Developmental and/or epileptic encephalopathy with spike-and-wave activation in sleep in Saudi Arabia: Electroclinical, etiologic, genetic, and outcome multicenter study.

OBJECTIVES: To investigate the clinical features of developmental and/or epileptic encephalopathy with spike-and-wave activation in sleep (D/EE-SWAS), its electrographic characteristics, and etiology and to compare the effects of different treatment strategies on the outcomes using a Saudi Arabian database. METHODS: This multicenter study included children with D/EE-SWAS who were evaluated between 2010 and 2020 at 11 tertiary centers. Data were collected on their baseline clinical features, etiologies, and treatment modalities. Seizure reduction, spike-wave index, and cognitive state were examined as potential therapeutic outcomes. RESULTS: Ninety-one children were diagnosed with D/EE-SWAS, with a median age of 7 years (IQR: 3-5) and an almost equal sex distribution. The average age at which epilepsy was diagnosed was 3 years (IQR: 5-2). A genetic/metabolic etiology was found in 35.1% of the patients, and a structural etiology was found in 27.4%. Children with underlying genetic/metabolic diseases exhibited an earlier seizure onset (P = 0.001) than children with other etiologies. Benzodiazepines (76.6%) were the most common treatment, followed by steroids (51.9%). Sodium valproate (75%) was the most frequently used antiseizure medication, followed by levetiracetam (64.9%). Children with a later seizure onset were more likely to have better clinical responses (P = 0.046), EEG responses (P = 0.012), and cognitive outcomes (P = 0.006) than children with an earlier onset. Moreover, better seizure response and electrographic response were seen in patients with bilateral interictal discharges on the EEG than otherwise. Children had a higher likelihood of both clinical and electrographic improvement with combination therapy of benzodiazepines (P = 0.001) and steroids (P = 0.001) than with other therapies. SIGNIFICANCE: This study shows a higher prevalence of genetic/metabolic causes and suggests the superior efficacy of combination therapy with steroids and benzodiazepines in D/EE-SWAS. Prospective studies that strictly assess the treatment protocols and outcomes are needed.

Case report: Aromatic L-amino acid decarboxylase deficiency in three patient cases from the Kingdom of Saudi Arabia.

Aromatic L-amino acid decarboxylase (AADC) deficiency is an ultra-rare and often severe neurometabolic disorder resulting from variants in the dopa decarboxylase (DDC) gene. A timely diagnosis is critical to prevent secondary complications, promote development, and optimize outcomes from future innovative treatment options, such as gene therapy. This article describes three patients with AADC deficiency managed in the Kingdom of Saudi Arabia (KSA). All three patients had homozygous variants within the DDC gene, including one novel gene variant (c.245G > A, p.Arg82Glu), and presented with symptoms from birth. In all cases, a diagnostic delay was observed owing to non-specific signs and symptoms, a lack of disease awareness among primary care physicians, and delays associated with outsourcing of genetic tests. All three patients were managed by a multidisciplinary team at a specialist tertiary center. Clinical outcomes for all three cases were poor, with one patient passing away at 3 years of age and the other two patients continuing to experience substantial disability and poor quality of life. There is an urgent need to raise awareness and improve diagnostic testing for rare diseases such as AADC deficiency in the KSA in order to improve outcomes, particularly as innovative disease-targeting therapies become available.

Autosomal recessive hereditary spastic paraplegia with thin corpus callosum among Saudis.

OBJECTIVE: To assess the mutational and clinical spectrum of spatacsin associated with autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum (TCC). METHODS: A retrospective study was carried out at King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia from February 2008 until March 2011. Four unrelated Saudi Arabian families with ARHSP-TCC were studied, totaling 13 affected individuals. Clinical presentations included gait disturbance at variable ages (2-18 years), spastic paraplegia with mild to moderate cognitive impairment and evidence of peripheral neuropathy in 2 families. Brain MRI showed TCC accompanied by periventricular white matter changes and cortical atrophy. RESULTS: A genome wide scan demonstrated linkage to the SPG11 locus. Sequencing revealed 4 mutations. The first is an insertion/deletion (indel) consisting of a 3 base pair (bp) deletion and 23 bp insertion (L1268L fsX), the second is a one bp deletion (S1923R fsX), and the third and the fourth are nonsense mutations (Q341X and R651X). All mutations predict premature truncation of the spatacsin protein. CONCLUSION: We report 2 novel mutations in this gene, including an indel considerably larger than any other identified to date. The identification of these mutations further confirms the causative link between SPG11 and ARHSP-TCC in these families.

Phenotypical spectrum of cerebellar ataxia associated with a novel mutation in the CA8 gene, encoding carbonic anhydrase (CA) VIII.

We define the neurological characteristics of familial cases from multiple branches of a large consanguineous family with cerebellar ataxia, mental retardation (MR), and dysequilibrium syndrome type 3 caused by a mutation in the recently cloned CA8 gene. The linkage analysis revealed a high logarithm of the odds (LOD) score region on 8q that harbors the CA8 in which a novel homozygous c.484G>A (p.G162R) mutation was identified in all seven affected members. The patients had variable cerebellar ataxia and mild cognitive impairment without quadrupedal gait. The brain MRI showed variable cerebellar volume loss and ill-defined peritrigonal white matter abnormalities. The Fluorodeoxyglucose Positron Emission Tomography (FDG PET) revealed hypometabolic cerebellar hemispheres, temporal lobes, and mesial cortex. This report expands the neurological and radiological phenotype associated with CA8 mutations. CA8 involvement should be considered in the differential diagnosis of other genetically unresolved autosomal recessive cerebellar ataxias.