Krabbe Disease Clinical Presentation

Updated: May 03, 2017
  • Author: Reem Saadeh-Haddad, MD; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG  more...
  • Print
Presentation

History

Signs and symptoms of early onset and late-onset Krabbe disease are described below. [6]

Infantile Krabbe disease  [23, 24, 25]

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  [21, 22, 26, 27]

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. [28]

Next:

Physical

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, 6]

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.

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.

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. [21, 22]

Previous
Next:

Causes

All 4 subtypes are caused by deficient galactosylceramide beta-galactosidase (GALC) activity, which results from mutations to the gene that encodes for the enzyme. [29] . Measurement of GALC activity shows 0%-5% of normal activity in leukocytes or cultured skin fibroblasts. All 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.

The gene has been mapped to chromosome band 14q31.3. [30]

Almost 70 mutations have been identified in the gene responsible for GALC production. Polymorphisms have been identified that may play a considerable role in the resultant phenotypes. [6, 29, 31] There are two common mutations. 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. [32, 33] 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. [20] This c.857G>A variant is common in those with late-onset Krabbe.

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

Previous