Loss of DIAPH1 causes SCBMS, combined immunodeficiency, and mitochondrial dysfunction.

BACKGROUND: Homozygous loss of DIAPH1 results in seizures, cortical blindness, and microcephaly syndrome (SCBMS). We studied 5 Finnish and 2 Omani patients with loss of DIAPH1 presenting with SCBMS, mitochondrial dysfunction, and immunodeficiency. OBJECTIVE: We sought to further characterize phenotypes and disease mechanisms associated with loss of DIAPH1. METHODS: Exome sequencing, genotyping and haplotype analysis, B- and T-cell phenotyping, in vitro lymphocyte stimulation assays, analyses of mitochondrial function, immunofluorescence staining for cytoskeletal proteins and mitochondria, and CRISPR-Cas9 DIAPH1 knockout in heathy donor PBMCs were used. RESULTS: Genetic analyses found all Finnish patients homozygous for a rare DIAPH1 splice-variant (NM_005219:c.684+1G>A) enriched in the Finnish population, and Omani patients homozygous for a previously described pathogenic DIAPH1 frameshift-variant (NM_005219:c.2769delT;p.F923fs). In addition to microcephaly, epilepsy, and cortical blindness characteristic to SCBMS, the patients presented with infection susceptibility due to defective lymphocyte maturation and 3 patients developed B-cell lymphoma. Patients' immunophenotype was characterized by poor lymphocyte activation and proliferation, defective B-cell maturation, and lack of naive T cells. CRISPR-Cas9 knockout of DIAPH1 in PBMCs from healthy donors replicated the T-cell activation defect. Patient-derived peripheral blood T cells exhibited impaired adhesion and inefficient microtubule-organizing center repositioning to the immunologic synapse. The clinical symptoms and laboratory tests also suggested mitochondrial dysfunction. Experiments with immortalized, patient-derived fibroblasts indicated that DIAPH1 affects the amount of complex IV of the mitochondrial respiratory chain. CONCLUSIONS: Our data demonstrate that individuals with SCBMS can have combined immune deficiency and implicate defective cytoskeletal organization and mitochondrial dysfunction in SCBMS pathogenesis.

A Novel Deletion Mutation of Exon 2 of the C19orf12 Gene in an Omani Family with Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN).

Mutations in the C19orf12 gene are known to cause mitochondrial membrane protein-associated neurodegeneration (MPAN), which is a neurodegeneration with brain iron accumulation (NBIA) type 4 disorder. To the best of our knowledge, this is the first report of a genetically confirmed case of MPAN from Oman. A novel homozygous deletion of exon 2 of the C19orf12 gene was confirmed on the proband, a seven-year-old girl, who presented with gait instability. Brain magnetic resonance imaging showed iron deposition on the basal ganglia. This report highlights the importance of genetic testing of such a clinically and genetically heterogeneous condition among a population with a high consanguinity rate. To overcome the diagnostic difficulty, implementation of a cost-effective approach to perform cascade screening of carriers at risk is needed as well as programs to address risky consanguineous marriages.

Atypical Presentations of Respiratory Syncytial Virus Infection: Case Series.

The respiratory syncytial virus (RSV) usually causes a lower respiratory tract infection in affected patients. RSV has also been infrequently linked to extrapulmonary diseases in children. We report four children who had unusually severe clinical manifestations of RSV infections requiring critical care admission. These patients presented to the Royal Hospital, Muscat, Oman, in December 2013 with acute necrotising encephalopathy (ANE), acute fulminant hepatic failure with encephalopathy, pneumatoceles and croup. A unique presentation of ANE has not previously been reported in association with an RSV infection. All patients had a positive outcome and recovered fully with supportive management.

What are the minimum requirements for ketogenic diet services in resource-limited regions? Recommendations from the International League Against Epilepsy Task Force for Dietary Therapy.

Despite the increasing use of dietary therapies for children and adults with refractory epilepsy, the availability of these treatments in developing countries with limited resources remains suboptimal. One possible contributory factor may be the costs. There is often reported a significant perceived need for a large ketogenic diet team, supplements, laboratory studies, and follow-up visits to provide this treatment. The 2009 Epilepsia Consensus Statement described ideal requirements for a ketogenic diet center, but in some situations this is not feasible. As a result, the International League Against Epilepsy (ILAE) Task Force on Dietary Therapy was asked to convene and provide practical, cost-effective recommendations for new ketogenic diet centers in resource-limited regions of the world.

Late Onset Central Hypoventilation Syndrome due to a Heterozygous Polyalanine Repeat Expansion Mutation in the PHOX2B Gene.

This report describes a 6 year old girl with late onset central hypoventilation syndrome due to a heterozygous polyalanine repeat expansion mutation in the PHOX2B gene. This report aims to increase the awareness of this condition among physicians to allow earlier clinical and genetic diagnosis and management of cases of unexplained hypoventilation.

Term intra-partum asphyxia: an analysis of acute non-specific supportive criteria and non-CNS organ injury.

OBJECTIVE: The purpose of this study was to describe the frequencies and relationships of non-specific non-essential diagnostic criteria and non-CNS organ system injury in term intra-partum asphyxia. METHODS: All children with term intra-partum asphyxia encountered in a single pediatric neurology practice with at least two years follow-up and an abnormal neurologic outcome were identified. RESULTS: A total of 40 children (28 males, 12 females) were identified. Twenty-four had moderate NE and sixteen severe NE. The mean number of non-specific non-essential diagnostic criteria (out of a possible 7) was 4.75+/-1.39 SD. Sixty percent had five or more criteria and all criteria were present in only 10% of newborns. The mean number of non-CNS organ systems affected was 2.88+/-1.96 SD (out of a possible 6). Ten percent of our sample showed no evident non-CNS organ injury acutely. CONCLUSION: Most asphyxiated neonates failed to consistently satisfy all elements of present consensus statements.

The spectrum of abnormal neurologic outcomes subsequent to term intrapartum asphyxia.

The purpose of this study was to describe the spectrum of possible abnormal neurologic outcomes in term infants with intrapartum asphyxia and to identify those clinical factors associated with the later occurrence of cerebral palsy. All children with term intrapartum asphyxia encountered in a single pediatric neurologic practice with at least 2 years of follow-up and an abnormal neurologic outcome were identified. Abnormal outcomes were grouped into those with or without cerebral palsy. A total of 40 children (28 male, 12 female) met study criteria. Of these, 23 developed cerebral palsy; the remaining 17 children developed an abnormal neurologic outcome that did not include cerebral palsy. A more severe grade of neonatal encephalopathy, a higher number of neonatal seizures, the neonatal use of phenytoin, diffuse abnormalities on imaging, and abnormal findings on neurologic examination at neonatal discharge were all significantly (P<0.05) associated with an abnormal outcome that included cerebral palsy. Abnormal neurologic outcomes other than cerebral palsy subsequent to term intrapartum asphyxia may occur. It appears that a more severe grade of apparent initial clinical injury is more likely to result in an outcome featuring cerebral palsy.