Medullary Tegmental Cap Dysplasia: Fetal and Postnatal Presentations of a Unique Brainstem Malformation.

BACKGROUND AND PURPOSE: Medullary tegmental cap dysplasia is a rare brainstem malformation, first described and defined by James Barkovich in his book Pediatric Neuroimaging from 2005 as an anomalous mass protruding from the posterior medullary surface. We describe the neuroimaging, clinical, postmortem, and genetic findings defining this unique malformation. MATERIALS AND METHODS: This is a multicenter, international, retrospective study. We assessed the patients' medical records, prenatal ultrasounds, MR images, genetic findings, and postmortem results. We reviewed the medical literature for all studies depicting medullary malformations and evaluated cases in which a dorsal medullary protuberance was described. RESULTS: We collected 13 patients: 3 fetuses and 10 children. The medullary caps had multiple characteristics. Associated brain findings were a rotated position of the medulla, a small and flat pons, cerebellar anomalies, a molar tooth sign, and agenesis of the corpus callosum. Systemic findings included the following: polydactyly, hallux valgus, large ears, and coarse facies. Postmortem analysis in 3 patients revealed that the cap contained either neurons or white matter tracts. We found 8 publications describing a dorsal medullary protuberance in 27 patients. The syndromic diagnosis was Joubert-Boltshauser syndrome in 11 and fibrodysplasia ossificans progressiva in 14 patients. CONCLUSIONS: This is the first study to describe a series of 13 patients with medullary tegmental cap dysplasia. The cap has different shapes: distinct in Joubert-Boltshauser syndrome and fibrodysplasia ossificans progressive. Due to the variations in the clinical, imaging, and postmortem findings, we conclude that there are multiple etiologies and pathophysiology. We suggest that in some patients, the pathophysiology might be abnormal axonal guidance.

Spectrum of brain malformations in fetuses with mild tubulinopathy.

OBJECTIVE: To report on a large cohort of fetuses with mild forms of tubulinopathy and to define prenatal ultrasound and magnetic resonance imaging (MRI) features that can facilitate prenatal diagnosis. METHODS: This was a retrospective multicenter study of fetuses diagnosed between January 2007 and February 2022 with a mild tubulinopathy (without lissencephaly or microlissencephaly). We collected and reviewed brain imaging and genetic data, and defined major criteria as findings observed in ≥ 70% of the patients and minor criteria as those observed in ≥ 50% but < 70% of the patients. RESULTS: Our cohort included 34 fetuses. The mean gestational age at ultrasound screening, when suspicion of a central nervous system anomaly was first raised, was 24.2 (range, 17-33) weeks. Callosal anomalies (n = 19 (56%)) and abnormal ventricles (n = 18 (53%)) were the main reasons for referral. The mean gestational age at neurosonography was 28.3 (range, 23-34) weeks and that at MRI was 30.2 (range, 24-35) weeks. Major ultrasound criteria were midline distortion, ventricular asymmetry, dysmorphic and/or dilated frontal horn(s) and abnormal sulcation. Minor ultrasound criteria were distortion of the cavum septi pellucidi, abnormal corpus callosum, absent or asymmetric olfactory sulci, ventriculomegaly and basal ganglia dysmorphism. Major MRI criteria were midline distortion, distortion of the cavum septi pellucidi, ventricular asymmetry, dilatation (generally unilateral) and/or distortion, dysmorphic and/or dilated frontal horn(s) and abnormal sulcation (mainly dysgyria). Minor MRI criteria were absent or asymmetric olfactory sulci, abnormal bulge of the pons, anteroposterior diameter of the pons ≤ 5th centile and brainstem asymmetry. A mutation was found in TUBB3 (44.1% of cases), TUBB (23.5%), TUBB2B (14.7%) or TUBA1A (17.6%). The mutation was inherited from a parent in 18/34 cases. The pregnancy was terminated in 23/34 cases. CONCLUSIONS: Prenatal diagnosis of mild forms of tubulinopathy is possible but challenging. We have defined, in this large series of fetuses, major and minor criteria that can help identify this entity in utero. Most findings can be visualized on ultrasound. This evaluation is also important for prenatal counseling. Once a prenatal diagnosis of mild tubulinopathy is suspected, the family members should be referred for exome sequencing and MRI. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Pyridoxine dependent epilepsy: Is late onset a predictor for favorable outcome?

AIM: In pyridoxine dependent epilepsy (PDE), patients usually present with neonatal seizures. A small subgroup is characterized by late-onset beyond 2 months of age. We aim to analyze the observation of relatively good cognitive outcome in this subgroup of late-onset PDE patients. METHODS: We retrospectively analyzed data from four metabolically and genetically confirmed late-onset patients with PDE due to antiquitin (ALDH7A1) deficiency. Data were analyzed regarding ALDH7A1 mutations, alpha-Aminoadipic semialdehyde (α-AASA) and pipecolic acid (PA) levels, medication during pregnancy, delivery, treatment delay, amount of seizures, pyridoxine dose, adjuvant therapy and findings on brain MRI. RESULTS: Results showed that three patients had relatively good outcome (IQ 80-97), while one patient did not undergo formal testing and was considered mildly delayed. We were unable to find a clear association between the above-mentioned variables and cognitive outcome, although a less severe genotype may be present in three patients, and maternal medication could be accountable for better outcome in two patients. INTERPRETATION: We suggest that favorable outcome in late onset PDE might be explained by a combination of factors. A yet unknown protective factor, different genetic variations, functional variation and secondarily variation in treatment regimens and absence of neonatal seizure induced brain damage.

RELN and VLDLR mutations underlie two distinguishable clinico-radiological phenotypes.

Pontocerebellar hypoplasias (PCH) are characterized by lack of development and/or early neurodegeneration of cerebellum and brainstem. We report five patients referred for PCH, showing atypical clinical and magnetic resonance imaging (MRI) features suggestive of defects in the Reelin pathway. We screened for mutations in RELN or VLDLR and compared the phenotype of these patients with that of previously reported patients. All patients had profound cerebellar hypoplasia on MRI with peculiar cerebellar morphology, associated with flattened pons and neocortical abnormalities. Patient 1 had profound motor and intellectual disability with moderate lissencephaly suggestive of RELN mutations and was shown to harbor a splicing homozygous RELN mutation. The four other patients had a milder phenotype consistent with CARMQ1 (cerebellar ataxia and mental retardation with or without quadrupedal locomotion). These patients showed mild simplification or thickening of cortical gyration and had VLDLR mutations. Reelin signaling regulates neuronal migration in the developing mammalian brain. VLDLR is a key component of the Reelin pathway. Our patients had a very small and dysplatic cerebellar vermis that should suggest the involvement of these genes. Moreover, differences in clinical severity, involvement of the cerebellar hemispheres, together with the severity of the neocortical defect, enables RELN-mutated patients to be distinguished from VLDLR-mutated patients.

Advantages of bilayered vascular grafts for surgical applicability and tissue regeneration.

Nanofibrous scaffolds are part of an intense research effort to design the next generation of vascular grafts. With electrospinning, the production of micro- and nano-fiber-based prostheses is simple and cost effective. An important parameter for tissue regeneration in such scaffolds is pore size. Too small pores will impede cell infiltration, but too large pores can lead to problems such as blood leakage. In this study, bilayered grafts were made by electrospinning a high-porosity graft with a low-porosity layer on either the luminal or the adventitial side. Grafts were characterized in vitro for fiber size, pore size, total porosity, water and blood leakage, mechanical strength, burst pressure and suture retention strength, and were evaluated in vivo in the rat abdominal aorta replacement model for 3 and 12 weeks. In vitro blood leakage through these bilayered grafts was significantly reduced compared with a high-porosity graft. All grafts had an excellent in vivo outcome, with perfect patency and no thrombosis. Cell invasion and neovascularization were significantly reduced in the grafts with a low-porosity layer on the adventitial side, and there was no significant difference between the grafts in endothelialization rate or intimal hyperplasia. By tailoring the microarchitecture of biodegradable vascular prostheses, it is therefore possible to optimize the scaffold for tissue regeneration while preventing blood leakage, and thus facilitating applicability in the clinic.