Balkan Journal of Medical Genetics

EXPERIENCE WITH THE KETOGENIC DIET IN A BOY WITH CLCN4 RELATED NEURODEVELOPMENTAL DISORDER
Sager G, Yukselmi̇s U, Güzel O, Turkyilmaz A, Akcay M
*Corresponding Author: Gunes SAGER, MD, Department of Pediatric Neurology, Kartal Dr. Lutfi Kirdar City Hospital, Semsi Denizer Avenue, Cevizli, 34890, Kartal, Istanbul, Turkey. ORCID-ID: 0000-0002-9876-2454, Tel: +905055983104, E-mail: sgunessenturk@gmail.com
page: 77

CASE PRESENTATIONS

Case 1 A 6-year-old male was evaluated in the pediatric neu- rology department due to multidrug resistance epilepsy. Perinatal history was uneventful (caesarean section; birth weight of 2850 g) and was born from a non-consanguin- eous marriage. The patient exhibited mild hypotonia during the first year of life. Eye contact was partial and social interaction was poor. The patient learned to walk at the age of 24 months and started speaking with few single words at the age of 3.5 years but could not form a sentence. The patient had severe intellectual disability and was receiving special training for the same. The patient’s height was 110 cm, in the 10 percentile (p), weight was 20 kg (50p), and head circumference was 49.6 cm (3-10p). Dysmorphological examination revealed a round face, bitemporal narrowing, depressed nasal bridge, narrow and downslanting pal- pebral fissures, and strabismus. Cerebellar examination revealed intentional tremor and ataxia; the extrapyramidal system examination was normal. Moreover, the cranial nervous system examination was normal, but strabismus was present. The patient’s first seizure, as cyanosis and motor ar- rest, occurred at 12 months of age. The electroencepha- logram (EEG) findings at that time were multifocal and accompanied by generalized spike slow wave activity, slow background activity, and paroxysmal rapid rhythms, which were found to be compatible with epileptic encepha- lopathy. After 20 months of age, the patient’s generalized tonic and atypical absence seizures continued intermit- tently. From a phenotypical perspective, Lennox–Gastaut Syndrome was considered. Metabolic scans of blood ami- no acids, organic acid analysis, creatine kinase, lactate, ammonia, and tandem mass spectrometry were normal (amino acids and acyl-carnitine profile). Cerebrospinal fluid examination for amino acid and glucose content were also normal. Past medical history included valproic acid, levetiracetam, and phenobarbital therapy. Topiramate was discontinued due to ineffectiveness, ethosuximide, and clobazam treatment increased tonic seizures in approximately 10 days of use, lamotrigine was discontinued due to an allergic reaction. The patient presented to our clinic with complaints of continuous absence seizure, non-responsiveness, and inability to walk. Continuous generalized 2.5–3 Hz spike slow wave activity was detected in the patient’s EEG (Fig- ure 1a). The patient was admitted to the intensive care unit with the diagnosis of atypical absence status. The patient was taking oral valproic acid, levetiracetam, and phenobar- bital medications. IV benzodiazepine infusion was started. However, the patient’s seizures assumed a tonic status after benzodiazepine infusion (Figure 1b); therefore, thiopental infusion was initiated. Thiopental infusion reduced the seizures; therefore, rufunamide and cannabidiol (CBD) oil therapy were added to the oral treatment. However, seizure activity increased with the reduction in thiopental infusion. Further, CBD oil therapy was terminated, and ketogenic diet therapy was initiated. Thiopental infusion began to be reduced at the 72nd hour of the ketogenic diet. The patient did not have any further seizures under the ketogenic diet. The patient was discharged from intensive care after 17 days with oral valproic acid, rufinamide, phenobarbital, levetiracetam, and a ketogenic diet therapy. EEG taken 8 months after discharge from the intensive care unit showed slow background without epileptic discharges. The patient is being followed up without seizures for 8 months (Figure 1c). Cranial MRI of the patient showed a thin corpus cal- losum, ventriculomegaly, and white matter atrophy (Figure 2). Chromosome analysis and array-CGH analyses of the patient were normal. Furthermore, the patient was evalu- ated using WES analysis, and a maternal hemizygous mis- sense variant NM_001830.4: c.1597G>A (p.V533M) was detected in exon 11 of the CLCN4 gene. Cases 2-3 Thise index case has two sisters, and the same vari- ant was found as heterozygous in one and wild-type in the other. The seven years old sister with the heterozygous vari- ant was born with term birth weight of 3200 g. She started walking at 18 months of age and began to speak at 24 months of age. She received special education due to learn- ing difficulties. The patient had no seizures with a normal EEG. Neurological examination of the patient was normal. Her height was 115 cm (10p), weight was 22 kg (25p), and head circumference was 50 cm (3-10p). The Wechsler Intel- ligence Scale for Children-Revised (WISC-R) evaluation revealed borderline mental retardation. A heterozygous variant was detected in the mother. The neurological evalu- ation of the mother was normal. The patient’s Porteus Maze Test score was 89, her Kent Egy intelligence test score was 64 (the average score was 77), and the mother was diagnosed with borderline mental retardation. The mother had no history of epilepsy. Moreover, it was found that the patient’s aunt had poor school achievement and the son of the aunt had epilepsy and learning difficulties.

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