John Libbey Eurotext

Epileptic Disorders

The Educational Journal of the

Epileptic spasms in congenital disorders of glycosylation Volume 19, issue 1, March 2017

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  • Epileptic spasms in congenital disorders of glycosylation

Tables

Since their first description in 1980 (Jaeken et al., 1980), congenital disorders of glycosylation (CDG) are still a rare but rapidly expanding family of inherited diseases, nowadays including over 70 identified autosomal recessive genetic disorders (Freeze et al., 2012; Barone et al., 2014).

Biochemically, these disorders are characterized by impaired glycosylation of proteins and lipids, caused by mutations in genes required for the synthesis of the glycan moiety or for the attachment of these glycans to proteins and lipids. According to their specific pattern on transferrin isoelectric focusing (TIEF), CDGs are divided into two groups. CDG type I comprise defects in the biosynthesis of dolichol-linked oligosaccharides in the cytosol or the endoplasmic reticulum, as well as defects involving the transfer of oligosaccharides onto nascent glycoproteins. CDG type II encompass all defects of further trimming and elongation of N-linked oligosaccharides in the endoplasmic reticulum and the Golgi apparatus (Schwarz et al., 2004; Jaeken, 2010, 2012). Following a recent revision of the nomenclature (Jaeken et al., 2009), CDG subtyping is now based on the affected gene.

The exact prevalence of this group of disorders is unknown. There are approximately 1,000 cases published in the literature (Vodopiutz and Bodamer,2008; Dupré et al., 2010). Of the CDG forms identified worldwide, 80% correspond to phosphomannomutase (PMM) 2 deficiency (PMM2-CDG or CDG-Ia) (Jaeken, 2010; Freeze et al., 2012). Phosphomannose-isomerase (MPI) deficiency (MPI-CDG) and glucosyltransferase I (ALG6) deficiency (ALG6-CDG), referred to as CDG-Ib and CDG-Ic, respectively, have been reported in more than 60 individuals worldwide (Jaeken, 2010).

However, in France, PMM2-CDG represents 62% of diagnosed CDG families, followed by MPI-CDG (6%), ALG1-CDG (mannosyltransferase 1 [MT-1] deficiency) or CDG Ik (6%), and ALG6-CDG (4%). About 15% of CDG families have a yet unidentified glycosylation defect, and thus remain to be subtyped, under the designation of CDG Ix (Dupré et al., 2010).

Because of the fundamental biological role of glycoproteins, impaired glycosylation mechanisms lead to multisystemic involvement and thus to a broad spectrum of clinical features (de Lonlay et al., 2001; Vodopiutz and Bodamer, 2008; Morava et al., 2008; Funke et al., 2013). Neurological impairment is often severe and disabling and includes structural abnormalities, such as rapidly progressive cerebellar atrophy and cortical atrophy, myopathies including congenital muscular dystrophies and limb-girdle dystrophies, seizures, stroke and “stroke-like” episodes, developmental delay, and demyelinating neuropathy (de Lonlay et al., 2001; Drouin-Garraud et al., 2001; Grubenmann et al., 2004; Kranz et al., 2004; Jaeken,2010; Freeze et al., 2012; Rahman et al., 2013).

Since CDG is a rare disorder, the exact incidence of epilepsy in these patients is yet to be determined, ranging from 0 (patients with only visceral disease) to 100% (patients with severe forms of neurological impairment). This also appears to correlate to the underlying genetic defect (de Lonlay et al., 2001; Morava et al., 2008; Dupré et al., 2010). Epilepsy is uncommon in the most frequent form of CDG, PMM2-CDG, but frequently present in other types of CDG (Fiumara et al., 2016). Seizures can begin from the neonatal period to later childhood and are described either as easily manageable or pharmacoresistant (de Lonlay et al., 2001; Clayton and Grunewald,2009; Dupré et al., 2010; Jaeken,2010; Freeze et al., 2012; Funke et al., 2013; Fiumara et al., 2016; OMIM database).

CDG disorders are considered as one of the underlying aetiologies for early-onset epilepsy and inborn errors of metabolism (Wolf et al., 2005; Bahi-Buisson et al., 2006; Fois,2010; Noh et al., 2012; Rahman et al., 2013; Fiumara et al., 2016). However, detailed characterization of seizure semiology and neurophysiological patterns is rare. We report the presence of epileptic spasms without hypsarrhythmia in five children with CDG syndrome.

Methods

Among the patients with CDG syndrome followed in the Pediatric Neurology and the Metabolism Department in Necker Enfants Malades Hospital, Paris, France, polygraphic video-EEG recordings performed between 2000 and 2013 in the Neurophysiology Department of the same hospital revealed, in five children, the presence of epileptic spasms. We retrospectively studied their clinical data, epileptic manifestations, and EEG findings.

In all patients, TIEF showed a type I pattern of serum transferrin, and molecular studies revealed three different mutations in four of the five children (table 1 table 1).

All patients had undergone one to 11 polygraphic video-EEG recordings in the Necker Enfants Malades Hospital.

Video-EEG recordings included polygraphic parameters, such as electrocardiogram (ECG), respiration measurements, and surface electromyography (EMG). The number of electrodes (silver chloride cup electrodes) was chosen depending on age and head size (ranging from 9 to 21) and placed according to the 10/20 international system using the medial frontal polar (FPz) as reference electrode. EMG was recorded by two cup electrodes placed 2 cm apart on one or both deltoid muscles. Recordings lasted at least one hour up to 24 hours. Signals were amplified (x1,000), band-pass filtered at 0.01-97 Hz, and digitized at 256 Hz using the Deltamed Coherence EEG system (Deltamed/Natus Paris, France).

Results

Patient 1

Patient 1 was an 11-year-old female and the third child to healthy, unrelated parents. Two aunts (on the father's side) with psychomotor delay of unknown aetiology died during infancy; both were born at term with uneventful pregnancy. From birth onwards, feeding difficulties, poor eye contact, pendulum eye movements, and severe global hypotonia were observed. Segmental myoclonias started at the age of 2 months; at 4 months of age, she presented clusters of flexor spasms, described as asymmetric, upon awakening and during drowsiness that could be decreased in frequency by anticonvulsant therapy (vigabatrin, hydrocortisone, and topiramate).

Studies of metabolic blockage and enzyme activity revealed a deficiency in MT-1 and a molecular study confirmed the diagnosis of ALG1-CDG.

The video-EEG recording performed at the age of 9 months (under treatment with vigabatrin, hydrocortisone, and topiramate) showed a preserved, although slow for age, background activity, with occipital anomalies predominating on the right side without any hypsarrhythmia (supplementary figures 1A, 2A). During sleep, the recorded distal hand and feet myoclonias had no EEG correlate. During awakening, a long-lasting cluster of spasms was recorded with typical EEG features, but with very subtle clinical manifestations (see video sequence [at 5 seconds] and supplementary figure 3).

Patient 2

Patient 2 was a 10-year-old male and a first child to unrelated parents. Pregnancy was complicated by maternal hypertension and foetal growth retardation. Absent eye contact, psychomotor retardation, and severe axial hypotonia, as well as pyramidal signs were noted in the first three months of life. At the age of 4 months, he started with clusters of symmetric flexion spasms upon awakening. A few months later, in addition to spasms, daily generalized tonic seizures and very frequent distal myoclonias, particularly during sleep, occurred. Spasms responded to vigabatrin treatment, but segmental myoclonic jerks concerning the head and shoulders persisted and severe encephalopathy with spastic tetraplegia was established.

Studies of metabolic blockage and enzyme activity revealed a deficiency in MT-1 and a molecular study of the ALG1 gene confirmed the diagnosis of ALG1-CDG.

Eleven polygraphic video-EEGs were recorded between the age of 13 months and 7 years. Awake and sleep EEG showed abundant occipital anomalies (supplementary figures 1B, 2B). At the age of 18 months, a long-lasting (15-minute) cluster of epileptic spasms on arousal was recorded (see video sequence [at 4 minutes] and supplementary figure 4). Myoclonic jerks had no EEG correlate. The posterior anomalies persisted after cessation of spasms.

Patient 3

Patient 3 was a 12-year-old male, and a third child to healthy, unrelated parents. One older brother (born in 1996) presented the same disorder. The patient had moderate hydramnios during the third trimester of pregnancy; he was born at term. Since early life, feeding difficulties were noted, as well as an absence of eye contact, severe global hypotonia, and pyramidal signs. At the age of 6 months, he started having daily clusters of spasms upon awakening and frequent segmental myoclonic jerks. Despite several antiepileptic treatments (vigabatrin, hydrocortisone, valproic acid, topiramate, clonazepam, and clobazam), spasms and myoclonic jerks persisted, as well as severe axial hypotonia, pyramidal signs, severe psychomotor retardation, and agitated behaviour.

A molecular study revealed two allelic mutations in the ALG6 gene, confirming the diagnosis of ALG6-CDG.

Four polygraphic video-EEGs were recorded between 11 and 21 months of age, disclosing an occipital polyrhythmic background activity with bilateral independent posterior spikes and sharp waves (supplementary figures 1C, 2C). Frequent segmental non-epileptic myoclonias were noted.

At the age of 11 months, a cluster of typical symmetric epileptic spasms was recorded after awakening, lasting for 30 minutes, as well as one isolated tonic spasm (see video sequence [at 6 minutes, 14 seconds] and supplementary figures 5 and 6). Posterior anomalies persisted and at the age of 21 months, these were also recorded as subclinical rhythmic sequences (supplementary figure 7).

Patient 4

Patient 4 was a 14-year-old male, and an only child of consanguineous parents. The patient had an unremarkable pregnancy, and was born at full term. Developmental delay was described, with late head control and free walking at the age of 2 years.

At the age of 18 months, massive jerks started, as well as rare generalized tonic or tonic-clonic seizures during sleep. Antiepileptic therapy (phenobarbital, levetiracetam, clonazepam, clobazam, and lamotrigine) controlled seizures only partially. At the age of 11 years, severe language retardation, agitated behaviour, pyramidal syndrome, and strabismus were present.

Studies for enzymatic activity associated with CDG were normal and the molecular study of CDG genes failed to identify any mutation, establishing the diagnosis of CDG Ix.

Five video-EEGs were performed between 4 and 8 years of age.

Interictal EEG showed slow, disorganized background activity, but physiological sleep graphoelements without interictal paroxysmal anomalies (supplementary figure 8).

At the age of 4 years, seizures were recorded during wakefulness or drowsiness; isolated segmental cortical myoclonias and massive jerks evoking into epileptic spasms, although with unusual components (see video sequence [10 minutes, 18 seconds] and supporting figure 9). At the age of 11 years, seizures were poorly controlled and development severely delayed, associated with an aggressive and impulsive behaviour, however, with the ability to walk alone and to speak a few words.

Patient 5

Patient 5 was a 4-year-old female, and a first child of healthy, unrelated parents. The patient was born at term, after an uneventful pregnancy. Since early life, absent eye contact and global hypotonia were described. At the age of 5 months, epileptic spasms occurring in long-lasting clusters were observed, as well as long-lasting focal clonic seizures, which were pharmacoresistant (to vigabatrine, hydrocortisone, ACTH, carbamazepine, topiramate, clobazepam, clonazepam, stiripentol, and zonisamide). After the introduction of a ketogenic diet at the age of 23 months, spasms diminished rapidly with regards to frequency and duration of clusters, and occurred as isolated jerks which then completely disappeared. Antiepileptic treatment could slowly be reduced and stopped.

A molecular study confirmed the diagnosis of ALG11-CDG.

Five video-EEGs were performed between 9 months and 2 years of age.

Interictal EEG showed slow, disorganized background activity with very abundant bilateral independent occipital anomalies (supplementary figures 1D, 2D). At the age of 2 years, spasms were recorded, either isolated or in short clusters of 3-5, and sometimes, as seen in Patient 4, with an unusual aspect associated with two distinct phases (see video sequence [11 minutes, 38 seconds] and supplementary figures 10 and 11).

Discussion

We report five children presenting epileptic spasms without hypsarrhythmia associated with various CDG syndromes. Despite the fact that epilepsy is one of the main neurological features described in CDG patients, detailed characterization of ictal semiology and neurophysiological patterns is rare (de Lonlay et al., 2001; Morava et al., 2008; Clayton and Grunewald,2009; Dupré et al., 2010; Jaeken, 2010; Freeze et al., 2012; Funke et al., 2013; Fiumara et al, 2016), and epileptic spasms without hypsarrhythmia associated with myoclonus have not yet been reported.

Epileptic spasms showed a typical EEG pattern in all patients, associated with particular features including only subtle motor manifestations, more sustained contractions, chewing movements, a combination of myoclonus and spasm, or a marked asynchrony and asymmetry. In contrast, typical hypsarrhythmia was never present during wakefulness or sleep.

Patients 1 and 2 (corresponding to two of the five patients described by Dupré et al., 2010), both suffering from ALG1-CDK, started epileptic spasms at 4 months of age; the seizures in Patient 1 were pharmacoresistant. EEG showed very abundant occipital anomalies. Severe, refractory epilepsy has been previously described in ALG1-CDG (Clayton and Grunewald, 2009; Dupré et al., 2010; Jaeken,2010; Freeze et al., 2012). All of the 11 ALG1-CDG patients published so far had “severe”, “multifocal”, “refractory” seizures or presented with an “early epileptic encephalopathy” (Grubenmann et al., 2004; Kranz et al., 2004; Dupré et al., 2010; Fiumara et al, 2016). EEG was reported as “abnormal” in four children, “multifocal” in one child, and “with electroclinical features of Ohtahara syndrome” in another (Grubenmann et al., 2004; Kranz et al., 2004; Dupré et al., 2010; Fiumara et al, 2016). The presence of epileptic spasms in this population, however, has never been described.

Concerning ALG6-CDG, the patient described here started refractory, generalized tonic seizures and clusters of epileptic spasms at 6 months of age. Similar to ALG1-CDG, there was no hypsarrhythmia and also very abundant interictal posterior anomalies. The majority of the 54 ALG6-CDG patients published so far (Haeuptle and Hennet, 2009; Ishikawa et al., 2009; Dercksen et al., 2012; Fiumara et al, 2016; Jaeken et al., 2015) also had early-onset epilepsy. However, few publications describe seizures types and EEG tracings. Grunewald et al. (2000) reported eight patients with: febrile seizures (3/8), atonic seizures (2/8), myoclonic seizures (2/8), generalized tonic-clonic seizures (1/8), as well as normal interictal EEG findings (6/8). Some case reports (Sun et al., 2005; Ishikawa et al., 2009; Al-Owain et al., 2010; Dercksen et al., 2012; Fiumara et al, 2016) also describe “severe epilepsy”, febrile seizures, generalized seizures, complex partial seizures, atonic and myoclonic seizures, as well as generalized tonic-clonic seizures. EEG is, in some children, reported as “abnormal” (Dercksen et al., 2012), but not further detailed. Overall, in the literature, many different seizure types in ALG6-CDG patients are reported, but epileptic spasms have not been described so far.

Our patient with ALG11-CDG presented typical epileptic spasms that were either in very long-lasting clusters or isolated, as well as very abundant posterior anomalies, but also focal clonic seizures and rare isolated massive jerks with a combination of myoclonus and spasm. Only four patients with ALG11-CDG subtype have been published so far (Rind et al., 2010; Thiel et al., 2012). Seizures were present in all children, but not further detailed, and EEG was described with generalized epileptic activity. Patients presented with early feeding difficulties, muscular hypotonia, and early-onset seizures.

Electroclinical presentation in our patient with CDG Ix was different compared to the other patients. EEG background activity was very slow and amplified, showing multifocal anomalies but preserved features of sleep. Seizures began later, at the age of 18 months, and consisted of tonic and tonic-clonic seizures, as well as sudden massive jerks, presenting as a combination of myoclonus and spasm. So far, 25 patients with CDG Ix have been described (Morava et al., 2008, Millón et al., 2011), presenting very heterogeneous clinical features. Epilepsy is reported in seven of them, but seizure types and EEG features are not detailed.

Epileptic spasms in the context of CDG have only been described in a case report of two siblings with dolichol kinase (DOLK) deficiency (DOLK-CDG or CDG-Im). Both started spasms at the age of 4 months (Helander et al., 2013), with typical hypsarrhythmia on EEG. Both children presented other seizure types, such as generalized tonic-clonic and focal seizures, with complete seizure control which was easily obtained. Psychomotor retardation was less severe compared to our patients with free sitting at the age of 2 years and walking and bike riding at the age of 10 years.

Epileptic spasms in the absence of hypsarrhythmia have, to our knowledge, never been reported in CDG, and were, in our patients, associated with ALG1-, ALG6-, ALG11-CDG and CDG Ix subgroups. Interestingly, none of the 31 patients suffering from PMM2-CDG followed at our hospital presented epileptic spasms. Seizures in these patients occurred in one third (11/31), at an older age (medium: 4 years), and in 75% cases associated with fever, either (6/11) as brief generalized tonic-clonic events or prolonged focal seizures which often revealed a stroke-like episode (personal data; in preparation).

Absence of hypsarrhythmia in the presence of epileptic spasms was described in cortical lesions as focal cortical dysplasia or tubers in tuberous sclerosis complex (Dulac et al., 2002; Caraballo et al., 2003, 2011). In four of our five patients with CDG syndrome, common features included abundant occipital spikes, polyspikes, and fast rhythmic bursts with lateralization. Together with asymmetry and asynchrony of spasms, as well as focal seizures in one child, posterior structural anomalies were suspected before the diagnosis of glycosylation disorder. This was further underlined by the presence of associated symptomatology during the clusters with behavioural changes, chewing movements, facial fear expression, and hypersalivation. However, brain MRI did not disclose any focalized cerebral lesion in any of the patients.

In conclusion, our data show that epileptic spasms, notably when associated with myoclonus, are a possible feature of epilepsy in non-PMM2-CDG and exhibit particular EEG patterns which should be taken into consideration when investigating a child with epileptic spasms. For children diagnosed with CDG, we recommend polygraphic video-EEG recording for precise identification and characterization of seizures, allowing for more specific antiepileptic treatment. In addition, for children presenting with severe psychomotor retardation, microcephaly, epileptic spasms, together with interictal posterior anomalies without underlying focal MRI lesion, screening for CDG disorders should be considered.

Supplementary data

Summary didactic slides and supplementary figures are available on the www.epilepticdisorders.com website.

Acknowledgements and disclosures

This work was not supported by a grant or otherwise.

None of the authors have any conflict of interest to disclose.