Clinical and Molecular Characteristics of Neuronal Ceroid Lipofuscinosis in Saudi Arabia.

BACKGROUND: Neuronal ceroid lipofuscinoses (NCLs) represent a heterogeneous group of inherited metabolic lysosomal disorders characterized by neurodegeneration. This study sought to describe the clinical and molecular characteristics of NCLs in Saudi Arabia and determine the most common types in that population. METHODS: A retrospective review of electronic medical records was conducted for 63 patients with NCL (55 families) from six tertiary and referral centers in Saudi Arabia between 2008 and 2022. Clinical, radiological, and neurophysiological data as well as genetic diagnoses were reviewed. RESULTS: CLN6 was the predominant type, accounting for 45% of cases in 25 families. The most common initial symptoms were speech delay (53%), cognitive decline (50%) and/or gait abnormalities (48%), and seizure (40%). Behavioral symptomatology was observed in 20%, whereas visual impairment was less frequently (9.3%) encountered. Diffuse cerebral and cerebellar atrophy was the predominant finding on brain magnetic resonance imaging. Electroencephalography generally revealed background slowing in all patients with generalized epileptiform discharges in 60%. The most common genotype detected was the p.Ser265del variant found in 36% (20 of 55 families). The most rapidly progressive subtypes were CLN2 and CLN6. Two patients with each died at age five years. The earliest age at which a patient was nonambulatory was two years in a patient with CLN14. CONCLUSIONS: This is the largest molecularly confirmed NCL cohort study from Saudi Arabia. Characterizing the natural history of specific NLC types can increase understanding of the underlying pathophysiology and distinctive genotype-phenotype characteristics, facilitating early diagnosis and treatment initiation as well as genetic counseling for families.

Effect of a ketogenic diet on decrease of seizures in refractory epilepsy among children (infancy to 14 years old) in Saudi Arabia: a cross-sectional study.

Background: Refractory (intractable/pharmaco-resistant) epilepsy in children is considered if disabling seizures continue despite appropriate trials of two anti-seizure drugs, either alone or in combination. Ketogenic diets are used as a treatment option in many countries for children with refractory seizures; however, few patients have tried it in Saudi Arabia. Therefore, we examined the relationship between the exposure to a ketogenic diet and its effect in decreasing seizure frequency in infants and children up to 14 years who had refractory epilepsy and assessed factors that could improve the outcome of seizures. Methods: This cross-sectional study was conducted at King Fahad Medical City, Riyadh, Saudi Arabia. Data were collected by reviewing medical records of eligible children (infants and children up to 14 years old) with refractory epilepsy who were on ketogenic diets. Socioeconomic data of the parents (guardians) were collected via phone interviews after verbal consent from the parents (guardians). Results: We recruited 95 children (aged 10 months to 14 years) with refractory epilepsy and on Ketogenic diets. Up to 44% of patients on 3:1 and 4.5:1 ratio ketogenic diets had decreased seizure frequency while patients on 1:1 and 2:1 ratio ketogenic diets showed no decrease in seizures. Patients with generalized epilepsy who were on ketogenic diets had the most improvement in seizure outcomes (56.1%) and patients on ketogenic diets who were ambulatory indoors and outdoors (66.7%) showed a high level of improvement in seizure outcomes compared to patients with who were non-ambulatory (21.9%). Lower improvements in seizure frequency in epileptic patients on ketogenic diets were associated with low education levels of parents (33.3% high school vs. 50% undergraduate school), low incomes [<11,400±7,560.864 Saudi riyal (SR)], and diagnosis of seizures in patients >8 years old. Conclusions: Ketogenic diets are a promising approach for treatment of refractory epilepsy among children. The improvement in seizure outcomes was associated with higher ratios of ketogenic diets (3:1 and 4.5:1), and higher physical activity. Sociodemographic factors, including parents' (guardians') education levels and income influenced the improvement of seizures.

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy.

Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients' primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.