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Krabbe Disease

Dr Healthism
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  • 6 May, 2019 5:02 pm
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Krabbe disease (KD) (also known as globoid cell leukodystrophy or galactosylceramide lipidosis) is a rare and often fatal lysosomal storage disease that results in progressive damage to the nervous system. KD involves dysfunctional metabolism of sphingolipids and is inherited in an autosomal recessive pattern. The disease is named after the Danish neurologist Knud Krabbe (1885–1965).

Signs and symptoms
Infants with Krabbe disease are normal at birth. Symptoms begin between the ages of 3 and 6 months with irritability, fevers, limb stiffness, seizures, feeding difficulties, vomiting, and slowing of mental and motor development. In the first stages of the disease, doctors often mistake the symptoms for those of cerebral palsy. Other symptoms include muscle weakness, spasticity, deafness, optic atrophy, optic nerve enlargement, blindness, paralysis, and difficulty when swallowing. Prolonged weight loss may also occur. Juvenile and adult-onset cases of Krabbe disease also occur, which have similar symptoms but slower progression.

Causes

Autosomal recessive inheritance pattern as seen in Krabbe disease
Krabbe disease is caused by mutations in the GALC gene located on chromosome 14 (14q31), which is inherited in an autosomal recessive manner. Mutations in the GALC gene cause a deficiency of an enzyme called galactosylceramidase. In rare cases, it may be caused by a lack of active saposin A (a derivative of prosaposin).

The buildup of unmetabolized lipids adversely affects the growth of the nerve’s protective myelin sheath (the covering that insulates many nerves) resulting in demyelination and severe progressive degeneration of motor skills. As part of a group of disorders known as leukodystrophies, Krabbe disease results from the imperfect growth and development of myelin.

GALC deficiency also results in a build-up of a glycosphingolipid called psychosine, which is toxic to oligodendrocytes, a type of non-neuronal cell found in the nervous system, collectively termed neuroglia.

Diagnosis
The disease may be diagnosed by its characteristic grouping of certain cells (multinucleated globoid cells), nerve demyelination and degeneration, and destruction of brain cells. Special stains for myelin (e.g., luxol fast blue) may be used to aid diagnosis.

New York, Missouri and Kentucky include Krabbe in the newborn screening panel. Indiana will start screening in 2020.

Treatment
Although there is no known cure for Krabbe disease, bone marrow transplantation has been shown to benefit cases early in the course of the disease. Generally, treatment for the disorder is symptomatic and supportive. Physical therapy may help maintain or increase muscle tone and circulation. Cord blood transplants from unrelated donors have been successful in stopping the disease as long as they are given before overt symptoms appear.

Prognosis
In infantile Krabbe disease, death usually occurs in early childhood. A 2011 study found one, two, and three year survival rates of 60%, 26%, and 14%, respectively. A few survived for longer. Patients with late-onset Krabbe disease tend to have a slower progression of the disease and live significantly longer.

Epidemiology
Krabbe disease occurs in about one in 100,000 births. A higher incidence, about six in 1,000, has been reported in certain communities in Israel. Scandinavian countries report incidence rates of one in 50,000 births.

Society and culture
Former Buffalo Bills quarterback Jim Kelly has been a leader in gaining recognition and research funding for Krabbe disease, following the diagnosis of his son, Hunter, in 1997. Hunter Kelly died of the disease on August 5, 2005, at the age of 8.

Cove Ellis is a child from Georgia, United States, that was diagnosed with the disease in early 2016. Cove’s family, along with her community, have worked to raise awareness of the disease and helped pass Cove’s Law. This law allows parents the option to have prenatal screening for the disease which can potentially save the child.

Other animals
Krabbe disease may also be found in cats and in dogs, particularly the West Highland White Terrier and Cairn Terriers. The disease may also be found in dolphins.

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