1. Patient Y.D. Clinicopathologic Conference (CPC) 12/18/15 Neurology Resident: Natalia Gonzalez Pathologist: Ronald Hamilton

2. History HPI: Y.D. was a male infant born at 37 weeks via elective C-section. A second trimester prenatal ultrasound was concerning for ventriculomegaly, a dilated left renal pelvis with hydroureter, a small VSD, and a two vessel cord. At delivery, the infant was limp with poor respiratory effort requiring intubation. A VPS shunt was placed. The infant passed at 2 weeks of age from cardiorespiratory failure after life support was withdrawn. FH: Mother was 33yo, G3P2. Family is from Mexico. Patient has a healthy 17 yo brother and 8 yo sister.

3. Physical Examination Vitals: Birth weight was 6.6 lbs. OFC 41cm (97 %ile). HEENT: Macrocephaly. Large anterior and posterior fontanelles. Microphthalmia. Low set and posteriorly rotated ears. Right iris coloboma. Slit lamp: anomolous iris b/l with multiple vessels and persistent pupillary membranes. Dense cataracts. Anterior and posterior fetal vasculature. Derm: Tuft of hair over sacral region (ultrasound normal underneath) Ext: Single palmar creases. Digitalized right thumb. Bilateral 5th clinodactyly. Neuro: Responds to stimulus with flexion of ext. Otherwise no movements. Pupils unreactive bilaterally. + oculovestibular response. Decreased axial tone. Normal tone in extremities. DTRs elicited in patella bilaterally. Babinski and plantar grasp present.

4. Fetal ventriculomegaly (ventricle width > 10mm) 1.Obstructive 1.Dysgenesis 1.Destructive

5. Obstructive -Ventricles are typically smooth-walled. -Ventricle orientation is normal. -Cortex is intact, but compressed. -Posterior fossa structures may be abnormal. If normal, consider aqueductal stenosis. -Cavum septum pellucidum may be absent if severe. -The falx is present.

6. Dysgenesis -Ventricle shape and position is abnormal -Ventricles are typically smooth-walled -Cavum septum pellucidum is abnormal -Falx may be abnormal -Other CNS abnormalities may be visible (e.g. fused frontal horns)

7. Destructive - infarcts, bleeds, infections, trauma -Ventricle position is normal -Thinning/loss of cerebral cortex in a patchy asymmetric distribution -Midline structures are normal -Posterior fossa structures are normal -Falx is present

8. MRI Brain

9. Workup Metabolic workup - normal peroxisomal panel and sterol panel CPK ranged from 2,000 to 23,280 Sent microarray for congenital muscular dystrophy panel…

10. Pt homozygous for POMT1 gene -for a sequence variant causing a frame-shift mutation -located on 9q34.13 -Defective glycosylation of alpha-dystroglycan complex (in skeletal muscle works as a transmembrane linkage between extracellular matrix and the cytoskeleton. In brain, impairs interaction of migrating neurons with matrix elements, causing malformations of cortical development. -Dystroglycan also found in other tissues including kidneys and retina

11. Walker-Warburg Syndrome -AKA Muscle-Eye-Brain Disease -Autosomal recessive - 25% chance of having another child with WWS -Life expectancy 4 months (but variable phenotypes and severities depending on exact mutation) -Can include macro or microcephaly, eye malformations (retinal dysplasia, ocular colobomas, cataracts), brain malformations (hydrocephalus, lissencephaly type II, Dandy-Walker, cerebellar malformations, encephalocele, agenesis of the corpus callosum), congenital muscular dystrophy

12. Expected pathology -Gross pathology: CNS structural abnormalities including cobblestoning of lissencephaly type II -Micro: Type II lissencephaly: Chaotic neuronal organization, interrupted glia, allowing passage of neurons into subarachnoid space -Muscle biopsy usually shows dystrophic changes. Immunohistochemistry shows deficient alpha-dystroglycan with normal dystrophin

14. References http://www.omim.org http://neuropathology-web.org http://www.nextprot.org UpToDate Radiopaedia.org http://brain.oxfordjournals.org/content/brain/early/2012/02/09/brain.awr357.full.pdf

15. Virtual Microscopy Cortex Slide A H&E NeuN Cortex Slide B H&E NeuN Cerebellum Slide F H&E NeuN Spinal Cord Slide J H&E