JLE

Epileptic Disorders

MENU

Epileptic spasms: a previously unreported manifestation of WDR45 gene mutation Volume 17, issue 4, December 2015

Figures


  • Figure 1

  • Figure 2

Tables

The WDR45 gene is one of several genes, of which the mutations are reported to cause neurodegeneration with brain iron accumulation (NBIA). This mutation results in an X-linked dominant disease subtype termed beta-propeller protein-associated neurodegeneration (BPAN) disease (Hayflick et al., 2013). The typical presentation consists of developmental delay, psychomotor slowing, and limitations in expressive language in early childhood. Later, dystonia, Parkinsonism, and epilepsy occur. Early in the disease course, brain imaging is normal. A review of the literature reveals various types of seizures including focal, absence, atonic, febrile, and myoclonic seizures (table 1). To date, epileptic spasms have not been reported to be associated with WDR45 mutation. In this article, we report a patient with such a presentation.

Case study

Our patient was a six-year-old female who was born at term with delivery complicated only by pre-eclampsia. The patient did well until the age of three months when she presented to a healthcare centre with a cluster of focal, febrile seizures consisting of right-sided, tonic-clonic activity, right gaze preference, and right-sided versive head deviation lasting several hours. The patient underwent a laboratory workup for infectious diseases and brain MRI without contrast, which were negative. A routine EEG showed left-sided slowing seizure activity. Phenobarbital was started but was subsequently weaned off three months later after a repeat routine EEG was normal. Despite seizure freedom, the patient was noted to have ongoing global developmental delay throughout her first year of life. At one year of age, the patient was unable to sit independently and was diffusely hypotonic. Additionally, her head circumference percentile was decreasing.

Epileptic spasms started at 11 months of age. These consisted of intermittent, isolated, brief episodes of stiffening and brief episodes of myoclonic jerking of the bilateral upper extremities, each lasting for one second or less. A repeat EEG showed a mixed-frequency, high-amplitude background with 3-5-Hertz activity predominating. During the subsequent months, these jerks persisted. By the age of 21 months, they were occurring in clusters of repetitive brief episodes of bilateral arm extension, two to three times per day, and most commonly upon awakening from sleep. These were initially treated with levetiracetam and then with zonisamide that was up-titrated to a dose of 13 mg/kg/day. The patient was also supplemented with high-dose vitamin B6 at a dose of 30 mg/kg/day. The patient responded with a reduction in the number of spasms per cluster but continued to have approximately four clusters per day with intervening periods of a few days to a few weeks without spasms. Developmentally, the patient began to make slow gains such that she eventually was able to start babbling, crawling, standing with assistance, pointing to indicate certain desires, feeding herself finger foods, and understanding “no” inconsistently. Given this improvement, the patient was tapered off vitamin B6 but was continued on zonisamide.

At the age of three years and eight months, the patient experienced an exacerbation with the recurrence of daily spasms. These consisted of head flexion with bilateral arm extension occurring in clusters of approximately four spasms per cluster and seven to ten clusters per day. She also developed tonic seizures during sleep occurring once a week and consisting of full-body stiffening and facial grimacing, lasting a few seconds. The patient then presented to our institution for a second opinion. Her examination showed developmental delay as described above, no definite hand preference, and moderate central hypotonia. Reflexes were 2+ bilaterally and plantar responses were flexor. EEG showed hypsarrhythmia with a diffuse, high-voltage, disorganized, slow background and with multifocal spikes in wakefulness and sleep (figure 1). Parents declined steroid or vigabatrin therapy. Medication trials with topiramate, rufinamide, clobazam, and clonazepam failed to change the frequency of her spasms or her tonic seizures. EEG continued to show hypsarrhythmia in wakefulness and sleep. The patient's development was not progressing. She was thus started on the ketogenic diet which led to a significant decrease in spasms during the month following initiation of the diet, with continued reduction in spasms to seizure freedom by the sixth month of the diet. Her EEG, four months after starting the ketogenic diet, showed only bilateral, independent, interictal spike discharges in the right frontal and left temporal regions with mild bilateral slowing. After eight months on the ketogenic diet, the EEG showed only mild background slowing. The patient has currently been on the diet for 14 months and has continued to be spasm-free for the last eight months. She also is making developmental progress. She is now able to stand independently for five minutes, take one to two independent steps, recognize some people around her, and communicate with augmentative devices and signs. The patient's physical examination is unchanged except for a finding of mildly increased tone in the lower extremities. Her EEG at the time of the last follow-up visit at age six years showed only mild diffuse slowing and no hypsarrhythmia (figure 2).

Extensive laboratory workup to investigate the aetiology of the patient's seizures was unremarkable with the exception of whole-exome sequencing. This included tests for: CPK, lactate, ammonia, plasma amino acids, urine organic acids, acylcarnitine profile, biotinidase, carbohydrate deficient transferrin, urine creatine/guanidinoacetate, as well as karyotyping, chromosomal microarray, SCN1A gene sequencing, MECP2 deletion/duplication testing, MECP2 gene sequencing, Prader Willi and Angelman syndrome methylation tests, TSC1 and TSC2 gene sequencing, and cerebrospinal fluid studies for cell count, glucose (with normal CSF to serum ratio), protein, lactate, amino acids, neurotransmitter metabolites (5-HIAA, HVA, 3-O-methyldopa), tetrahydrobiopterin, neopterin, 5-methyltetrahydrafolate, and oligoclonal bands. The presence of infectious diseases, including EBV, CMV, VZV, HSV, HHV6, enterovirus, and Cryptococcus antigen, were also investigated in CSF and were all negative. Whole-exome sequencing was significant for a heterozygous deleterious mutation c.400C>T (p.R134X) in WDR45 which was not present in either of the patient's parents and was therefore felt to arise de novo in our patient. This specific mutation has been previously reported to be disease-causing in BPAN or NBIA5 with the accompanying phenotype of global developmental delay starting in early childhood, slow gains in motor and cognitive skills in adolescence, and progression to dystonia, Parkinsonism, and dementia in young adulthood (Haack et al., 2012).

Discussion

Since the discovery of the WDR45 gene, studies have delineated the common phenotypic manifestations associated with mutation in this gene (Haack et al., 2012; Haack et al., 2013; Hayflick et al., 2013). Our patient presented with many of the characteristics previously described in relation to this mutation. These included global developmental delay in childhood, limitations in expressive language, seizures, and abnormal tone. However, our patient also manifested epileptic spasms which have not previously been described as a phenotypic presentation associated with this mutation. Interestingly, our patient's spasms did not begin until 11 months of age which is slightly later than the classic onset of infantile spasms. Our patient's robust response to the ketogenic diet is encouraging but not surprising as the ketogenic diet is shown to be quite efficacious against epileptic spasms with a variety of aetiologies (Kossoff et al., 2002; Pires et al., 2013). Our patient does not show signs of progressive extrapyramidal symptoms yet, but this is classically described to start in early adulthood. Additionally, the two MRI examinations of our patient, obtained in early childhood, were normal. This is similar to the normal MRI during childhood of previously reported patients, and is not unexpected since brain MRI changes occur later during the course of the disease after significant neurodegeneration (Haack et al., 2012). Likewise, although epileptic spasms have not previously been reported with this mutation, it is well-documented that various other seizure types do occur as an early manifestation of WDR45 mutations. Previously reported seizure presentations associated with this mutation are outlined in table 1. Reported cases reference childhood onset of seizures but do not cite specific ages. Our patient initially presented with focal seizures in infancy at the age of three months. As such, our case is the earliest known presentation of a patient with a WDR45 mutation. Furthermore, a recent article cited the WDR45 gene as a gene of interest in infantile spasms as it was located in an area of duplication on the X chromosome in a patient with otherwise unexplained infantile spasms (Michaud et al., 2014). This lends further support to WDR45 gene mutation as the unifying abnormality responsible for the presentation of our patient. Given our experience, we conclude that BPAN should be considered during differential diagnosis for patients with otherwise unexplained early-onset focal seizures and otherwise unexplained epileptic spasms.

Supplementary data

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

Acknowledgements and disclosures

This study was completed at Duke University Medical Center, Division of Pediatric Neurology in Durham, North Carolina. The authors did not receive financial support for the authorship and/or publication of this article.

This manuscript represents the views of all listed authors. No duplicate or overlapping manuscripts have been submitted elsewhere for publication. The authors have no conflict of interest to disclose.


* This study was presented in the form of a poster presentation at the 13th International Child Neurology Congress in Brazil, in May 2014.