globoid cell leukodystrophy

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Krabbe disease, also known as globoid cell leukodystrophy, is an autosomal recessive lysosomal storage disorder resulting in damage to cells involved in myelin turnover. It thus affects both the peripheral nervous system and the central nervous system (manifesting as a leukodystrophy).

Epidemiology

The majority of individuals with Krabbe disease present in early childhood although adult presentations as late as the 5decade are encountered .

Krabbe disease can be divided according to the age of onset into two or three forms depending on the author :

  • infantile form (85-90%): rapidly progressive usual onset <2 years of age
  • late-onset/adult form (10-15%): more slowly progressive

Clinical presentation

Clinical presentation can vary and depends on the age of onset with numerous clinical features including :

  • hypertonia
  • irritability
  • delayed milestones
  • loss of developed milestones
  • fever
  • myoclonus
  • opisthotonus
  • nystagmus
  • bulbar palsies
  • blindness
  • cognitive decline

Pathology

Genetics 

Krabbe disease is caused by mutations in the GALC gene (mapped to chromosome14q) which encodes galactocerebrosidase, an enzyme that degrades galactosylceramide, a normal constituent of myelin. Deficiency of galactocerebrosidase results in the accumulation of galactosylceramide within the lysosomes of Schwann cells and oligodendrocytes which eventually results in apoptosis with secondary abnormal activation of microglia and macrophages with subsequent demyelination and gliosis . The multinucleated macrophages are known as globoid cells .

Radiographic features

Changes typically involve the corticospinal tracts.

CT

Initially, CT may show hyperdense areas symmetrically involving the thalami , cerebellum, caudate nuclei, posterior limbs of the internal capsule, and brainstem. Changes may also extend into the centrum semiovale/corona radiata region .

Later, hypoattenuation develops in the white matter of the centrum semiovale . Eventually, atrophy of the cerebellum and cerebrum develops .

MRI

When diffuse white matter involvement develops, MRI features are characterized by:

  • T2: may show high signal involving periventricular white matter centrum semiovale and deep grey matter; subcortical U-fiber may be spared until late in the course of the disease
  • T1 C+ (Gd): no contrast enhancement in these areas
  • MRS: adult form may show abnormal choline elevation in centrum semiovale

Enhancement and enlargement of the optic nerves and occasionally peripheral nerves (e.g. lumbosacral plexus) can also be seen .

Treatment and prognosis

Therapy primarily centers on hematopoietic stem cell transplantation which can delay disease progression.

Prognosis depends to a large degree on the age at which a diagnosis is made. Infantile-onset represents a more aggressive course, presenting early and leading to a more rapid neurological decline.

History and etymology

It is named after Knud Haraldsen Krabbe, a Danish neurologist (1885-1961) .

Differential diagnosis

The differential diagnosis is largely that of other leukodystrophies.

Perinatal profound asphyxia

Siehe auch:
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Assoziationen und Differentialdiagnosen zu Morbus Krabbe: