Yea Autosomal recessive disease due to deficiency of lysosomal enzyme galactocerebrosidase and failure of myelination in the central and peripheral nervous systems leading to progressive and rapid neurologic deterioration and death.
More than 60 mutations exist that impair enzymatic activity leading to decreased myelin galactolipid degradation and its accumulation results in inflammation, dysmyelination and demyelination of the developing brain.
Lack of galactosylceramidase impairs degradation of galactosylceramide and psychosine, which are components of myelin.
In the absence of galactocerebrosidase psycholine accumulates and it is highly cytotoxic, contributing to demyelinization.
Histologically associated with loss of myelin, massive loss of oligodendrocytes, gliosis, and accumulation of globoid cells.
Onset varies with the underlying genetic abnormalities: early onset associated with less visual loss than later onset disease.
Krabbe disease, also known as globoid cell leukodystrophy or galactosylceramide lipidosis.
A rare and often fatal lysosomal storage disease that results in progressive damage to the nervous system.
Occurs in about one in 100,000 births in the US.
Scandinavian countries report incidence rates of one in 50,000 births.
The incidence in Japan is between 5 and 10 cases per 1,000,000 live births.
In the Druze community in Israel, it has an incidence rate of 6 out of every 1,000 live births, due, in part, to a high frequency of consanguineous marriages.
Incidence rates vary widely from population to population.
It involves dysfunctional metabolism of sphingolipids and is inherited in an autosomal recessive pattern.
The brain with Krabbe disease shows giant cells with PAS stain inclusions within astrocytic gliosis and loss of myelinated fibers.
Developmental delay, irritability, spasticity, hypotonia, microcephaly, optic atrophy occurs in infancy.
Muscle weakness, vision loss, developmental regression occurs during juvenile period.
Burning paresthesias in extremities, loss of manual dexterity, muscle weakness, sensory neuropathy, muscle atrophy which appear in adult life.
Usual onset is within 3 to 6 months of birth, but can present in childhood or even adulthood.
Three Types:
Infantile
juvenile
adult
Cause Mutation of GALC gene
Risk factors Parents who are heterozygous for the mutation to the GALC gene.
Prevention includes prenatal diagnosis and screening of at-risk couples.
Symptomatic and supportive treatment only available.
Stem cell transplantation may be beneficial.
One-, two-, and three-year survival rates of 60%, 26%, and 14%, respectively.
85-90% of individuals with infantile-onset Krabbe disease display progressive neurologic deterioration in infancy and death before the age of two.
Symptoms of infantile onset Krabbe’s disease include irritability, fevers, limb stiffness, seizures, feeding difficulties, vomiting, staring episodes, and slowing of mental and motor development,muscle weakness, spasticity, deafness, optic atrophy, optic nerve enlargement, blindness, paralysis, difficulty when swallowing and prolonged weight loss may also occur.
10-15% of individuals with later-onset Krabbe disease have a much slower disease progression, and have symptoms such as esotropia, slurred speech, and slow development or loss of motor milestones.
Time of onset also varies in frequency by location.
Early infantile Krabbe Disease is the most common form of the disease overall.
Nordic communities tend to have higher rates of early infantile onset Krabbe disease.
Southern European countries have higher incidences of late-onset cases.
Autosomal recessive inheritance pattern caused by mutations in the GALC gene located on chromosome 14.
Mutations in the GALC gene cause a deficiency in galactosylceramidase enzyme.
In rare cases, it may be caused by a lack of active saposin A.
The process results in the buildup of unmetabolized lipids which adversely affects the growth of the nerve’s protective myelin sheath.
It results in demyelination and severe progressive degeneration of motor skills.
It is in the group of disorders known as leukodystrophies, resulting from the imperfect growth and development of myelin.
Galactosylceramidase deficiency also results in a buildup of a glycosphingolipid called psychosine.
Psychosine is toxic to oligodendrocytes.
Newborn screening for Krabbe disease includes assaying blood cells for GALC enzyme activity and molecular analysis for evidence of GALC enzyme mutations.
0-5% GALC enzyme activity is observed in all symptomatic individuals with Krabbe disease.
Patients with Krabbe disease, more so in later-onset individuals, tend to have increased in CSF protein concentration.
Diagnosis is made by characteristic multinucleated globoid cells, nerve demyelination and degeneration, and destruction of brain cells.
Stains for myelin may be used to aid diagnosis.
Some states include Krabbe in the newborn screening panel.
There is no known cure.
Treatment for the disorder is symptomatic and supportive.
Physical therapy may increase muscle tone and circulation, and can help to alleviate motor difficulties and increase strength, mobility, and flexibility.
Bone marrow transplantation may benefit cases early in the course of the disease: better prognosis for both lifespan and functionality, with a slower progression of the disease.
Gastrostomy tubes are used for feeding difficulties and to prevent aspiration.
Routine vaccines may accelerate disease progression.
Late-onset Krabbe disease patients tend to have a slower progression of the disease and live longer: with older children generally surviving two to seven years after the initial diagnosis.
The mortality rate of early infantile Krabbe disease is 90% before the age of two.
Umbilical cord transplantation can alter the disease (Escolar ML).
Treatment after onset of neurologic symptoms does not result in clinical improvement, therefore newborn screening is advocated.