Krabbe Disease Clinical Presentation

Updated: Dec 18, 2019
  • Author: Anna V Blenda, PhD; Chief Editor: Luis O Rohena, MD, PhD, FAAP, FACMG  more...
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Signs and symptoms of early onset and late-onset Krabbe disease are described below. [7]

Infantile Krabbe disease  [31, 32, 33, 34]

Stage 1 includes the following:

Stage 2 includes the following:

  • Hyperreflexia

  • Hyporeflexia

  • Opisthotonus

  • Seizures

  • Psychomotor deterioration

  • Optic atrophy

  • Visual loss

  • Sluggish pupillary light response

  • Rapid and severe psychomotor deterioration

Stage 3 includes the following:

  • Decerebrate posturing

  • Blindness

  • Deafness

  • No voluntary movement

  • No interaction with the environment

Late-onset Krabbe disease  [28, 29, 35, 36]

Symptoms include the following:

  • Paresthesias

  • Decreased muscle strength

  • Spasticity

  • Ataxia

  • Paresis

  • Psychomotor arrest

  • Psychomotor deterioration

  • Seizures

  • Optic atrophy

  • Visual loss

  • Blindness

  • Unpredictable rate of regression

Macular cherry red spots were reported in 1 patient. Head circumference may be diminished, although macrocephaly also has been reported. [37]

To compare quality of life, the Leukodystrophy Quality of Life Assessment (LQLA) was administered to 33 patients with Krabbe disease or their caretakers. The assessment provided additional quantitative distinctions between these phenotypes. [38]



No visceromegaly, dysmorphic features, or skeletal abnormalities are associated with Krabbe disease, nor does the disease cause direct cardiovascular complications. Manifestations of types 1-4 Krabbe disease are as follows:

Type 1 Krabbe Disease

The infantile or classic form accounts for the vast majority of recognized cases (85-90%) and is considered the prototype of Krabbe disease. The clinical course in patients with the infantile form has 3 stages. [1, 7]

Stage 1 includes irritability, hypertonia, hyperesthesia, peripheral neuropathy and arrest of psychomotor development occur following normal early development. Onset usually occurs at age 3-6 months. Feeding difficulties, such as vomiting and reflux, may cause failure to thrive.

In stage 2, rapid psychomotor deterioration, increasing hypertonia, opisthotonus, hyperreflexia, and optic atrophy ensue. Seizures may occur.

In stage 3, severe neurologic impairment often ensues within weeks to months with loss of voluntary movements and persistent decerebrate posturing. Patients become blind, deaf, and unaware of external stimuli. This final stage sometimes is termed the burnt-out stage.

Cousyn et al reported a rare case of a stable 6-year-old Saudi girl with the phenotype of early infantile-onset Krabbe disease, which is usually characterized by high morbidity and mortality. Her stability was explained by relatively higher GALC enzyme activity. In addition, this patient presented with new features of hypoventilation and skin hypopigmentation. [39]

Type 2 Krabbe Disease

Late infantile Krabbe disease follows a similar but less rapid course. After a variable period of normal early development (6 mo to 3 y), the patient develops irritability, hypertonia, ataxia, and psychomotor arrest followed by progressive deterioration and vision loss, eventually followed by death.

An exceptional case of late infantile–onset Krabbe disease was characterized by a very mild non-progressive phenotype with predominant features of peripheral neuropathy mixed with pyramidal sign, selective corticospinal tract involvement, and compound heterozygous GALC missense mutations, including a novel pathogenic variant. [40]

Type 3 Krabbe Disease

Juvenile Krabbe disease is characterized by later age of onset (3-8 y) and greater variability in the tempo of disease progression. Early normal development is followed by a period of rapid psychomotor regression, although the disease then tends to subside into a slower, but progressive, degeneration.

Type 4 Krabbe Disease

Age of onset of adult Krabbe disease varies widely (8 y through adulthood). This type has a more varied clinical symptomatology and course of progression. Patients may present with signs of peripheral neuropathy, cerebellar dysfunction, spasticity, and impaired higher cortical functioning. Patients with type 4 disease may experience a rapid degenerative course or endure an indolent progression. [28, 29]



All 4 subtypes are caused by deficient galactosylceramide beta-galactosidase (GALC) activity, which results from mutations to the gene that encodes for the enzyme. [41] Measurement of GALC activity shows 0%-5% of normal activity in leukocytes or cultured skin fibroblasts. All homozygous individuals with deficient GALC enzyme activity have symptoms, which are confirmed with either physical examination or imaging findings that are consistent with the diagnosis of leukodystrophy.

Recent findings show that even heterozygous carriers of mutations able to cause Krabbe disease (including all parents of affected children) are at an increased risk for development of open angle glaucoma, pulmonary artery enlargement in association with chronic obstructive pulmonary disease, and impaired microglial function and defective repair of myelin damage. [42]

The GALC gene has been mapped to chromosome band 14q31.3. [43]

More than 70 mutations displaying molecular heterogeneity have been identified in the gene responsible for GALC production. [7, 41, 44, 45, 46] Two common mutations were detected in this group. A 30kb deletion has been reported in 40%-45% of individuals with infantile forms of Krabbe disease in northern Europe and in 35% of infantile Krabbe cases among Mexican patients. [47, 48] This deletion results in the infantile form of Krabbe, whether in the homozygous or the heterozygous state. However, when it is coupled with the c.857G>A mutation, it always results in the late-onset form of Krabbe disease. [27] This c.857G>A variant is common in those with late-onset Krabbe.

A rare case of atypical Krabbe disease involved an 18-month-old boy with clinical and radiological findings typical of Krabbe disease despite normal GALC enzyme activity and normal GALC gene sequence. He was found to have a homozygous variant, c.257 T > A (p.I86N), in the saposin A peptide of the PSAP gene. These findings suggest that individuals with saposin A deficiency may have elevated levels of psychosine, similar to children with classic Krabbe disease due to GALC deficiency. [49]

Genotype-phenotype correlations are being further delineated to provide a molecular explanation for the clinical variability seen in patients with Krabbe disease. [50, 51, 34] However, there is no known correlation between enzyme activity and age of onset.



Irreversible neurologic deterioration and death can occur. Patients are at risk for aspiration pneumonia and recurrent respiratory infections caused by neurologic compromise.