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Krabbe disease

Introduction

Krabbe disease or Globoid Cell Leukodystrophy (GLD) is a rare lysosomal disorder occurring in 1 in 100.000 newborns. An enzyme called beta-galactosylceramidase (GALC) which usually degrades toxic substances is not working in this disorder. Psychosines accumulate in the brain and in peripheral nerves and are toxic for myelinating cells. The by far most common form is the infantile form with first symptoms starting in early infancy, usually before the age of 6 months. Children suffering from this form usually deteriorate rapidly and die early. There are also forms with later onset, albeit these are much less frequent.

Clinical symptoms

The by far most common form is the infantile form with first symptoms starting in early infancy, with a median age of onset of 4 months and almost always before the age of 6 months, with rapid deterioration and early death, usually before the second birthday. A Swedish neurologist, professor Hagberg, has divided this form into 3 stages. In stage I, infants are very irritable, cry easily, develop elevated muscle tone and start to lose skills as head control or turning round. Feeding becomes more difficult. In stage II, opisthotonus (this is a particular position with the head extended backwards) is virtually permanent, arms are stiff and flexed and legs stiff and extended. About half of the children develop epilepsy. In stage III, also called the "burnt-out" stage, children have lost all abilities including vision and hearing, they do not react any longer. Later, children may become quite weak again. This disease is a particular burden for families with restless, irritable infants and a dramatic deterioration within a short period of time. Treatment aims at maximizing comfort.

Later-onset forms are rare and are defined as onset after the first 18 to 24 months. These patients experience a progressive spastic paraparesis (stiff muscles, especially of the legs) and slow dementia. There is usually peripheral neuropathy.

Diagnosis

The diagnosis of Krabbe disease is based on the typical clinical findings, typical MRI abnormalities and a undetectable or very low activity of galactocerebrosidase which can be measured in a bloodspot.  
 
 Figure A, B and C are from a 7 month-old child with Krabbe disease, D, E and F are from a healthy child the same age. All images are axial T2-weighted images. Cerebrospinal fluid appears white, myelinated white matter dark-grey, unmyelinated white matter light-grey. The white matter is not fully myelinated at that age. In the infant with Krabbe disease, there is some volume loss of the brain. Normal myelination does not occur. There are typical abnormalities in the cerebellum (A) and the thalami (B).

Therapy

There is no established therapy for GLD. Hematopoietic stem cell transplantation (HSCT), often also called bone marrow transplantation, has been tried in all forms of the disease. If the infantile form has already become symptomatic, treatment is no longer possible as the disease process cannot be stopped once begun. If performed in the neonatal period before first symptoms have developed, HSCT cannot cure the disease. It is only able to modify the natural progression of the disease in children with the infantile form: children remain severely handicapped. All develop spasticity, many become microcephalic, only a minority is able to walk without support and a considerable number of transplanted children require gastrostomy for tube feeding. Mental development is also retarded. In most patients, these neurological symptoms are slowly progressive. In patients with late-onset disease, HSCT has been reported to stabilize the disease. Enzyme replacement therapy has not yet been studied in patients with Krabbe disease.

It is important to achieve comfort, and this is the main goal of therapy. Stiffness and irritability can be partly improved by medication, also epilepsy can be treated with drugs. All children with the early form will have feeding problems from quite early on and have to be fed via a nasogastric tube or a PEG.

Genetics

Krabbe disease is genetic. It is inherited in an autosomal recessive manner and caused by mutations in the gene coding for  beta-galactosylceramidase (GALC). This means that parents are healthy, but carry each one defective copy of the responsible gene. Click here for more information.  If a child inherits two defective copies of this gene, it will be affected. Prenatal diagnosis is possible.

References

1. Duffner PK, Caggana M, Orsini JJ, Wenger DA, Patterson MC, Crosley CJ, Kurtzberg J, Arnold GL, Escolar ML, Adams DJ, Andriola MR, Aron AM, Ciafaloni E, Djukic A, Erbe RW, Galvin-Parton P, Helton LE, Kolodny EH, Kosofsky BE, Kronn DF, Kwon JM, Levy PA, Miller-Horn J, Naidich TP, Pellegrino JE, Provenzale JM, Rothman SJ and Wasserstein MP. Newborn screening for Krabbe disease: the New York State model. Pediatr Neurol 2009; 40: 245-252; discussion 253-245.

2. Duffner PK, Caviness VS, Jr., Erbe RW, Patterson MC, Schultz KR, Wenger DA and Whitley C. The long-term outcomes of presymptomatic infants transplanted for Krabbe disease: report of the workshop held on July 11 and 12, 2008, Holiday Valley, New York. Genet Med 2009; 11: 450-454.

3. Escolar ML, Poe MD, Provenzale JM, Richards KC, Allison J, Wood S, Wenger DA, Pietryga D, Wall D, Champagne M, Morse R, Krivit W and Kurtzberg J. Transplantation of umbilical-cord blood in babies with infantile Krabbe's disease. The New England Journal of Medicine 2005; 352: 2069-2081.

4. Hagberg B. Krabbe's disease: clinical presentation of neurological variants. Neuropediatrics 1984; 15 Suppl: 11-15.

5. Hagberg B, Kollberg H, Sourander P and Akesson HO. Infantile globoid cell leucodystrophy (Krabbe's disease). A clinical and genetic study of 32 Swedish cases 1953--1967. Neuropadiatrie 1969; 1: 74-88.

6. Siddiqi ZA, Sanders DB and Massey JM. Peripheral neuropathy in Krabbe disease: effect of hematopoietic stem cell transplantation. Neurology 2006; 67: 268-272.


 

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