Krabbe Disease Workup

Updated: Dec 18, 2019
  • Author: Anna V Blenda, PhD; Chief Editor: Luis O Rohena, MD, PhD, FAAP, FACMG  more...
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Laboratory Studies

Routine blood chemistries and urinalysis do not provide any significant abnormalities that assist in establishing a diagnosis of Krabbe disease.

Galactosylceramide beta-galactosidase (GALC) activity measurement can help confirm a diagnosis of Krabbe disease when GALC activity levels are 0-5% of reference values in peripheral blood leukocytes, cultured fibroblasts, cultured amniocytes, and chorionic villi. Because overlap is often observed between unaffected noncarriers and heterozygote carriers, screening for heterozygote carriers by enzyme analysis is unreliable. The level of GALC activity does not absolutely delineate clinical subtypes. [5, 50, 52, 53]

After establishing a diagnosis of Krabbe disease by GALC assay, molecular analysis to provide GALC genotyping can help detect heterozygous carriers and identify candidates for prenatal testing. [50]

CSF analysis in patients with Krabbe disease reveals highly elevated protein levels in patients with types 1 and 2 Krabbe disease, an abnormal protein electrophoresis pattern (elevated albumin and alpha2-globulin levels, decreased beta1-globulin and gamma-globulin levels), and a cell count within the reference range. [7]

Assay of GALC activity levels in cultured amniocytes or chorionic villi has helped provide successful prenatal diagnoses. Accurate interpretation requires that parental GALC activity levels be determined. Molecular diagnostic procedures are also available. [7, 54]

In 2006, Krabbe disease was added to the New York State newborn screening panel. Subsequently, the Krabbe Consortium of New York State has published an article delineating a model for the implementation of newborn screening for Krabbe disease. [55] This model involves a multidisciplinary, standardized approach to the initial evaluation as well as long-term follow-up of infants at risk. Some of the components include the following:

  • A standardized clinical evaluation protocol (including screening and confirmatory enzyme and genetic testing)

  • Criteria for hematopoietic stem cell transplantation for the early infantile phenotype

  • A clinical database and registry

  • A study of the developmental and functional outcomes


Imaging Studies

Brain CT scans [7, 56] may reveal progressive, diffuse, symmetric cerebral atrophy usually develops, involving both gray and white matter. White matter may appear diffusely hypodense, predominantly in the parieto-occipital region. Focal areas of altered signal intensity have been reported.

Brain MRI is a more sensitive modality with which to detect high-intensity areas of demyelination in the brainstem and cerebellum. [57] Contrast-enhanced MRI of the brain effectively revealed abnormalities of the corticospinal tract in a 6-month-old patient with Krabbe disease. [6] In adult-onset Krabbe disease, the corticospinal tract was affected by white matter hyperintensities (100% of studied patients), with the precentral gyrus, corona radiata, and posterior internal capsule being highly abnormal. [58]

The Loes MRI severity scale has been historically used for evaluation of children with Krabbe disease. It was originally devised for measuring the degree of brain abnormality in X-linked adrenoleukodystrophy. Statistically significant correlations are noted between whole brain imaging assessment (total Loes score) and 3 clinical test scores (ie, mental development, gross motor skills, and fine motor skills). [59] These results suggest that Loes MRI scoring may also be useful in evaluating neurological outcomes in Krabbe disease.

Brain MR spectroscopy may reveal elevated myoinositol-containing and choline-containing compounds with decreased N-aspartylaspartate in affected white-matter areas. [57, 60]

Diffusion tensor imaging is being investigated as a sensitive and noninvasive quantitative imaging technique for assessing and monitoring white-matter development in patients who have received hematopoietic stem cell transplants. [61]


Other Tests


Electroencephalography (EEG) reveals a nonspecific slowing and disorganization of background rhythm and may show evidence of epileptogenic activity. Electromyography (EMG) changes often are consistent with peripheral neuropathy. Tests for brainstem-evoked auditory responses (BEAR) and visual-evoked potentials (VEP) show only nonspecific abnormalities.

Genetic Testing

The testing strategy always begins with measurement of the GALC activity. This can be used to confirm the diagnosis. Molecular genetic analysis is important, as it allows identification of carriers within a family, helps identify at-risk pregnancies, and, in some cases, predicts the phenotype based on detected genotype. [46] As an example, if the late-onset c.857G>A allele is identified, a later-onset presentation may be expected. Thus, testing follows a 2-step approach, as follows:

  • Targeted testing for the 30-kb deletion if the presentation is infantile Krabbe disease; targeted testing for the c.857G>A allele if the presentation is late-onset Krabbe disease
  • If two pathogenic variants are not detected with testing above, sequencing and deletion/duplication of the gene, also called GALC, should be performed.


Lumbar puncture is helpful, especially to help identify elevated CSF protein levels and an abnormal protein electrophoretic pattern. Skin biopsy to quantitate GALC activity in cultured fibroblasts is not necessary for diagnosis because GALC activity levels can be detected in peripheral blood leukocytes. Brain biopsy was, is, and will continue to be the last resort for diagnosis. Brain biopsy has rarely been necessary since the advent of enzymatic and molecular testing.


Histologic Findings

White matter demonstrates gliosis, demyelination, secondary axonal degeneration, severely diminished numbers of oligodendroglial cells, and multinucleated macrophages with abundant cytoplasm (globoid cells) that cluster around blood vessels. [7, 62]

Gray matter may show neuronal degeneration.

Peripheral nerves demonstrate demyelination, endoneural fibrosis, fibroblast proliferation, and perivascular histiocyte-macrophage aggregation. [33]