Krabbe Disease

Excerpt

Clinical characteristics: Krabbe disease comprises a spectrum ranging from infantile-onset disease (i.e., onset of extreme irritability, spasticity, and developmental delay before age 12 months) to later-onset disease (i.e., onset of manifestations after age 12 months and as late as the seventh decade). Although historically 85%-90% of symptomatic individuals with Krabbe disease diagnosed by enzyme activity alone have infantile-onset Krabbe disease and 10%-15% have later-onset Krabbe disease, the experience with newborn screening (NBS) suggests that the proportion of individuals with possible later-onset Krabbe disease is higher than previously thought. Infantile-onset Krabbe disease is characterized by normal development in the first few months followed by rapid severe neurologic deterioration; the average age of death is 24 months (range 8 months to 9 years). Later-onset Krabbe disease is much more variable in its presentation and disease course.

Diagnosis/testing: The two diagnostic scenarios are the following:

1. Scenario 1. The diagnosis of Krabbe disease, suspected in a symptomatic proband based on clinical findings (by age) and other supportive laboratory, neuroimaging, and electrophysiologic findings, is established by detection of deficient GALC enzyme activity in leukocytes. Abnormal results require follow-up molecular genetic testing of GALC; elevated psychosine levels can also help establish the diagnosis.

2. Scenario 2. In an asymptomatic newborn with low GALC enzyme activity on dried blood spot specimens on NBS urgent time-critical measurement of blood psychosine levels and GALC molecular genetic testing is necessary to identify – before age 14 days – those newborns with evidence of infantile-onset Krabbe disease who are candidates for early treatment with hematopoietic stem cell transplantation (HSCT).

Management: Treatment of manifestations: Treatment of a child who is symptomatic before age six months is supportive and focused on increasing the quality of life and avoiding complications. For older individuals, treatment with HSCT is individualized based on disease burden and manifestations.

Prevention of primary manifestations: Consensus guidelines recommend that asymptomatic newborns identified by either prenatal/neonatal evaluation because of a positive family history of Krabbe disease or an abnormal NBS result undergo additional testing to identify those with infantile-onset Krabbe disease. Those with laboratory findings consistent with infantile-onset Krabbe disease are candidates for HSCT before age 30 days.

Surveillance: Monitor symptomatic individuals with Krabbe disease for development of: hydrocephalus, swallowing difficulties and chronic microaspiration, scoliosis, hip subluxation, and osteopenia, decreased vision, and corneal ulcerations.

Agents/circumstances to avoid: Atypical antipsychotics and multiple medications for seizures can cause over-sedation (affecting cognition, respiratory drive, and rate of neurologic decline). Routine childhood vaccinations can accelerate disease progression.

Evaluation of relatives at risk: Couples who have had one child with molecularly confirmed infantile-onset Krabbe disease may choose prenatal molecular genetic testing in subsequent pregnancies so that newborns with biallelic GALC pathogenic variants can be promptly tested and – if appropriate -- referred for HSCT.

Genetic counseling: Krabbe disease 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. Once the GALC pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic diagnosis are possible.