

|cognitive) regression with myoclonus in a previously normal child, second line investigations were performed |

|during the course of illness, in parallel with a focused search for the specific progressive myoclonus epilepsy|

|type (the primary working diagnosis, see manuscript). These included: |

|Metabolic (blood and urine): |

|Disorders of purine/pyrimidine synthesis, Disorders of creatine synthesis, Screen for porphyria, Plasma |

|biotinidase (for biotinidase deficiency). |

|Paraneoplastic screen: |

|Total body MRI, plasma metanephrines, urine metanephrines, neuron specific enolase, paraneoplastic antibody |

|screen. |

|CSF examination: |

|Microscopy, cell count, oligoclonal bands, protein. |

|CSF Metabolic: amino acids, monoamine metabolites, pterins, 5-MTHF, lactate, and paired plasma to CSF glucose |

|ratio of 0.61 (i.e. GLUT1 deficiency screen). |

|Autoimmune encephalopathy: |

|Anti TPO, GAD, NMDAR, VGKC antibodies (serum testing). ANA, antiphospholipid antibodies, anti-cardiolipin |

|antibodies, basal ganglia antibodies. |

|Infective: |

|Borrelia serology, routine viral PCRs, viral titres, HIV 1+2 PCRs. |

|Genetic: |

|Neurodegeneration with brain iron accumulation: although clinical presentation was not suggestive progressive |

|loss of skills and cerebellar atrophy prompted testing for neuroaxonal dystrophy (PLA2G6). |

|Copy number variation (duplication or deletion): chromosomal microarray negative (indicated in refractory |

|epilepsy or progressive developmental disorders). |

|POLG1 gene sequencing negative: wide spectrum of neurological presentations including myoclonus and regression,|

|although presentation atypical. |

|table e-1. Disorders to consider in a juvenile with predominant cognitive regression |

|Selective neurometabolic inborn errors: |

|A) Lysosomal disorders (i) the neuronal ceroid lipofuscinoses (many different types), (ii) |

|sphingolipidoses [Nieman Pick C disease, GM2 gangliosidoses (Tay-Sachs disease, Sandhoff disease)], |

|(iii) metachromatic leukodystrophy, (iv) mucopolychaccharidosis type III (Sanfillipo disease). |

|B) Peroxisomal disorders (mainly X-linked adrenoleukodystrphy, males usually). |

|C) Homocystinurias. |

|D) Wilson’s disease. |

| |

|Intracranial structural brain lesions, hydrocephalus. |

| |

|Chronic CNS infection (e.g HIV, prion disease, etc)/inflammatory disorder including autoimmune |

|encephalopathies/encephalitides and paraneoplastic disorders. |

| |

|Treatable systemic conditions (e.g. vitamin B12 deficiency, hypothyroidism) or environmental toxins |

|(e.g. lead poisoning, drug ingestion). |

| |

|Creutzfeldt-Jakob disease (CJD) and trinucleotide repeat disorders (e.g. Juvenile Huntington’s/ |

|spinocerebellar ataxias) although very rare, may also be relevant in this age group. |

| |

|Childhood disintegrative disorder: presents in previously normal children and is characterised by |

|acute/subacute onset regression in language, social skills, adaptive behavior, and play. Regression in |

|wider skills than that seen in autism spectrum. It occurs beyond age 2 years (usually age 3 to 4 years,|

|but up to 10 years is allowable). Etiology has not been determined. |

| |

|Functional, factitious or induced illness and primary psychiatric disorders |

[pic]

Low magnification of hematoxylin-eosin section of a left temporal lobe biopsy (A) showed numerous eosinophilic inclusions contained in the cytoplasm of neurons of all cortical layers (arrows). Contrary to previous published cases, inclusions are partly detached from their vacuoles (B and C). They are PAS positive (B, arrow) and stained with an anti-neuroserpin antibody (C, arrow). These Collin bodies cause ballooning of the perikaryon and peripheral displacement of the nucleus. Each affected neuron may contain more than one inclusion. Reproduced from Coutelier et al. 2008 (Neurology).

figure e-1: Collin’s Bodies

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