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KCTD7-Related Progressive Myoclonus Epilepsy

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KCTD7-Related Progressive Myoclonus Epilepsy Journal Identification = EPD Article Identification = 0856 Date: October 5, 2016 Time: 10:21 pm Review article Epileptic Disord 2016; 18 (Suppl. 2): S115-S119 KCTD7-related progressive myoclonus epilepsy Patrick Van Bogaert Department of Pediatric Neurology, Université Libre de Bruxelles, Hôpital Erasme, Belgium ABSTRACT – Progressive myoclonic epilepsy associated with KCTD7 muta- tions has been reported in 19 patients from 12 families. Patients show homozygous mutations in the coding regions of the KCTD7 gene. The disease starts in infancy. Patients typically show an initial severe epilep- tic disorder, with abundant epileptiform discharges on EEG and myoclonic seizures in the foreground, associated with cognitive regression and ataxia. Continuous multifocal myoclonus aggravated by action is observed in more than half of the cases. After a few years, the disease tends to stabilize and long survival can be expected. Some patients remain able to walk indepen- dently. The severity of the disease is variable from one patient to another, even within the same family. It is hypothesized that the epileptic disorder may influence the neurological regression observed in patients. Key words: KCTD7, progressive myoclonus epilepsies, infancy, encephalopathy In 2007, three siblings from a patients after exclusion of neuro- consanguineous family with a clini- nal ceroid lipofuscinosis (NCL), five cal picture of progressive myoclonic positive families were identified, epilepsy (PME) (Minassian et al., suggesting that KCTD7 is not an 2016) were reported, associated with exceptional cause of PME (Kousi et a homozygous mutation of the al., 2012). In a pilot study evalua- gene encoding potassium channel ting a panel of 265 genes, including tetramerization domain-containing KCTD7, in 33 index patients with protein 7 (KCTD7) (Van Bogaert et various epileptic syndromes ran- al., 2007). Since this original family, domly selected in Germany and 16 other patients from 11 new fami- Switzerland, one patient was shown lies have been reported (Blumkin to have a homozygous mutation et al., 2012; Kousi et al., 2012; for KCTD7 (Lemke et al., 2012). Krabichler et al., 2012; Staropoli et The present article focuses on the al., 2012; Farhan et al., 2014). The clinical characteristics of KCTD7- Correspondence: disease is inherited as an autoso- related PME from the 19 published Patrick Van Bogaert mal recessive trait and its incidence cases reported so far and discusses Department of Pediatric Neurology, is unknown. In a study in which the pathophysiology and geno- Université Libre de Bruxelles, Hôpital Erasme, Belgium KCTD7 was screened in a cohort type/phenotype correlation of the <[email protected]> of more than 100 unconfirmed PME disease. doi:10.1684/epd.2016.0856 Epileptic Disord, Vol. 18, Supplement 2, September 2016 S115 Journal Identification = EPD Article Identification = 0856 Date: October 5, 2016 Time: 10:21 pm P. Van Bogaert Clinical characteristics The search for storage material was performed by skin biopsy in nine patients from eight different fami- The 12 families reported so far (Van Bogaert et al., lies and was normal except for one patient who was 2007; Blumkin et al., 2012; Kousi et al., 2012; Krabichler reported to have electron-dense storage material in et al., 2012; Staropoli et al., 2012; Farhan et al., 2014) fibroblasts and a lymphoblastoid cell line based on had variable ethnic origin and showed a high rate of electron microscopy (Staropoli et al., 2012). This fin- consanguinity (5/12). Epileptic seizures were the first ding is noteworthy as it was the only finding of storage signs in all cases. Onset ranged between five months material in a patient mutated for KCTD7, which promp- and three years, after a period of psychomotor deve- ted the authors to designate KCTD7 mutations as the lopment that was described as either normal or slightly cause of a new subtype of NCL that was called ‘NCL delayed. Independent walking was usually acquired. type 14’. It should be noted that the screening for However, one reported patient with onset in the KCTD7 mutation performed in a cohort of 22 NCL second year of life never walked (Kousi et al., 2012). patients with storage material demonstrated by elec- The first seizures were described as either myoclonic tron microscopy analysis was negative, suggesting that or generalized tonic-clonic seizures, and were precipi- KCTD7 is not a common cause of NCL after exclu- tated by fever in some cases. Myoclonic seizures were sion of the already known NCL genes (Kousi et al., reported in the course of the disease in all but one 2012). Moreover, the patient reported by Starapoli et patient. In 11 patients, continuous multifocal myoclo- al. (2012), as well as his affected brother, had a very aty- nus, aggravated by action and posture, was reported pical clinical course that differed from other KCTD7 either at presentation or during the course of the patients. First, these 2 patients were the only reported disease. In one patient, myoclonus was associated with cases with severe ocular involvement, i.e. optic atrophy opsoclonus, which prompted the authors to consi- leading to visual loss. Second, constant clinical dete- der a diagnosis of opsoclonus-myoclonus syndrome rioration was observed in these 2 patients who died in (Blumkin et al., 2012). Other types of seizures (atonic their mid-teens. This contrasted with the other repor- seizures and atypical absences) were also reported. ted KCTD7 patients who showed clinical stabilization Epilepsy responded poorly to antiepileptic drugs in 2/3 after a period of early regression, most of whom were of patients, the most effective drugs being levetirace- still alive at the last assessment. tam, valproate and clobazam. All patients had cognitive To our knowledge, the oldest patient (Patient 2 from decline leading to severe dementia. Progressive ataxia the original report [Van Bogaert et al., 2007]) is now was reported in all but one patient, and two thirds aged 25 years and is still able to walk independently. of them became wheelchair-bound. Pyramidal signs were described in eight patients and microcephaly in Differential diagnosis six patients. Concerning complementary examinations, EEGs were The typical presentation follows a 3-stage evolution described to be abnormal, except for those very early that is quite unique among PME: during the course of the disease. The most com- (1) a period of normal development; mon findings were very frequent multifocal and/or (2) a period of mental and motor regression with epi- generalized spike-waves associated with an excess of leptic myoclonic seizures that starts at around 1-2 years slow activity. In a number of patients, EEG abnormali- of age; ties were more prominent in the posterior areas, and (3) and a period of stabilization after a few years. intermittent light stimulation evoked generalized or Rare cases with optic atrophy and storage material posterior epileptiform discharges. In some patients, on skin biopsy may complicate differential diagno- the EEG was reported as either hypsarrhythmic or sho- sis with the classic late-infantile form of NCL. Clues wing continuous spike waves during slow-wave sleep. to resolve this differential diagnosis are summarized Action myoclonus was not associated with concomi- in table 1. The rare presence of associated opso- tant epileptiform discharges. One patient had negative clonus can evoke opsoclonus-myoclonus syndrome. focal myoclonus. Figure 1 illustrates EEG findings from Finally, in rare patients, ataxia or myoclonus may not two affected siblings from the first family (Van Bogaert be present, which raises the issue of whether such et al., 2007). patients have an epileptic syndrome other than PME. Cerebral magnetic resonance imaging was either nor- mal or showed non-specific findings (atrophy or posterior white matter hyperintensities). Metabolic Physiopathology work-up of blood and cerebrospinal fluid was not sug- gestive of mitochondrial dysfunction. Fundoscopy was All 11 different mutations identified so far are within normal in most patients. the coding region of KCTD7, which is a member of S116 Epileptic Disord, Vol. 18, Supplement 2, September 2016 Journal Identification = EPD Article Identification = 0856 Date: October 5, 2016 Time: 10:21 pm KCTD7-related progressive myoclonus epilepsy FP1-F7 A FP1-F7 B F7-T3 F7-T3 T3-T5 T3-T5 T5-01 T5-01 FP1-F3 FP1-F3 F3-C3 F3-C3 C3-P3 C3-P3 P3-O1 P3-O1 FP2-F4 FP2-F4 F4-C4 F4-C4 C4-P4 C4-P4 P4-O2 P4-O2 FP2-F8 FP2-F8 F8-T4 F8-T4 T4-T6 T4-T6 T6-02 T6-02 EKG EKG FP1-F7 N 4 FP1-F7 F7-T3 C D F7-T3 T3-T5 T3-T5 T5-01 FP1-F3 T5-01 F3-C3 FP1-F3 C3-P3 F3-C3 P3-O1 C3-P3 FP2-F4 P3-O1 F4-C4 FP2-F4 C4-P4 F4-C4 P4-O2 C4-P4 FP2-F8 P4-O2 F8-T4 FP2-F8 T4-T6 T6-02 F8-T4 EOG T4-T6 EKG T6-02 EKG I EOG EKG r EKG Figure 1. The EEG of Patients 1 and 2 from the original report by Van Bogaert et al. (2007). (A) EEG of Patient 1 at the age of 5 years, awake and at rest, showing slow dysrythmia and multifocal high-amplitude epileptiform discharges. (B) Intermittent light stimulation (ILS) at 12 Hz inducing occipital spikes in addition to the spike-wave complexes still present at rest. (C) EEG of Patient 2 at the age of 14 years, awake with arms maintained in flexion and forearms in extension. On EMG, performed with surface electrodes placed over the left (l) and right (r) deltoid muscles, two negative myocloni appear as flattening of the EMG discharge (arrows), the first one on the left side and the second on both sides. Myoclonus was preceded by right-sided spike-wave discharges, followed by generalized spike-wave discharges. (D) ILS, at 15 Hz, induced generalized spike-waves, together with clinical bilateral myoclonus; these discharges were followed by rhythmic occipital spikes diffusing into a secondary generalized tonic-clonic seizure.
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