(I) Friedreich ataxia: It is an inherited, progressive neurodegenerative disorder that primarily affects peripheral nerves, spinal cord, brain and heart muscle. It is seen more commonly in individuals with European ancestry and is inherited as an AR disorder. The mutation is in the gene FXN which codes for the protein frataxin. A triplet repeat expansion of an abnormal number of GAA repeats, hundreds or even up to a thousand times is seen. The GAA repeat sequence greatly reduces the amount of frataxin produced by the cell. Frataxin is a component of mitochondria. The defect interferes with the cell’s energy metabolism and causes free radical mediated oxidative stress.
Symptoms typically begin between the ages of 5 and 15 years, although they sometimes appear in adulthood. It presents as gait ataxia or difficulty walking and poor balance, truncal ataxia; slowness and slurring of speech or dysarthria; hesitant and jerky or “scanning of 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 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 and sensory ataxia with 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 due to 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 there is a hairy patch of skin over the defect. In spina bifida cystica (meningo or meningomyelocele), there is a cyst-like protrusion through the vertebral defect. In meningocele, the cyst contains CSF and is lined by the dura and arachnoid maters. In meningomyelocele, in addition to the above, the spinal cord is also displaced into the cyst. It may present with paresthesias or paralysis of the lower limbs, 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 determination of 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 in the period 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 or 4 mg in women who have a history of NTD affected pregnancy.
(III) Microcephaly: Microcephaly is a condition in which the circumference of the head 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 it 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 a cytomegalovirus, rubella (German measles), varicella (chicken pox) virus, or possibly Zika virus; intranatal exposure to certain toxic chemicals; untreated phenylketonuria in mother; Down’s syndrome, chromosomal syndromes, and neurometabolic syndromes. It presents as impaired cognitive development, delayed motor functions and speech, facial distortions, dwarfism or short stature, hyperactivity, seizures, difficulties with coordination, feeding and balance.
(IV)
Sturge Weber syndrome (somatic mutation in GNAQ gene that codes for Gaq 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 in the base of the skull and cerebellum. They are congenital defects. They present clinically with occipital headaches, diplopia, photophobia, nystagmus, tinnitus, vertigo, dizziness, ataxia, muscle weakness, paresthesias, 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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