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.

Ceguera cortical como manifestación inicial de endocarditis trombótica no bacteriana / Cortical blindness as initial manifestation of nonbacterial thrombotic endocarditis

La endocarditis trombótica no bacteriana, antiguamente conocida como endocarditis marántica, es una entidad infrecuente en la que se desarrollan vegetaciones estériles, compuestas por fibrina en las válvulas del corazón. Suele diagnosticarse en el momento de la autopsia o en enfermedades oncológicas avanzadas. Las neoplasias malignas más frecuentemente asociadas con esta entidad son las de pulmón, páncreas, estómago y adenocarcinomas de origen primario desconocido. Es necesario descartar la endocarditis infecciosa y establecer la presencia de vegetaciones valvulares mediante ecocardiografía. Presentamos el caso de una paciente con diagnóstico reciente de adenocarcinoma de estómago en estadio avanzado que presentó ceguera cortical e imágenes compatibles con isquemia cerebral. El ecocardiograma transesofágico mostró dos vegetaciones en válvula mitral. Los hemocultivos fueron negativos. Se enfatiza la importancia de sospechar endocarditis trombótica no bacteriana en enfermos con cáncer y embolismo sistémico.

Nonbacterial thrombotic endocarditis, formerly known as marantic endocarditis, it is an infrequent entity in which sterile, fibrin vegetations develop on heart valve leaflets. It is often diagnosed at the time of autopsy or in late-stage malignancies. The most common malignancies associated with nonbacterial thrombotic endocarditis are lung, pancreatic, gastric cancer and adenocarcinomas of an unknown primary site. Diagnosis requires ruling out infective endocarditis and establishing the presence of valvular vegetations using echocardiography. We report the case of a patient with a recent diagnosis of advanced gastric adenocarcinoma who presented with cortical blindness. The computed tomography was compatible with cerebral ischemia. The transoesophageal echocardiogram showed two vegetations in mitral valve. Blood cultures were negative. We emphasize the importance of suspecting nonbacterial thrombotic endocarditis in patients with cancer and systemic embolism.

[Cortical blindness as initial manifestation of nonbacterial thrombotic endocarditis]. / Ceguera cortical como manifestación inicial de endocarditis trombótica no bacteriana.

Nonbacterial thrombotic endocarditis, formerly known as marantic endocarditis, it is an infrequent entity in which sterile, fibrin vegetations develop on heart valve leaflets. It is often diagnosed at the time of autopsy or in latestage malignancies. The most common malignancies associated with nonbacterial thrombotic endocarditis are lung, pancreatic, gastric cancer and adenocarcinomas of an unknown primary site. Diagnosis requires ruling out infective endocarditis and establishing the presence of valvular vegetations using echocardiography. We report the case of a patient with a recent diagnosis of advanced gastric adenocarcinoma who presented with cortical blindness. The computed tomography was compatible with cerebral ischemia. The transoesophageal echocardiogram showed two vegetations in mitral valve. Blood cultures were negative. We emphasize the importance of suspecting nonbacterial thrombotic endocarditis in patients with cancer and systemic embolism.

Progressive cortical visual failure associated with occipital calcification and coeliac disease with relative preservation of the dorsal 'action' pathway.

We describe the first reported case of a patient with coeliac disease and cerebral occipital calcification who shows a progressive and seemingly selective failure to recognise visual stimuli. This decline was tracked over a study period of 22 years and occurred in the absence of primary sensory or widespread intellectual impairment. Subsequent tests revealed that although the patient was unable to use shape and contour information to visually identify objects, she was nevertheless able to use this information to reach, grasp and manipulate objects under central, immediate vision. This preservation of visuo-motor control was echoed in her day-to-day ability to navigate and live at home independently. We conclude that occipital calcification following coeliac disease can lead to prominent higher visual failure that, under prescribed viewing conditions, is consistent with separable mechanisms for visual perception and action control.

Cortical blindness associated with autonomic dysreflexia in a man with tetraplegia: a rare but serious complication.

CONTEXT: To describe a case of a 44-year-old man with complete C4 tetraplegia who developed transient cortical blindness in the subacute setting following episodes of autonomic dysreflexia. FINDINGS: Transient cortical blindness the day after surgery for appendicitis that had resulted in severe autonomic dysreflexia (AD) requiring aggressive blood pressure management. Imaging showed no evidence of acute stroke, but did show vasospasm in the occipital lobes. Vision improved over the next couple of months. CONCLUSION/CLINICAL RELEVANCE: This case illustrates a possible profound vasomotor phenomenon (cortical blindness) associated with AD and its symptomatic treatment. Early recognition of AD and treatment of its underlying cause cannot be overemphasized.

Noncompaction in a HIV-positive with cortical blindness as initial manifestation of progressive multifocal leucencephalopathy.

OBJECTIVES: Though progressive multifocal leucencephalopathy (PML) may manifest with visual impairment, including bilateral visual loss as the presenting manifestation, in single patients, it has not been described in association with left ventricular hypertrabeculation/noncompaction (LVHT). CASE REPORT: A 37 years old HIV-positive Caucasian male developed visual impairment, which continuously progressed to near blindness within two weeks. He could differentiate bright and dark but was unable to count fingers, and there was bradydiadochokinesia. Ophthalmologic investigations exclusively revealed severe visual field defects bilaterally. Visually-evoked-potentials were absent bilaterally. MRI of the cerebrum revealed bilateral occipital, non-enhancing T2-hyperintensities, which extended towards the temporal lobe. On diffusion weighted imaging hyperintense areas were intermingled with hypointense areas. H-MR-spectroscopy disclosed an increased lactate peak, but reduced creatine, cholin, and N-acetyl-aspartate peaks. CSF-protein was slightly elevated, oligoclonal bands were positive, and PCR positive for the JC-virus. T-helper cells were markedly reduced. Cardiologic investigations revealed right bundle-branch-block, left ventricular wall thickening and LVHT in the left ventricular apex and the lateral wall. During follow-up visual acuity transiently improved but lastly deteriorated again despite a highly-active anti-retroviral therapy. CONCLUSIONS: This case shows that cortical blindness may be the initial clinical manifestation of PML and that isolated LVHT is not causally related to a HIV-infection but rather to a subclinical neuromuscular disorder.

Cross-sectional comparison of periventricular leukomalacia in preterm and term children.

OBJECTIVE: To document and contrast the characteristics of preterm and term-born children with cerebral palsy attributed to underlying radiologic periventricular white matter injury (leukomalacia) (PVWMI/PVL). METHODS: A comprehensive cerebral palsy population-based registry (REPACQ) for a 4-year inclusive (1999-2002) birth cohort was systematically searched for all children with radiologic evidence for PVWMI/PVL. Clinical features, neurologic subtype, gross motor functional impairment, and comorbidities were compared in those children born preterm (<37 weeks) and those born at term (> or = 37 weeks). RESULTS: Of 242 children with cerebral palsy in the registry, 213 had available neuroimaging, in which 41 had PVWMI/PVL: 26 preterm born and 15 term born. Neurologic subtype differed significantly between preterm and term-born children with respect to the frequency of spastic hemiplegia (5/26 vs 8/15; p < 0.05) and spastic diplegia (9/26 vs 2/15; p < 0.05). The groups also differed significantly from a functional perspective (Gross Motor Function Classification System for Cerebral Palsy level I-II; 12/26 vs 12/15; p < 0.05). The comorbidity spectrum was similar between the 2 groups except for the occurrence of cortical blindness in the term-born children (3/15 vs 0/26; p < 0.05). CONCLUSION: Differences between preterm and term-born children with cerebral palsy with periventricular white matter injury (leukomalacia) suggest that despite a common radiologic pattern, these are different clinicopathologic entities with perhaps a different gestational timing of acquired injury.

Posterior reversible encephalopathy syndrome due to severe hypercalcemia.

Posterior reversible encephalopathy syndrome (PRES) is a leukoencephalopathy clinically characterized by headache, altered mental status, visual loss and seizures. Neuroimaging demonstrates symmetrical posterior cortical and subcortical lesions. The exact pathophysiology is unknown but there is a strong association with immunosuppressants and hypertension. We report two cases of PRES in normotensive patients with severe hypercalcemia as the only identifiable cause. Possible pathophysiological mechanisms are discussed.

Postoperative blindness.

This chapter discusses the cases of postoperative blindness reported in the literature and the theories that attempt to explain the mechanisms involved. Although uncommon, alterations in vision and blindness after anesthesia for major surgical procedures, particularly cardiopulmonary bypass or spine surgery, are well documented, with an incidence varying between 0.05% and 1%. Accurate incidence data are unavailable because it is not known what percentages are reported. However, the large number of case reports over many years has provided some significant information. Although sustained compression of the eye is an important cause, postoperative visual loss may also occur, in an unrelated manner, because of ischemic optic neuropathy, central retinal artery or vein occlusion, or cortical blindness.

Cerebral visual impairment in periventricular leukomalacia.

Infants with cerebral palsy (CP) frequently present cerebral visual impairment (CVI) often caused by damage to retrochiasmatic pathways. This is particularly true of subjects with damage to the periventricular white matter. Thirty-eight preterm infants with periventricular leukomalacia (PVL) diagnosed by MRI were examined to correlate binocular visual acuity with neuroradiological findings. Binocular visual acuity was evaluated using Teller Acuity Cards and a complete ophthalmological examination was also performed. Three infants with ROP III were excluded from the sample. The age of observation ranged from 20 months to 5 and a half years (mean 42 months). The possible involvement of the optic radiations and/or of the calcarine cortex was detected by brain MRI. Twenty-three infants (66%) presented visual impairment. Of these, 9 (26%) were totally or nearly totally blind and 14 (40%) were low vision children. The other 12 (34%) had normal (2) or near normal (9) vision. MRI findings correlated with visual acuity; a relationship was detected between the degree of visual acuity and the reduction of the peritrigonal white matter, and also between the degree of visual acuity and the extent of calcarine atrophy. This report clearly establishes a relationship between visual impairment and specific MRI findings in children with PVL. Teller Acuity Cards and MRI are useful for detecting potential visual impairment and for improving both the clinical diagnosis of these disorders and the therapeutic approach to these subjects.