(I) Friedreich ataxia: Friedreich ataxia is an inherited, progressive neurodegenerative disorder that primarily affects the peripheral nerves, spinal cord, brain, and heart muscle. It is more common in individuals with European ancestry and is inherited as an autosomal recessive (AR) disorder. The mutation occurs in the FXN gene, which codes for the protein frataxin. A triplet repeat expansion is present, with an abnormal number of GAA repeats (hundreds, and sometimes up to a thousand). This GAA repeat expansion greatly reduces the amount of frataxin produced by the cell.
Frataxin is a mitochondrial protein. The defect interferes with cellular energy metabolism and leads to free radical-mediated oxidative stress.
Symptoms typically begin between ages 5 and 15 years, although they can also appear in adulthood. It presents with gait ataxia (difficulty walking) and poor balance, truncal ataxia; slowness and slurring of speech (dysarthria); hesitant and jerky or “scanning” speech; spasticity; scoliosis; difficulty swallowing; loss of sensation in the arms and legs; loss of reflexes; muscle weakness; hearing and vision loss; palpitations and shortness of breath, etc. Cardiac involvement occurs in the form of hypertrophic cardiomyopathy, myocardial fibrosis, arrhythmias, heart block, and heart failure. There is degeneration of the spinocerebellar tracts, dorsal columns, and corticospinal tracts, leading to sensory ataxia with a positive Romberg sign. Patients often develop carbohydrate intolerance and diabetes mellitus.
(II) Neural tube defects (e.g. spina bifida, anencephaly) or NTDs: Neural tube defects are caused by defects in closure of the neural tube. They are multifactorial. Spina bifida is the most common NTD.
| Disorders of primary neurulation (up to day 26 after fertilization) | |
| Craniorachischisis | Neural tube fails to initiate closure, leaving most of the brain and the entire spine open. |
| Anencephaly | Cranial neural folds fail to close |
| Open spina bifida/ meningomyelocele | Spinal neural folds/neuropore fail to close; failure to form neural arches of lumbar and/or sacral vertebrae from mesoderm |
| Disorders of secondary neurulation (up to day 35 post fertilization) | |
| Spinal dysraphism and lipoma | Failure of the neural tube to separate completely from adjacent tissues, tethering and diminished mobility, lipoma |
| Post-neurulation defects (around 4 months post fertilization) | |
| Encephalocele and meningocele | Bony structure of the skeleton fails to develop fully, herniation of the meninges, with or without brain tissue, through a skull defect (encephalocele) or spinal region (meningocele) |
Spina bifida commonly presents in the lumbosacral area.
In spina bifida occulta, the vertebral arches are absent, but the skin over the defect is intact and may show a hairy patch.
In spina bifida cystica (meningocele or meningomyelocele), there is a cyst-like protrusion through the vertebral defect:
Meningomyelocele may present with paresthesias or paralysis of the lower limbs, and bowel and bladder incontinence due to stretching of the lumbosacral spinal nerves.
In anencephaly, the forebrain fails to develop properly. Polyhydramnios is seen. Fetuses with anencephaly die in utero.
Neural tube defects can be detected in utero by finding increased alpha-fetoprotein and acetylcholinesterase in the amniotic fluid and maternal blood. Polymorphisms in the enzyme tetrahydrofolate reductase are associated with an increased risk for NTDs. Diabetes mellitus and the antiepileptic drug valproate also increase the risk.
Administration of 0.4 mg of folic acid from 4 weeks before to 8 weeks after conception significantly reduces the occurrence of NTDs. The dose of folic acid is increased to 4000 microgram (4 mg) in women with a history of an NTD-affected pregnancy.
(III) Microcephaly: Microcephaly is a condition in which head circumference is smaller than normal because the brain (most often the cerebral cortex) has not developed properly or has stopped growing. Microcephaly can be present at birth or may develop in the first few years of life.
It is most commonly seen in infants of mothers who abused drugs or alcohol; became infected with cytomegalovirus, rubella (German measles), varicella (chicken pox) virus, or possibly Zika virus; had intranatal exposure to certain toxic chemicals; had untreated phenylketonuria; or in association with Down’s syndrome, chromosomal syndromes, and neurometabolic syndromes.
It presents with impaired cognitive development, delayed motor functions and speech, facial distortions, dwarfism or short stature, hyperactivity, seizures, and difficulties with coordination, feeding, and balance.
(IV)
Sturge Weber syndrome (somatic mutation in GNAQ gene that codes for Gαq protein that is involved in blood vessel proliferation)
Tuberous sclerosis (mutations in TSC 1 tumor suppressor gene that codes for hamartin; and mutations in TSC 2 tumor suppressor gene that codes for tuberin); leads to hyperactivation of mTOR pathway; AD or sporadic
Von Hippel-Lindau disease (AD, mutation in VHL tumor suppressor gene on chromosome 3q, regulates function of hypoxia inducible factor and several growth factors.
(V) Arnold-Chiari malformations and Dandy-Walker syndrome: Chiari malformations are structural defects at the base of the skull and cerebellum. They are congenital defects. Clinically, they may present with occipital headaches, diplopia, photophobia, nystagmus, tinnitus, vertigo, dizziness, ataxia, muscle weakness, paresthesias, and symptoms due to syringomyelia, etc.
They are classified as follows:
| Type of malformation | Characteristics |
| Type I | Cerebellar tonsils herniate into foramen magnum; most common, often asymptomatic, syringomyelia, scoliosis, fusion defects of upper cervical vertebrae |
| Type II (Classic) | Both cerebellum and brain stem protrude into the foramen magnum, meningomyelocele, hydrocephalus |
| Type III | Cerebellum and brainstem protrude through an opening in the back of the skull , hydrocephalus |
| Type IV | Underdeveloped cerebellum, no herniation, fatal in infancy |
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