Expanding the genetic heterogeneity of intellectual disability

Intellectual disability (ID) is a common morbid condition with a wide range of etiologies. The list of monogenic forms of ID has increased rapidly in recent years thanks to the implementation of genomic sequencing techniques. In this study, we describe the phenotypic and genetic findings of 68 families (105 patients) all with novel ID-related variants. In addition to established ID genes, including ones for which we describe unusual mutational mechanism, some of these variants represent the first confirmatory disease-gene links following previous reports (TRAK1, GTF3C3, SPTBN4 and NKX6-2), some of which were based on single families. Furthermore, we describe novel variants in 14 genes that we propose as novel candidates (ANKHD1, ASTN2, ATP13A1, FMO4, MADD, MFSD11, NCKAP1, NFASC, PCDHGA10, PPP1R21, SLC12A2, SLK, STK32C and ZFAT). We highlight MADD and PCDHGA10 as particularly compelling candidates in which we identified biallelic likely deleterious variants in two independent ID families each. We also highlight NCKAP1 as another compelling candidate in a large family with autosomal dominant mild intellectual disability that fully segregates with a heterozygous truncating variant. The candidacy of NCKAP1 is further supported by its biological function, and our demonstration of relevant expression in human brain. Our study expands the locus and allelic heterogeneity of ID and demonstrates the power of positional mapping to reveal unusual mutational mechanisms

Prevalence and outcomes of Guillain-Barré syndrome among pediatrics in Saudi Arabia: a 10-year retrospective study

Safiyyah Asiri,1 Waleed A Altwaijri,1,2 Duaa Ba-Armah,1 Ahmed Al Rumayyan,1,2 Muhammad T Alrifai,1,2 Mahmoud Salam,3 Adel F Almutairi3 1Pediatric Neurology, Pediatric Department, King Abdullah Specialist Children’s Hospital, Ministry of National Guard-Health Affairs (MNGHA), Riyadh, Saudi Arabia; 2College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia; 3Science and Technology Unit, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia Background: Guillain-Barré syndrome (GBS) is a progressive acute form of paralysis most probably secondary to an immune-mediated process. GBS among Saudis has been seldom investigated, which leaves both clinicians and researchers with scarcity in knowledge. Therefore, this study aims to assess the prevalence and clinical prognosis of GBS among pediatrics admitted with acute paralysis at a large healthcare facility in Riyadh, Saudi Arabia. Methods: This retrospective study reviewed patients’ medical records between 2005 and 2015. Eligible cases were children (<14 years old) admitted to the hospital complaining of acute paralysis and later diagnosed with one form or variant of GBS. Pearson’s chi-square, Fisher’s exact test, and binary logistic regression were employed to analyze the collected data. Results: The prevalence of GBS was 49%. The male-to-female ratio was 1.45:1. The mean ± standard deviation age was 7±3.7 years. There were 34 (69.4%) cases with progression to maximum paralysis in ≤2 weeks, while 15 (30.6%) cases occurred beyond 2 weeks. Males (n=24, 82.8%) were more likely to endure progression to maximum paralysis in ≤2 weeks after the disease onset, compared to females (n=10, 50%), P=0.014. All cases complaining of respiratory problems exhibited a progression to maximum paralysis in ≤2 weeks, compared to those with no respiratory problems, P=0.027. Residual paralysis at 60 days post disease onset was highly associated with GBS patients of age 8–14 years (n=15, 65.2%), compared to younger patients (n=8, 30.8%), P=0.016. Patients admitted in colder seasons (n=14, 63.6%) were more likely to suffer residual paralysis too, compared to those in warmer seasons (n=9, 33.3%), P=0.035. GBS cases who complained of facial weakness (n=9, 75%) and ocular abnormalities (n=10, 71.4%) were also more likely to endure residual paralysis at 60 days post disease onset, P=0.025 and P=0.03, respectively. Conclusion: Male gender could be a determinant of rapid progression to maximum paralysis, while the older age group in pediatrics is expected to endure residual paralysis at 60 days post disease onset. GBS can be accounted as a rare disease, especially in pediatrics, so confirmed cases should be investigated comprehensively for research purposes. Keywords: GBS, factors, prognosis, residual, paralysis, neur

Abnormal Cerebellar Development and Axonal Decussation Due To Mutations in Ahi1 in Joubert Syndrome

Scopu

Further delineation of the phenotypic spectrum of ISCA2 defect: A report of ten new cases

Iron-Sulfur Cluster (ISC) biogenesis is a vital cellular process required to produce various ISC-containing proteins. These ISC proteins are responsible for essential functions such as glycine cleavage and the formation of lipoic acid, an essential cofactor of respiratory chain complexes. Defects in ISC biogenesis lead to multiple mitochondrial dysfunction syndromes including: ISCA2 with infantile onset leukodystrophy. Recently, a founder mutation, c.229G > A, p.Gly77Ser in ISCA2 was reported to cause Multiple Mitochondrial Dysfunction Syndrome type 4. In a retrospective review of children diagnosed with the ISCA2 defect, we were able to identify ten new patients who were not reported previously with the identical founder mutation. High CSF glycine levels and elevated glycine peaks on MR spectroscopy were demonstrated in all tested probands. All patients were between 3 and 7 months of age with a triad of neurodevelopmental regression, nystagmus and optic atrophy and leukodystrophy. MRI findings were typical in the patients with diffuse, abnormal white matter signal in the cerebrum, cerebellum, brain stem and spinal cord. The patients ended up in a vegetative state, and often premature death due to respiratory infections. We alert clinicians to consider the ISCA2 defect as a differential diagnosis of infantile onset leukodystrophies affecting the brain as well as the spinal cord, especially in the presence of elevated CSF glycine or elevated glycine peaks in MR spectroscopy

Expanding the genetic heterogeneity of intellectual disability

Intellectual disability (ID) is a common morbid condition with a wide range of etiologies. The list of monogenic forms of ID has increased rapidly in recent years thanks to the implementation of genomic sequencing techniques. In this study, we describe the phenotypic and genetic findings of 68 families (105 patients) all with novel ID-related variants. In addition to established ID genes, including ones for which we describe unusual mutational mechanism, some of these variants represent the first confirmatory disease\u2013gene links following previous reports (TRAK1, GTF3C3, SPTBN4 and NKX6-2), some of which were based on single families. Furthermore, we describe novel variants in 14 genes that we propose as novel candidates (ANKHD1, ASTN2, ATP13A1, FMO4, MADD, MFSD11, NCKAP1, NFASC, PCDHGA10, PPP1R21, SLC12A2, SLK, STK32C and ZFAT). We highlight MADD and PCDHGA10 as particularly compelling candidates in which we identified biallelic likely deleterious variants in two independent ID families each. We also highlight NCKAP1 as another compelling candidate in a large family with autosomal dominant mild intellectual disability that fully segregates with a heterozygous truncating variant. The candidacy of NCKAP1 is further supported by its biological function, and our demonstration of relevant expression in human brain. Our study expands the locus and allelic heterogeneity of ID and demonstrates the power of positional mapping to reveal unusual mutational mechanisms