A. Normal Development [1]

1. Neural tube formation and closure occurs in first month
2. Notocord and precordal plate differentiate under mesodermal influence
3. Thus, ectoderm is converted to neural tissue
   1. No increase in ectodermal (neurectoderm) cell number
   2. Instead, changes in cell shape and function occur
4. Closure of Tube
   1. Occurs by invagination of neurectoderm
   2. First closure point is the medulla (so rarely have isolated openings here)
5. Last closure points are the neuropores:
   1. Anterior neuropore - closes day 25; brain area
   2. Posterior neuropore - closes day 27; lower spinal cord
6. Neural crest migration begins within first month
   1. Sympathetic ganglia
   2. Dorsal root ganglia
   3. Schwann cells
   4. Adrenal Medulla
   5. Other neuroendocrine cells

B. Defects

1. Abnormalities in brain and spinal cord will be reflected by superficial changes
   1. Particularly when abnormal trapping of ectodermal and/or neurectodermal tissue occurs during tube formation and closure
   2. These "blebs" of tissue may form sacs or other structures, ± nerve tissue
   3. Chromosomal and other genetic disorders found in <10% of cases
2. Environmental and genetic influences combine to cause neural tube defects
   1. Neural tube closure requires adequate folate intake [2,3,7]
   2. Certain genetic mutations (such as MTHFR mutations)
3. Epidemiology of Dysraphic Disoders
   1. Failed tube formation and/or closure is called a dysraphic disorder
   2. Occurs in 0.2-0.3% of live births
   3. Failed tube formation from evagination of neuronal tube area
   4. Leads to atrophy of exposed CNS tissue
4. Dysraphic Diseases
   1. Anencephaly
   2. Spina bifida
   3. Encephalococele
   4. Craniorachischisis
   5. Iniencephaly
5. Also classified as open or closed dysraphic diseases
   1. Open means that the defect is only covered by membrane or neural tissue is exposed
   2. Closed means that the defect is covered with skin

C. Specific Dysraphic Diseases [1]

1. Anencephaly
   1. Failure to close tube high up
   2. Medulla intact, so primative responses intact
   3. Respiration and cardiac control intact
2. Spina Bifida
   1. Congenital anomaly of the spinal cord
   2. Refers to nonfusion of the embryonic halves of the vertebral arches
   3. Occurs during the fourth week of fetal development
   4. Sometimes allows the brain or spinal cord to herniate through the opening
   5. Initial care costs of spina bifida are about $300,000 for first year per infant [1]
3. Spina bifida cystica
   1. Failure to close tube lower down
   2. Contents of the "Cyst" determine diagnosis:
   3. Meningocele - no neural elements in cysts
   4. Meningomyelocele - neural elements in cyst
4. Meningomyelocele
   1. Sacral nerve invovlement - motor and sensory dysfunction
   2. Parasympathetic nerve dysfunction - bladder and bowel dysfunction
   3. Hydrocephalus, usually due to Arnold-Chiari malformation
   4. Hindbrain herniation also occurs
5. Encephalocele
   1. Sac in cephalic area, usually filled with brain tissue
   2. Tissue within sac is usually abnormal
   3. Occurs more commonly in posterior encephalon than in anterior region
6. Craniorachischisis totalis
   1. Complete failure of neural tube closure
   2. Very rare disorder
7. Iniencephaly
   1. Dysraphia in the occipital region
   2. Severe retroflexion of the neck and trunk
8. Arnold-Chiari Malformation
   1. Occurs in ~100% of Meningomyelocele
   2. Specifically, lower part of brainstem and cerebellum sink below foramen magnum
   3. Superior and Inferior colliculi fuse - visual auditory malfunction
   4. Stenosis of the cerebral aquaduct occurs leads to hydrocephalus
   5. Also thought to contribute to formation of syringohydromyelia
9. Syringohydromyelia
   1. Abnormal accumulation of cerebrospinal fluid (CSF) within spinal cord
   2. When present as dilations of central spinal canal, called "hydromyelia"
   3. When cyst-like structures occur within spinal cord, called "syringomyelia"
   4. Often associated with pain; need to distinguish from transverse myelopathy
10. Occult (Minimal) Spinal Dysraphism
    1. Tube abnormally closes, with trapped (neuro-) ectodermal tissue
    2. Typical presentation with Hairy patch, Lipoma (extends in), dimple, neural cyst
    3. Symptoms include leg length differences, gait changes, bowel problems
11. VANGL1 Associated Neural Tube Defects [13]
    1. VANGL1 expressed in ventral neural tube, involved in cell polarity determination
    2. Three mutations in VANGL1 associated with neural tube defects in humans
    3. Myelomeningocele, lipomyeloschisis, caudal regression all reported
    4. Mutated VANGL1 does not interact with proteins called "disheveled"

D. Prevention and Treatment [1,7]

1. Folic acid intake 400µg during first month of pregnancy reduces risk >50% [7]
2. Folic acid fortification of US food supply has likely contributed to reduced neural tube defects [10]
3. Surgical correction in utero may be beneficial [8,9]
   1. Reduces incidence of hindbrain herniation
   2. Reduces incidence of shunt-dependent hydrocephalus
   3. Increases incidence of premature delivery
4. Cesarean section may reduce neurological damage during delivery in spina bifida

1. Single neural tube divides up into various parts or segments
2. Early divisions with later progression
   1. Prosencephalon: Telencephalon (hemispheres) and Diencephalon
   2. Mesencephalon: Midbrain
   3. Rhombencephalon: Metencephalon (Pons and Cerebellum) and Myencephalon (Medulla)

B. Diverticulation

1. Outpouchings of various cephalic structures
2. Dorsal - Pineal Gland
3. Ventral - Neurohypophysis
4. Diencephalon - Optic system, Lateral Geniculate; Olfactory Tract and Bulb

C. Abnormalities: Holoprosencephalon

1. Failure to split brain into two halves
2. Chromosome 7q36 defects associated with disease [12]
   1. Gene involved (HPE3) maps to region of sonic hedgehog (SHH) gene
   2. Familial prosencephalopathy associated with mutations of SHH gene
3. Major cerebral function impairment
4. Single Ventricle, Cyclops, Cleft Lip

1. Intermitotic migration of nerve nuclei (M phase cells close to ventricles)
2. Nearly all neural division occurs near the ventricles
   1. Basal ganglia is one major exception; develop away from ventricles
   2. Cerebellar granular cells develop in the external granular layer
3. Hierarchical development occurs as follows:
   1. Glial cells (small numbers) develop first
   2. Neurons, larger ones first, smallest last, develop next
   3. Glial cells, major wave, develop finally

B. Defects in Proliferation

1. Microcephaly Vera
   1. Brain looks normal
   2. Histology shows fewer than normal neuronal cells
   3. Major intellectual deficits
2. Macrocephaly
   1. Usually due to an increase number of neural connections
   2. Can also have increased number of cells
   3. Range from few symptoms to major deficits
   4. Likely due to reduced levels of nerve cell death (apoptosis) during development

C. Migration (3-5 months)

1. Glial cells are required before neural migration - lay down a fiber as guide cord
2. Neuronal cells travel up the fibers in columns, then get off at various levels
   1. Neuronal layers are arranged from 1 (outside layer) to 6 (deepest layer)
   2. Neurons ascend up this radial fiber, and stop in layer 6 (lowest) first
3. Astrotactin is a protein made by neural cells to climb up the glial fibers
   1. Allows ordered climbing along the glial guide cords
   2. Animal models lacking astrotactin have random neural cell migration
4. Ordered, normal cell migration is requiered for normal formation of Gyri (and sulci)
   1. This occurs at 6 months into development
   2. Failure of normal migration is a major cause of cerebral dysfunction

D. Cerebellar Maturation

1. Main cells in cerebellum are Purkinje Cells and Granular Cells
   1. Recall cerebellar layers -
   2. Outside - External Granular Layer - Molecular - Purkinje - Internal Granular
2. Purkinje cells develop around 4th ventricle
3. Granular cells are derived from rhombic lip
   1. Divide in external granular layer
   2. Then migrate down from EGL to internal granular layer

E. Synapse Formation (>6 months of gestation onward)

1. Axons, dendrites, and connections
2. Question of how synapses are formed
   1. Trophic factors
   2. Cell Adhesion Molecules (eg. NCAM)
   3. Role of target cell (post-synaptic cell)
3. Neuronal Cell death
   1. If axonal projections do not reach a post-synaptic cell body or dentrite, axons die
   2. This axonal death occurs by dying back neuropathy
   3. Increasing numbers of synaptic targets lead to decreased nerve cell death
   4. Neurons which fail to have axonal connections made die by apoptosis
4. Synapse Formation - Recent data indicate that at least in some systems, post-synaptic transmitter receptors are present before axons reach the synapse area
5. Synaptic changes occur during development and for years after birth

F. Abnormalities

1. Heterotopia - failed normal migration
2. Polymicrogyria - small gyri, fewer neuronal cell layers (eg. 4 instead of 6)
3. Lissencephaly - smooth brain, no Sulci or Gyri
4. Cerebellar Defects of failed migration

1. Mitochondria
2. Peroxisomes
3. Lysosomes
4. Cytosolic Enzymes

B. Stored Material

1. Sphingolipid
2. Glycogen
3. Mucopolysaccharides
4. Lysosomal enzymes

C. Lysosomes

1. Required for removal of stored substances
   [Figure] "Sphingolipid Storage Diseases"
2. Especially for ganglioside degradation
   1. GM2 accumulation leads to Tay-Sach's Disease
   2. Gaucher's Disease
3. Pathologic Changes in Lysosomal Storage Diseases
   1. May occur in Grey Matter: Cell ballooning, full of stored material
   2. Axonal (White Matter): degeneration of axons
4. Neuronal Malfunction in Storage Diseases
   1. Filled cells simply overstuffed, cannot function
   2. Altered nerve conduction properties

D. Krabbe's Disease

1. Also called Globoid Leucodystrophy
2. Missing Galactocerebrosidase
3. Presence of globoid cells on pathology - macrophages ingesting dead cells
4. Much decreased numbers of oligodendrocytes
   1. This apparently due to accumulation of toxin called psychosine
   2. This is normally degraded by galactocerebrosidase

E. Dysmyelinating Disease

1. Trouble forming or maintaining axons
2. Myelin synthesis requires proteins and many complex lipids
3. Sulfatases also required for metabolism (degradation) of sulfatides (cerebroside sulfate)
4. Galactocerebrosidase deficiency = Krabbe's Disease

F. Symptoms

1. Depend on whether Grey or White Matter, or both, are affected
2. Grey Matter
   1. Delayed Psychomotor Development
   2. Adult Dementia
   3. Seizures Prominant
   4. Retinal Cherry Red spots (Tay Sachs, Lipofuscinosis)
   5. Ataxia
3. White Matter
   1. Upper Motor Neuron: Spasticity, Hyperreflexia, Babinsky
   2. Polyneuropathy
   3. Optic Nerve Atrophy
   4. Ataxia
   5. Decreased Intelligence
   6. Seizures
4. Pyramidal Signs
   1. Very characteristic findings
   2. Anti-gravity muscle (biceps, quadriceps, others) strength largely (~80%) preserved
   3. Non-anti-gravity muscle (triceps, arm extensors, hamstrings, others) severely affected
   4. Hemiparetic posture: tonic spastic flexion of the arm and spastic extension of legs
   5. Loss of independent finger control and other fine motor movements
   6. Increased reflexes and muscle tone, upgoing toes on Babinski reflex

G. Friedreich's Ataxia [4,6]

1. Autosomal recessive ataxia
2. Most common of the hereditary ataxias, ~1 per 30-50,000 persons
3. Linked to mutations in the frataxin gene on chromosome 9
   1. Frataxin is 210 amino acid protein
   2. Associated with mitochondria
   3. May be important for cellular energy metabolism
   4. Found in muscle, cerebellar cortex and cerebral cortex
4. Mutations are variable length inserts of repeated GAA in the first intron of frataxin gene
   1. Leads to inactivation of function on Frataxin
   2. Abnormalities in aconitase, a Krebs cycle protein, in hearts of these patients
   3. Additional down regulation of mitochondrial respiratory chain complexes I, II and III
   4. These anomolies lead to Increased production of oxygen free radicals
   5. Free radical damage is likely contributor to cardiac and neurological abnormalities
5. Larger GAA insertions correlate with earlier age of onset and more rapid progression
6. Onset of symptoms by age 20 with relentless progression
7. Symptoms and Signs
   1. Ataxia of all four limbs
   2. Cerebellar dysarthria
   3. Absent reflexes in lower limbs
   4. Sensory loss
   5. Pyramidal signs
   6. Skeletal abnormalities
   7. Hypertrophic cardiomyopathy
   8. Pes cavus
8. Spinocerebellar ataxias may have similar symptoms
9. Treatment [5]
   1. Iron overload may contribute to disease
   2. Avoid iron chelators such as desferrioxamine
   3. Avoid anti-oxidants such as ascorbate (vitamin C)
   4. Idebenone is a free radical scavenger
   5. Idebenone reduced cardiac hypertrophy in three patients with Friedrich's ataxia

H. Neuronal Ceroid Lipofuscinosis [11]

1. Heterogeneous group of disease
   1. Progressive neurodegeneration
   2. Usually occurs in children
   3. 1:12,500 live births
2. Symptoms
   1. Visual loss (cherry red spots)
   2. Epilepsy
   3. Psychomotor deterioration (often progressive myoclonic epilepsy)
3. Group of 8 Distinct Genetic Diseases (CLN 1-8)
   1. Infantile CLN1
   2. Late onset infantile (CLN2): Jansky-Bielschowsky Disease (formerly amaurotic idiocy)
   3. CLN3 juvenile and CLN4 adult
   4. CLN8 progressive epilepsy with mental retardation
4. Cherry red spots on retinal examination, "bull's eye" macula
5. Pathology
   1. Loss of neurons and widespread intracellular lipid pigment accumulation
   2. Lymphocytes, vascular endothelium, muscle particularly accumulate pigment
   3. Pigment accumulates in liposomes
   4. Pigment consists of lipid + proteins
   5. Subunit c of mitochondrial ATP synthetase in CLN2, 3, 4
6. No current therapy

References

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2. Daly LE, Kirke PN, Molloy A, et al. 1995. JAMA. 274(21):1698
3. Daly S, Mills JL, Molloy AM, et al. 1997. Lancet. 350(9091):1666
4. Martin JB. 1999. NEJM. 340(25):1970
5. Rustin P, von Kleist-Retzow JC, Chantrell-Goussard K, et al. 1999. Lancet. 354(9177):477
6. Durr A, Cossee M, Agid Y, et al. 1996. NEJM. 335(16):1169
7. Berry RJ, Li Z, Erickson JD, et al. 1999. NEJM. 341(20):1485
8. Bruner JP, Tulipan N, Paschall RL, et al. 1999. JAMA. 282(19):1819
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10. Honein MA, Paulozzi LJ, Mathews TJ, et al. 2001. JAMA. 285(23):2981
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13. Kibar Z, Torban E, McDearmid JR, et al. 2007. NEJM. 356(14):1432