Childhood Ataxia with Central Nervous System Hypomyelination / Vanishing White Matter

Clinical characteristics: Childhood ataxia with central nervous system hypomyelination / vanishing white matter (CACH/VWM) is characterized by ataxia, spasticity, and variable optic atrophy. The phenotypic range includes a prenatal/congenital form, a subacute infantile form (onset age <1 year), an early childhood-onset form (onset age 1 to <4 years), a late childhood-/juvenile-onset form (onset age 4 to <18 years), and an adult-onset form (onset ≥18 years). The prenatal/congenital form is characterized by severe encephalopathy. In the later-onset forms initial motor and intellectual development is normal or mildly delayed, followed by neurologic deterioration with a chronic progressive or subacute course. While in childhood-onset forms motor deterioration dominates, in adult-onset forms cognitive decline and personality changes dominate. Chronic progressive decline can be exacerbated by rapid deterioration during febrile illnesses or following head trauma or major surgical procedures, or by acute and extreme fright.

Diagnosis/testing: The diagnosis of CACH/VWM can be established in an individual with typical clinical findings, characteristic abnormalities on cranial MRI, and identification of biallelic pathogenic variants in one of five genes (EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5), which encode the five subunits of the eukaryotic translation initiation factor 2B (eIF2B).

Management: Treatment of manifestations: Physical therapy and rehabilitation for motor dysfunction (mainly spasticity and ataxia); anti-seizure medication for seizures.

Prevention of secondary complications: Prevention of infections and fever when possible through the use of vaccinations, low-dose maintenance antibiotics during winter, antibiotics for minor infections, and antipyretics for fever. For children, wearing a helmet when outside helps minimize the effects of head trauma.

Surveillance: Close monitoring of neurologic status for several days during febrile infections and following head trauma or surgical procedures with anesthesia.

Agents/circumstances to avoid: Contact sports, head trauma, infections, high body temperature and, if possible, major surgery.

Genetic counseling: CACH/VWM is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variants in an affected relative have been identified.