Fahad A. Bashiri

Biotin-responsive basal ganglia disease should be renamed biotin-thiamine-responsive basal ganglia disease: a retrospective review of the clinical, radiological and molecular findings of 18 new cases

BackgroundBiotin-responsive basal ganglia disease (BBGD) is an autosomal recessive neurometabolic disorder. It is characterized by sub acute encephalopathy with confusion, seizure, dysarthria and dystonia following a history of febrile illness. If left untreated with biotin, the disease can progress to severe quadriparesis and even death.MethodA retrospective chart review of 18 patients with BBGD from two tertiary institutions describing their clinical, magnetic resonance imaging and molecular findings was conducted.ResultEighteen children from 13 families seen over a period of nine years (2003–2012) were included. (Age range: 14month to 23 years, M: F: 1:1). The clinical features included sub acute encephalopathy, ataxia (n= 18), seizures (n= 13) dystonia (n=12) ,dysarthria (n= 9), quadriparesis and hyperreflexia (n=9). Magnetic resonance imaging demonstrated abnormal signal intensity with swelling in the basal ganglia during acute crises (n= 13/13) and atrophy of the basal ganglia and necrosis during follow up (n= 13/13). One-third of the present patients showed the recurrence of acute crises while on biotin therapy alone, but after the addition of thiamine, crises did not recur. All of the patients have a homozygous missense mutation in exon 5 of the SLC19A3 gene. The frequency of acute crises, delay in diagnosis and initiation of treatment significantly influenced the outcome. On follow up, four patients died, two had spastic quadriplegia, six had normal outcome and the rest had speech and motor dysfunctions.ConclusionClinicians should suspect BBGD in any child presenting with sub acute encephalopathy, abnormal movement and MRI findings as described above. Both biotin and thiamine are essential for disease management. Since biotin alone could not prevent the recurrence of crises in some patients, a more appropriate term to describe the disease would be biotin-thiamine-responsive basal ganglia disease (BTBGD).

SLC25A22 is a Novel Gene for Migrating Partial Seizures in Infancy

To identify a genetic cause for migrating partial seizures in infancy (MPSI).

Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield

Intellectual disability (ID) is a measurable phenotypic consequence of genetic and environmental factors. In this study, we prospectively assessed the diagnostic yield of genomic tools (molecular karyotyping, multi-gene panel and exome sequencing) in a cohort of 337 ID subjects as a first-tier test and compared it with a standard clinical evaluation performed in parallel. Standard clinical evaluation suggested a diagnosis in 16% of cases (54/337) but only 70% of these (38/54) were subsequently confirmed. On the other hand, the genomic approach revealed a likely diagnosis in 58% (n=196). These included copy number variants in 14% (n=54, 15% are novel), and point mutations revealed by multi-gene panel and exome sequencing in the remaining 43% (1% were found to have Fragile-X). The identified point mutations were mostly recessive (n=117, 81%), consistent with the high consanguinity of the study cohort, but also X-linked (n=8, 6%) and de novo dominant (n=19, 13%). When applied directly on all cases with negative molecular karyotyping, the diagnostic yield of exome sequencing was 60% (77/129). Exome sequencing also identified likely pathogenic variants in three novel candidate genes (DENND5A, NEMF and DNHD1) each of which harbored independent homozygous mutations in patients with overlapping phenotypes. In addition, exome sequencing revealed de novo and recessive variants in 32 genes (MAMDC2, TUBAL3, CPNE6, KLHL24, USP2, PIP5K1A, UBE4A, TP53TG5, ATOH1, C16ORF90, SLC39A14, TRERF1, RGL1, CDH11, SYDE2, HIRA, FEZF2, PROCA1, PIANP, PLK2, QRFPR, AP3B2, NUDT2, UFC1, BTN3A2, TADA1, ARFGEF3, FAM160B1, ZMYM5, SLC45A1, ARHGAP33 and CAPS2), which we highlight as potential candidates on the basis of several lines of evidence, and one of these genes (SLC39A14) was biallelically inactivated in a potentially treatable form of hypermanganesemia and neurodegeneration. Finally, likely causal variants in previously published candidate genes were identified (ASTN1, HELZ, THOC6, WDR45B, ADRA2B and CLIP1), thus supporting their involvement in ID pathogenesis. Our results expand the morbid genome of ID and support the adoption of genomics as a first-tier test for individuals with ID.

Confirming the recessive inheritance of SCN1B mutations in developmental epileptic encephalopathy

Dominant SCN1B mutations are known to cause several epilepsy syndromes in humans. Only 2 epilepsy patients to date have been reported to have recessive mutations in SCN1B as the likely cause of their phenotype. Here, we confirm the recessive inheritance of 2 novel SCN1B mutations in 5 children from 3 families with developmental epileptic encephalopathy. The recessive inheritance and early death in these patients is consistent with the Dravet‐like phenotype observed in Scn1b−/− mice. The ‘negative’ clinical exome in one of these families highlights the need to consider recessive mutations in the interpretation of variants in typically dominant genes.

The clinical utility of molecular karyotyping for neurocognitive phenotypes in a consanguineous population

Purpose:Molecular karyotyping has rapidly become the test of choice in patients with neurocognitive phenotypes, but studies of its clinical utility have largely been limited to outbred populations. In consanguineous populations, single-gene recessive causes of neurocognitive phenotypes are expected to account for a relatively high percentage of cases, thus diminishing the yield of molecular karyotyping. The aim of this study was to test the clinical yield of molecular karyotyping in the highly consanguineous population of Saudi Arabia.Methods:We have reviewed the data of 584 patients with neurocognitive phenotypes (mainly referred from pediatric neurology clinics), all evaluated by a single clinical geneticist.Results:At least 21% of tested cases had chromosomal aberrations that are likely disease-causing. These changes include both known and novel deletion syndromes. The higher yield of molecular karyotyping in this study as compared with the commonly cited 11% can be explained by our ability to efficiently identify single-gene disorders, thus enriching the samples that underwent molecular karyotyping for de novo chromosomal aberrations. We show that we were able to identify a causal mutation in 37% of cases on a clinical basis with the help of autozygome analysis, thus bypassing the need for molecular karyotyping.Conclusion:Our study confirms the clinical utility of molecular karyotyping even in highly consanguineous populations.Genet Med 17 9, 719–725.

Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination.

Progressive limb spasticity and cerebellar ataxia are frequently found together in clinical practice and form a heterogeneous group of degenerative disorders that are classified either as pure spastic ataxia or as complex spastic ataxia with additional neurological signs. Inheritance is either autosomal dominant or autosomal recessive. Hypomyelinating features on MRI are sometimes seen with spastic ataxia, but this is usually mild in adults and severe and life limiting in children. We report seven individuals with an early-onset spastic-ataxia phenotype. The individuals come from three families of different ethnic backgrounds. Affected members of two families had childhood onset disease with very slow progression. They are still alive in their 30s and 40s and show predominant ataxia and cerebellar atrophy features on imaging. Affected members of the third family had a similar but earlier-onset presentation associated with brain hypomyelination. Using a combination of homozygozity mapping and exome sequencing, we mapped this phenotype to deleterious nonsense or homeobox domain missense mutations in NKX6-2. NKX6-2 encodes a transcriptional repressor with early high general and late focused CNS expression. Deficiency of its mouse ortholog results in widespread hypomyelination in the brain and optic nerve, as well as in poor motor coordination in a pattern consistent with the observed human phenotype. In-silico analysis of human brain expression and network data provides evidence that NKX6-2 is involved in oligodendrocyte maturation and might act within the same pathways of genes already associated with central hypomyelination. Our results support a non-redundant developmental role of NKX6-2 in humans and imply that NKX6-2 mutations should be considered in the differential diagnosis of spastic ataxia and hypomyelination.

ARL6IP6, a susceptibility locus for ischemic stroke, is mutated in a patient with syndromic Cutis Marmorata Telangiectatica Congenita.

Cutis Marmorata Telangiectatica Congenita (CMTC) is a congenital localized or generalized vascular anomaly, usually sporadic in occurrence. It can be associated with other cutaneous or systemic manifestations. About 300 cases have been reported. The molecular etiology remains largely unknown. The main purpose of this study is to delineate the molecular basis for a syndromic CMTC phenotype in a consanguineous Saudi family. Clinical phenotyping including detailed neurological imaging, followed by autozygosity mapping and trio whole exome sequencing (WES) are also studied. We have identified a homozygous truncating mutation in ARL6IP6 as the likely cause of a syndromic form of CMTC associated with major dysmorphism, developmental delay, transient ischemic attacks and cerebral vascular malformations. This gene was previously implicated by genome wide association study (GWAS) as a susceptibility locus to ischemic stroke in young adults. We identify ARL6IP6 as a novel candidate gene for a syndromic form of CMTC. This suggests that ischemic stroke or transient ischemic attacks (TIA) may represent, at least in some cases, the mild end of a phenotypic spectrum that has at its severe end autosomal recessive CMTC. This finding contributes to a growing appreciation of the continuum of Mendelian and common complex diseases.

GWAS signals revisited using human knockouts

PurposeGenome-wide association studies (GWAS) have been instrumental to our understanding of the genetic risk determinants of complex traits. A common challenge in GWAS is the interpretation of signals, which are usually attributed to the genes closest to the polymorphic markers that display the strongest statistical association. Naturally occurring complete loss of function (knockout) of these genes in humans can inform GWAS interpretation by unmasking their deficiency state in a clinical context.MethodsWe exploited the unique population structure of Saudi Arabia to identify novel knockout events in genes previously highlighted in GWAS using combined autozygome/exome analysis.ResultsWe report five families with homozygous truncating mutations in genes that had only been linked to human disease through GWAS. The phenotypes observed in the natural knockouts for these genes (TRAF3IP2, FRMD3, RSRC1, BTBD9, and PXDNL) range from consistent with, to unrelated to, the previously reported GWAS phenotype.ConclusionWe expand the role of human knockouts in the medical annotation of the human genome, and show their potential value in informing the interpretation of GWAS of complex traits.

Management of convulsive status epilepticus in children: an adapted clinical practice guideline for pediatricians in Saudi Arabia

Objective: To increase the use of evidence-based approaches in the diagnosis, investigations and treatment of Convulsive Status Epilepticus (CSE) in children in relevant care settings. Method: A Clinical Practice Guideline (CPG) adaptation group was formulated at a university hospital in Riyadh. The group utilized 2 CPG validated tools including the ADAPTE method and the AGREE II instrument. Results: The group adapted 3 main categories of recommendations from one Source CPG. The recommendations cover; (i)first-line treatment of CSE in the community; (ii)treatment of CSE in the hospital; and (iii)refractory CSE. Implementation tools were built to enhance knowledge translation of these recommendations including a clinical algorithm, audit criteria, and a computerized provider order entry. Conclusion: A clinical practice guideline for the Saudi healthcare context was formulated using a guideline adaptation process to support relevant clinicians managing CSE in children.

Mycoplasma pneumoniae Infection Risk Factor for Childhood Stroke

Cerebrovascular disorders constitute the top 10 causes of death in children and result in significant morbidity as well.1 The estimated incidence of childhood stroke varies, depending on the definition and inclusion criteria, and ranges from 2 to 13 per 100 000 children under age 18 per year in North America and Europe.2 Risk factors for stroke can be identified in the majority of patients. Infectious illnesses are the second most common cofactor (30%) according to analyses of national data for the United States3 and the United Kingdom.4 Mycoplasma pneumoniae infection causes neurological complications, although it rarely causes stroke. In this article, we report a 10-year-old boy who had a cough and low-grade fever 2 weeks before he presented with right-sided weakness due to an acute ischemic stroke.