Further delineation of Temtamy syndrome of corpus callosum and ocular abnormalities.

Temtamy syndrome is a syndromic form of intellectual disability characterized by ocular involvement, epilepsy and dysgenesis of the corpus callosum. After we initially mapped the disease to C12orf57, we noted a high carrier frequency of an ancient startloss founder mutation [c.1A>G; p.M1?] in our population, and variable phenotypic expressivity in newly identified cases. This study aims to combine 33 previously published patients with 23 who are described here for the first time to further delineate the phenotype of this syndrome. In addition to the known p.M1? founder, we describe four novel homozygous variants, thus increasing the number of Temtamy syndrome-related C12orf57 variants to seven, all but one predicted to be loss of function. While all patients presented with intellectual disability/developmental delay, the frequency of other phenotypic features was variable: 73.2% (41/56) had epilepsy, 63% (34/54) had corpus callosal abnormalities, 14.5% (8/55) had coloboma, and 16.4% (9/55) had microphthalmia. Our analysis also revealed a high frequency of less recognized features such as congenital heart disease (51.4%), and brain white matter abnormalities (38%, 19/50). We conclude that C12orf57 variants should be considered in the etiology of developmental delay/intellectual disability, even when typical syndromic features are lacking, especially in those who trace their ancestry to Saudi Arabia where a founder C12orf57 mutation is among the most common recessive causes of intellectual disability.

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.