Developmental Disease

1. Developmental Disease

2. Selected diseases correlated with stages of nervous system development . ​1. Induction ​ 2. Neurulation: leads to neural tube defects ​Spina bifida cystica ​- Meningocele (outpouching of meninges) or myelomeningocele (spinal cord in outpouching) formation.

3. ​- Folate supplementation reduces risk ​- Etiology is varied ​- Prenatal detection by a-fetoprotein (AFP) available ​- Associated with Chiari

4. 2 malformation (cerebellar tonsil herniation & kinking of spinal cord at cervical-medullary junction, usually accompanied by myelomeningocele and spinal cord tethering, and hydrocephalus) ​ 3. Segmentation & diverticulation ​Holoprosencephaly​ Failure of prosencephalon to segment. ​

5. Different degrees of segmentation failure (alobar, semilobar, lobar) ​Associated craniofacial abnormalities ​Some forms caused by mutations in SHH or related genes.

6. 4. Cell proliferation ​Microcephalyvera, hemimegalencephaly, macroencephaly​ This is why you measure head size at birth ​ 5. Migration ​Neuronal heterotopia: ? ​Lissencephaly: agyria (no cortical involutions) or pachygyria (large gyri).

7. Polymicrogyria: many small gyri ​6. Axonal projection, synaptogenesis, and myelination Pediatric neurodevelopmentaldisorderes ​Cerebral Palsy (CP)

8. ​Nonprogressive motor disorder of varying degree due to brain damage ​Occurs ~2/1000 births due to pre or postnatal events ​4 main types with indicated prevalance: spastic > dyskinetic > mixed > ataxic ​Associated with mental retardation, strabismus, epilepsy, vision/hearing disorders ​RettSyndrome.

9. ​- A disease of girls with initially normal development followed by arrest and regression, associated with hand washing/wringing movements, acquired microcephaly, hyperventilation, and seizures.

10. Degenerative diseases ​Definition: loss of previously acquired skills ​Early signs of ​- Gray matter disease: delayed psychomotor development, intellectual disorientation, seizures, retinal involvement (cherry red spot), ataxia.

11. - White matter disease: UMN signs, peripheral neuropathy, optic atrophy, ataxia ​ (Note that these are early signs only and later they converge).

12. ​Tay-Sachs disease ​ A lysosomal storage disease & degenerative disease ​ Due to ganglioside accumulation due to hexosaminidase A mutation ​Prenatal diagnosis available, but treatment is only symptomatic.

13. ​Metachromaticleukodystrophy, a white matter disease (as the name implies) ​Progressive demyelinating disease due to defect in arylsulfataseA

14. Developmental Neurological Disorders Neural Induction: notochord induces formation of the neural plate and neural tube. These neural ​tissues induce surrounding mesoderm to form the dura, vertebrae, and skull.

15. Defects of Neurulation (Neural tube defects) --CraniorachischisisTotalis is non-fusion of the neural folds along their length. --Anencephaly is failure of anterior neural tube closure, resulting in a lethal malformation in ​which the brain and skull vault are absent.

16. Hindbrain is present, so there may be crying ​and swallowing. Can be considered a defect of synaptogenesis.

17. --Encephalocele is failure of anterior neural tube closure, resulting in a large craniofacial cyst. Causes severe retardation, visual problems, and hydrocephalus. --Spina Bifida Occulta is a failure of dorsal spine closure without any symptoms or signs.

18. --Occult Spinal Dysraphism is a failure of caudal neural tube closure, resulting in lipoma and ​spinal cord tethering. The defective area is marked with a hairy patch, dimple or lipoma. ​Spinal cord tethering damages the cord as they grow.

19. Children often have abnormal gait, ​growth abnormalities in the lower limbs, and poor bladder control. --Spina Bifida Cystica is failure of dorsal spine closure, often in the lumbar region.

20. This can take the form of a meningocele (no neural elements in the cyst) or a myelomeningocele (neural elements in the cyst). High risk of trauma and infection. ​Causes are multifactorial. Risks include Depakote and being a twin. Folic acid is protective.

21. Prenatal diagnosis of Spina Bifida can be made using α-fetoprotein (AFP). ​Neurological deficits include motor, sensory, cognitive, and bowel/bladder. ​Hydrocephalus is associated with the Arnold-Chiari 2 malformation (cerebellarvermis ​ ​ migrates into the spinal canal, blocking CSF flow out of ventricles. (Ventricles swell).

22. Defects of Segmentation and Diverticulation The neural tube develops three segmental dilations. The cavities become the ventricular system. The walls become the prosencephalon, mesencephalon, and rhombencephalon. Diverticulation creates the pituitary and pineal glands, optic nerve/chiasm, and olfactory bulb.

23. --Agenesis of the Corpus Callosum is one of the most common brain malformations. --Holoprosencephaly can be lobar, semilobar, or alobar. It always has facial anomalies, especially ​cyclopia and midline cleft palate/lip. Other features include microcephaly, hypotonia,​siezures, and severe retardation.

24. Defects of Neuron Proliferation --Microcephaly Vera is defined by an occipitofrontal head circumference <2 SD below the mean. ​Brain is well-formed but very small. Moderate to severe retardation, quadriplesia, epilepsy. --Macroencephaly and Hemimegalencephaly

25. Defects of Neuron Migration --Schizencephaly is a “cleft-brain” malformation. Clefts are lined by microgyri all the way from ​the pial surface into the lateral ventricles. --Neuronal Heterotopia is gray matter buried within the white matter, often near lateral ventricles.

26. --Lissencephaly (“smooth brain”) is the absence of fissures or gyri. The cerebral wall only has 3-4 layers, as in a young fetus. Often comes with craniofacial defects (Miller-Dieker Syndrome). ​The gene mutation is in Lis1 on chromosome 17p. Lis1 is involved in dynein-mediated ​ ​ neuron migration.

27. There is also an X-linked form. Female carriers will have diffuse aberrant bands of gray matter beneath and parallel to the cortical gray matter (“subcortical band heterotopia”). The X-linked form is caused by a mutation in the doublecortin gene.