Background and Purpose-Cerebral microangiopathy, indicated on MRI by lacunar infarctions (LI) and deep white matter lesions (DWML), is said to lead to vascular dementia. Methods-Fifty-seven patients with proven cerebral microangiopathy were assessed for changes in regional cerebral blood flow (rCBF) and glucose metabolism (rMRGlu) and compared with 19 age-matched controls.

Volume 129 Number 3 March 2019 conjugation of L-serine and palmitoyl-CoA, the rate-limiting step catalyzed by serine palmitoyltransferase (SPT). The immediate product 3-keto-sphinganine is reduced to sphinganine (SA), which is then N-acylated to dihydroceramide (dhCer) by 1 of 6 ceramide synthase isoforms (CerS1-6) (4). In the final step, dhCer is converted to ceramide by the insertion of a Δ4,5 trans (Δ4E) double bond into the SA backbone. This final conversion is catalyzed by the Δ4-dihydroceramide desaturase DEGS1 (5). On the catabolic side, ceramides are deacylated by ceramidases to form sphingosine (SO), which can be either recycled back to ceramides (sal-BACKGROUND. Sphingolipids are important components of cellular membranes and functionally associated with fundamental processes such as cell differentiation, neuronal signaling, and myelin sheath formation. Defects in the synthesis or degradation of sphingolipids leads to various neurological pathologies; however, the entire spectrum of sphingolipid metabolism disorders remains elusive. METHODS.A combined approach of genomics and lipidomics was applied to identify and characterize a human sphingolipid metabolism disorder. RESULTS.By whole-exome sequencing in a patient with a multisystem neurological disorder of both the central and peripheral nervous systems, we identified a homozygous p.Ala280Val variant in DEGS1, which catalyzes the last step in the ceramide synthesis pathway. The blood sphingolipid profile in the patient showed a significant increase in dihydro sphingolipid species that was further recapitulated in patient-derived fibroblasts, in CRISPR/Cas9-derived DEGS1-knockout cells, and by pharmacological inhibition of DEGS1. The enzymatic activity in patient fibroblasts was reduced by 80% compared with wild-type cells, which was in line with a reduced expression of mutant DEGS1 protein. Moreover, an atypical and potentially neurotoxic sphingosine isomer was identified in patient plasma and in cells expressing mutant DEGS1. CONCLUSION.We report DEGS1 dysfunction as the cause of a sphingolipid disorder with hypomyelination and degeneration of both the central and peripheral nervous systems.(OMIM #617575) (19-21), but also with axonal peripheral neuropathy without renal or adrenal deficiencies (22).Here, we identify DEGS1 dysfunction as the cause of an SL disorder with leukodystrophy and hypomyelination of the peripheral nervous system.

We identified an oligophrenin 1 (OPHN1) gene mutation in a family with five brothers affected by a recognizable pattern of clinical and neuroradiological hallmarks. The distinctive phenotype comprised moderate to severe mental retardation, myoclonic-astatic epilepsy, ataxia, strabismus and hypogenitalism. Neuroimaging displayed fronto-temporal atrophy with rostral enlargement of the lateral ventricles, lower vermian agenesis and asymmetric cerebellar hypoplasia. Mutation analysis of the OPHN1 gene on Xq12 disclosed a genomic deletion of exon 19 causing a frameshift. Notably, OPHN1 mutations have been previously reported as a rare cause of non-syndromic X-linked mental retardation. Our findings, however, indicate that OPHN1 mutations result in a recognizable syndrome. In addition, identification of OPHN1 as a further gene associated with epileptic seizures will help to unravel aetiologic factors of epilepsy.

Microemboli are a frequent phenomenon in patients with acute stroke arising from a variety of causes, both in the very early stages and several days after the onset of symptoms. The prevalence of MES decreases significantly over time. MES occur more frequently in patients with carotid artery disease than in patients with a potential cardiac source of embolism. Ipsilateral MES are frequent in patients with carotid artery disease, whereas bilateral MES are suggestive of a cardioembolic origin. Anticoagulation treatment appears to decrease the prevalence of MES, but microemboli still occur in patients receiving intravenous therapy with heparin. Because MES occur intermittently, TCD examinations should be repeated several times, even in patients without MES in the first examination, and long-term monitoring equipment is necessary.

Spinal vascular malformations are rare diseases that consist of true inborn cavernomas and arteriovenous malformations (including perimedullary fistulae, glomerular and juvenile AVMs) and presumably acquired dural arteriovenous fistulae. This review article gives an overview of the imaging features both on MRI and angiography, the differential diagnoses, the clinical symptomatology and the potential therapeutic approaches to these diseases. It is concluded that MRI is the diagnostic modality of first choice in suspected spinal vascular malformation and should be complemented by selective spinal angiography. Treatment in symptomatic patients offers an improvement in the prognosis, but should be performed in specialized centers. Patients with spinal cord cavernomas and perimedullary fistulae type I are surgical candidates. Dural arteriovenous fistulae can either be operated upon or can be treated by an endovascular approach, the former being a simple, quick and secure approach to obliterate the fistula, while the latter is technically demanding. In spinal arteriovenous malformations, the endovascular approach is the method of first choice; in selected cases, a combined therapy might be sensible.