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Spinal Muscular Atrophy Associated with Progressive Myoclonus Epilepsy

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Spinal Muscular Atrophy Associated with Progressive Myoclonus Epilepsy Journal Identification = EPD Article Identification = 0858 Date: October 4, 2016 Time: 3:33 pm Review article Epileptic Disord 2016; 18 (Suppl. 2): S128-S134 Spinal muscular atrophy associated with progressive myoclonus epilepsy Haluk Topaloglu 1, Judith Melki 2 1 Hacettepe University Departments of Pediatric Neurology, Ankara, Turkey 2 Unité mixte de recherche (UMR)-1169, Inserm and University Paris Sud, Le Kremlin Bicêtre, France ABSTRACT – A rare syndrome characterized by lower motor neuron dis- ease associated with progressive myoclonic epilepsy, referred to as “spinal muscular atrophy associated with progressive myoclonic epilepsy” (SMA- PME), has been described in childhood and is inherited as an autosomal recessive trait. SMA-PME is caused by mutation in the ASAH1 gene encod- ing acid ceramidase. Ceramide and the metabolites participate in various cellular events as lipid mediators. The catabolism of ceramide in mammals occurs in lysosomes through the activity of ceramidase. Three different ceramidases (acid, neutral and alkaline) have been identified and appear to play distinct roles in sphingolipid metabolism. The enzymatic activity of acid ceramidase is deficient in two rare inherited disorders; Farber disease and SMA-PME. Farber disease is a very rare and severe autosomal recessive condition with a distinct clinical phenotype. The marked difference in dis- ease manifestations may explain why Farber and SMA-PME diseases were not previously suspected to be allelic conditions. The precise molecular mechanism underlying the phenotypic differences remains to be clarified. Recently, a condition with mutation in CERS1, the gene encoding ceramide synthase 1, has been identified as a novel form of PME. This finding under- lies the essential role of enzymes regulating either the synthesis (CERS1) or degradation (ASAH1) of ceramide, and the link between defects in ceramide metabolism and PME. Key words: spinal muscular atrophy,myoclonus, Farber disease, progressive myoclonus epilepsies Progressive myoclonus epilepsy is inherited as an autosomal reces- (PME) (Minassian et al., 2016) rep- sive trait and the disease-causing resents a heterogeneous group gene has been recently identified. of epilepsies characterized by SMA-PME is caused by muta- myoclonic and generalised seizures tion in the ASAH1 gene, which with progressive neurological dete- encodes acid ceramidase (Zhou rioration (Girard et al., 2013). A rare et al., 2012). A total of 11 affected doi:10.1684/epd.2016.0858 syndrome characterized by lower individuals have been reported thus Correspondence: motor neuron disease associated far, leading to a relatively precise Haluk Topaloglu with progressive myoclonic epilepsy phenotypic characterization (Zhou Hacettepe University Departments (SMA-PME) has been described in et al., 2012; Dyment et al., 2014, 2015; of Pediatric Neurology, Ankara, Turkey childhood (Jankovic & Rivera, 1979; Rubboli et al., 2015; Giráldez et al., <[email protected]> Haliloglu et al., 2002). This condition 2015). S128 Epileptic Disord, Vol. 18, Supplement 2, September 2016 Journal Identification = EPD Article Identification = 0858 Date: October 4, 2016 Time: 3:33 pm Spinal muscular atrophy associated with progressive myoclonus epilepsy Mutations in the same gene are responsible for Farber evidence of motor neuron disease despite only mild disease, a very rare autosomal recessive condition with proximal muscle weakness (Dyment et al., 2014, a distinct clinical phenotype, resulting from marked 2015). reduction or complete lack of acid ceramidase activ- ity (Sugita et al., 1972; Levade et al., 2009). The marked Progressive myoclonus epilepsy characteristics difference in disease manifestations may explain why Farber and SMA-PME diseases were previously not sus- Later on, myoclonic epilepsy is observed from 3 to pected to be allelic conditions. 12 years of age (table 1). This is characterized by Several therapeutic strategies have been adopted to brief myoclonic seizures without loss of conscious- treat Farber disease, including allogeneic bone mar- ness, generalized epileptic seizures and myoclonic row transplantation and introduction of wild-type jerks, myoclonic seizures, absences with head drop or human acid ceramidase cDNA, using recombinant postural lapses in the upper limbs, atonic seizures, or oncoretroviral or lentiviral vectors. The latter approach upper limb myoclonic jerks. The EEG shows subcor- performed in non-human primates was recently tical myoclonic epileptiform abnormalities which are shown to result in increased acid ceramidase activ- sensitive to hyperventilation, paroxysmal activity con- ity. This underlines the importance of screening for sisting of frequent, diffuse bursts of sharp waves and ASAH1 or acid ceramidase activity in patients with polyspike and wave complexes, bursts of generalized undiagnosed SMA or PME, for the purposes of diag- spike- and polyspike-and-wave complexes associated nosis and future treatment. with myoclonic phenomena, generalized polyspike- and-wave discharges, or interictal bursts of posterior delta activity and ictal generalized spike-wave and Clinical description of SMA-PME polyspike-wave discharges. Brain MRI is most often normal or displays mild supratentorial and subtento- Based on the clinical description of cases reported to rial cortical atrophy. Myoclonic seizures are most often date (n = 11), SMA-PME is mainly characterized by pro- refractory to antiepileptic drugs. gressive lower motor neuron degeneration followed by progressive myoclonic epilepsy (table 1) (Jankovic Other symptoms & Rivera, 1979; Haliloglu et al., 2002; Zhou et al., 2012; Dyment et al., 2014, 2015; Rubboli et al., 2015; Giráldez Variable degrees of cognitive impairment occur. When et al., 2015). reported, cognition is usually mildly impaired. Neither skin, joint abnormalities, or hoarseness of the voice, as observed in Farber disease, has been reported. Lower motor neuron disease manifestations Ophthalmological examination did not reveal corneal opacities or cherry red spots. Early development milestones are usually normal, with an ability to walk unaided between 14 to 17 months of age. Progressive symmetric weakness and muscle SMA-PME is caused atrophy of the lower and then the upper limbs are by mutations in ASAH1 the main clinical features, usually occurring between 2.5 to 6 years of age (table 1). The patients begin to This condition is inherited as an autosomal reces- show slowness of gait and difficulties in standing from sive trait. Genome-wide linkage analysis combined the sitting position. The motor deficit is purely periph- with exome sequencing in two multiplex families and eral, with a decrease in or absence of deep tendon one sporadic case suffering from childhood SMA-PME reflexes. The disease is progressive, leading to the revealed mutations in ASAH1 which were responsi- inability to stand up from the floor, the inability to sit ble for the disease (Zhou et al., 2012). ASAH1, located unsupported, a lack of head control, difficulty swallow- on chromosome 8, was the only gene to have a ing, fasciculations of the tongue, severe scoliosis, and mutation that was shared by the unrelated affected subsequent respiratory insufficiency. Electromyogra- individuals. The same missense mutation in exon 2 phy (EMG) shows a chronic denervation process while of ASAH1 (NM_177924.3; c.125C>T; p.Thr42Met) was muscle biopsy shows neurogenic atrophy, although found in the affected individuals. The p.Thr42Met there are no changes suggestive of a mitochondrial missense substitution affected an evolutionarily con- disorder. served amino acid among different species and was However, in 1 of these 11 patients, atonic and absence predicted to be damaging. In 2 families, both par- seizures and myoclonic jerks were the main and first ents were heterozygous and affected siblings were clinical features. Once the ASAH1 gene mutations homozygous for this missense mutation. In one fam- were identified, an EMG was performed, showing ily, the affected child carried compound heterozygous Epileptic Disord, Vol. 18, Supplement 2, September 2016 S129 Journal Identification = EPD Article Identification = 0858 Date: October 4, 2016 Time: 3:33 pm H. Topaloglu, J. Melki S130 Table 1. Literature review. Zhou et al., 2012 Rubboli et al., 2015 Dyment et al., Giráldez et al., 2014 & 2015 2015 Family D Family ITA Family ITB Case 1 Case 2 Case 3 Nb. of 3 211 11 1 1 affected individuals MOTOR DEVELOPMENT Ability to 14 Normal Normal Normal 17 Not Not 17 walk (m.) (abnormal reported reported (unsteady deambula- gait) tion) Age of 5 4 to 5 5 6 2,4 3 ? 3 onset of weakness (y.) Muscle Proximal Progressive Progressive Progressive Progressive Mild Mild Proximal symptoms weakness muscle muscle muscle muscle proximal proximal muscle weakness weakness weakness weakness weakness muscle weakness and limb weakness tremor EMG Chronic Denervation Denervation- Chronic Chronic Chronic Evidence of Chronic denervation process reinnervation denervation denervation denervation motor denervation process process process process process neuron process disease Epileptic Disord, Vol. 18, Supplement 2, September 2016 Muscle Neurogenic Denervation Denervation- Neurogenic Neurogenic Neurogenic nd Neurogenic biopsy atrophy process reinnervation damage damage damage atrophy EPILEPSY Age of 7 121083 12107 onset (y.) Clinical symptoms Brief Generalized Loss of con- Brief episodes Staring and Myoclonic Absence Multiple and myoclonic epileptic sciousness of impairment myoclonic seizures, and atonic brief
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