Krabbe Disease

Etiology

Krabbe disease is due to loss of function gene mutation coding for galactosylceramide beta hydrolase (GALC). About 200 GALC gene mutations have been identified. Usually, it is challenging to establish the phenotype severity with the genotype, but large deletions like 30 kilobase (kb) gene deletions, truncations, frameshift mutations, and nonsense mutations are associated with severe clinical manifestations.[5] The 30-kilobase gene deletion is common and accounts for 40% of 45% of mutations in the infantile form in Northern Europe and 35% in Mexican patients.[6] 

Approximately 50% of patients with juvenile and adult types are heterozygous for 30kb gene deletion or have mutations leading to reduced GALC enzyme activity.

Epidemiology

Krabbe disease is a genetic disorder, and its frequency varies widely with the population. It is a rare lysosomal storage disorder that is rapidly progressive and fatal. The incidence in Europe is estimated to be 1 per 100,000 live births. After analyzing death certificates, a U.S. estimate of 1 per 250,000 was made, but a more precise estimate can approach the European incidence.[7]

Its rate is as high as 6 per 1000 live births in Israel's Druze community due to consanguineous marriages. Among the four subtypes, 85% to 90% of the cases are of the infantile subtype, which is also the most severe and rapidly progressing. The mortality rate is as high as 90% in the first two years of life. The late-onset type has a better prognosis, and life expectancy is 5 to 7 years after the onset of symptoms.

Pathophysiology

Krabbe disease is due to the GALC enzyme deficiency, present in the lysosomes of microglial cells of the brain and the spinal cord. Microglia cells are responsible for the physiological turnover of myelin components and the elimination of toxic compounds. GALC metabolizes two galactolipids, galactosylceramide, and psychosine. Galactosylceramide is present in high concentrations in Schwann cells and oligodendroglial cells. GALC degrades galactosylceramide; its deficiency leads to the building up of galactosylceramide in the central and peripheral nervous system. Psychosine is a cytotoxic sphingosine lipid formed as a byproduct during myelin synthesis.[8][9]

The mechanism of how the accumulation of psychosine manifests its cytotoxic effect on oligodendroglia is unclear. Multiple hypotheses, like the microglia hypothesis and the psychosine hypothesis, have been formulated. The accumulation of these two compounds in the oligodendrocytes and Schwann cells leads to apoptosis of these cells and, hence, demyelination. In turn, the apoptosis leads to secondary activation of microglial cells and its transformation into multinucleated giant cells known as globoid cells, which are pathognomic of Krabbe disease.

Histopathology

Blood vessels will have clusters of multinucleated macrophages with abundant cytoplasm (globoid cells).[1] Neuronal degeneration at the gray matter is found. Hypomyelination and segmental demyelination occur in the early and late-onset forms, respectively. Curvilinear lamellar inclusions can be seen in Schwann cells and histiocytes on electron microscopy.

History and Physical

The severity of the symptoms depends on the age of presentation of symptoms. The infantile disease is rapidly progressive and fatal by age 2. Late-onset disease has relatively milder symptoms and longer life expectancy.[10][11][12]

Infantile disease: The symptom progression is best explained by categorizing it into stages.[11][12][13][14][15][16]

Stage 1- The child grows well until 4 to 6 months of age, when the clinical illness manifests. The symptoms commence with restlessness, irritability, vomiting, feeding difficulty, and failure to thrive. The child may be hypersensitive to touch, noise, or bright light and can develop tonic spasms in the presence of these instigating factors.

Stage 2- The child develops visual difficulty, optic atrophy, and opisthotonic posturing. They experience seizure-like episodes that have to be differentiated from epilepsy as these don't respond to anticonvulsants.

Stage 3- The most debilitating form of the disease is when the child develops blindness, deafness, and decerebrate posturing. Spasticity can be severe enough to halt any voluntary movement.[15]

Late infantile disease: Manifests between 13 to 36 months of age with irritability, visual difficulties, and abnormal gait. As the condition progresses, these symptoms worsen with the development of seizures, apneic episodes, and temperature instability. The median age of mortality is usually six years.[4]

Juvenile onset disease: The child develops visual difficulties, tremors, gait abnormalities, and attention deficit hyperactivity disorder. The rate of progression of the disease is highly variable, but the disease eventually debilitates the patient, and they die within ten years of the diagnosis.

Late-onset disease: Characterized by burning paresthesias in the extremities, mood and behavior alterations, ataxia, spasticity, visual difficulty/blindness, seizures, hearing loss/deafness, and psychomotor retardation. The patients can present with motor and sensory neuropathy associated with muscular atrophy and scoliosis. Few patients present with symptoms confined to a physical weakness without intellectual disability; on the other hand, others deteriorate both mentally and physically.[17][18]

Evaluation

Newborn Screening

Many states in the U.S. include screening for Krabbe disease in a standard newborn screening protocol. The initial screening test involves measuring the GALC enzyme activity in the peripheral leukocytes or cultured skin fibroblasts.[19][20] Values falling below 5% of the normal range confirm the diagnosis. However, it does not correlate with the severity of disease manifestation. This screening method's specificity is low; therefore, a second tier of the screening method is added to help identify the true positives. It can either be measuring blood psychosine levels or performing sequencing for the GALC gene. The high levels of psychosine are indicative of infantile Krabbe's disease. As not all laboratories are equipped to detect all GALC gene mutations and multiple variants of GALC mutations of unknown significance, measuring psychosine levels is more feasible and reliable.[9][21][22][23]

Imaging Studies

Computed tomographic scan: Initially shows symmetrical hyperdense areas (due to demyelination) in the cerebellum, cerebrum, thalamus, brainstem, internal capsule, and corona radiata. Later in the course, hypodense areas (due to atrophy) develop in the corona radiata, and cerebral/cerebellar atrophy develops.

Magnetic resonance imaging: It is particularly useful in identifying brain lesions in Krabbe disease. In the infantile forms, there is increased T2 signal intensity in deep cerebral white matter, dentate nucleus, and cerebellar white matter. In juvenile and adult disease, there is increased T2 signal intensity in the parieto-occipital regions and the corticospinal tracts; the dentate nuclei and the cerebellar white matter are usually spared.[13][24][25] There is no contrast enhancement in the affected areas; however, optic nerve and peripheral nerve (e.g., lumbosacral plexus) thickening and enhancement can be seen.

Magnetic Resonance Spectroscopy

The centrum semiovale may show raised choline levels in the adult subtype.[26]

Electroencephalography

May show epileptiform activity. Generalized slowing or disorganized rhythms are expected.

Ophthalmologic and Otolaryngologist Evaluation

The child needs an otolaryngologist assessment and an eye examination to determine the degree of hearing and vision loss and to provide hearing and vision aids to the patient.

Genetic Testing

Molecular genetic analysis is crucial, as it identifies carriers within a family. It also identifies at-risk pregnancies, and, in some cases, predicts the phenotype based on detected genotype.

Lumbar Puncture

A lumbar puncture may reveal elevated cerebrospinal fluid (CSF) protein levels and an abnormal protein electrophoretic pattern. The protein analysis demonstrates an increase in albumin and alpha-1 globulin levels and decreased beta-1 globulin and gamma globulin levels. CSF protein levels greater than 61.5mg/dl are associated with low/shorter survival.

Electromyography and Nerve Conduction Studies

Electromyography changes are usually consistent with peripheral neuropathy. There is a significant slowing of conduction velocity in both motor and sensory nerves in most patients with the infantile type of disease and about 20% of patients with the late-onset Krabbe disease.

Brain Biopsy 

The pathology findings show demyelination of white matter, loss of oligodendroglial cells, and areas of atrophy. The classical multinucleated globoid cells can be demonstrated on the periodic acid-Schiff stain.[11]

Treatment / Management

Currently, the therapeutic options are limited to asymptomatic or minimally symptomatic patients with Krabbe disease's infantile form.

Hematopoietic Stem Cell Transplant (HSCT)

The hematopoietic cells from a healthy donor are transplanted to the patient. HSCT helps the patient to populate the brain with microglia with normal function and good GALC enzyme activity. HSCT works best before the onset of symptoms and helps plateau or slow its progression. Studies have shown its efficacy in halting the cognitive and motor decline in the patient.[27][28][29][30][31] 

A study focused on diffusion tensor imaging in patients with Krabbe disease demonstrated that HSCT reduces the fraction anisotropy (FA) across six tracts measured. The decrease in FA in corticospinal tracts is associated with better cognitive and motor outcomes. A reduction in FA in the splenium and uncinate fasciculus is correlated with better cognitive outcomes.[32] The risk factors associated with HSCT are due to the chemotherapy the patient receives to limit the donor stem cells' immune rejection. There is ongoing research to make this treatment safer for the patient and with fewer side effects.

Cord Blood Stem Cell Transfusion

Cord blood stem cells collected from an unrelated donor's umbilical cord are transfused into the patient. However, this procedure has also been beneficial to only those patients treated before symptoms appear.[16](B2)

Supportive

More research is required to find better treatment options for patients suffering from Krabbe disease. Until then, the patient can be provided with supportive care.

• Muscle relaxants for spasms
• Anticonvulsants might sometimes be helpful for seizures
• Physiotherapy to increase mobility
• Occupational therapy for children to improve motor function
• Speech therapy to maintain swallowing functioning and maximize communication
• Tube feedings for good nutrition if swallowing is affected

Differential Diagnosis

The differential diagnosis of infantile Krabbe disease is broad and includes several neurodegenerative conditions that can present with neurodevelopmental delay and white matter abnormalities on neuroimaging studies:[33][34]

• Alexander disease
• Canavan disease
• GM2 gangliosidoses
• Metachromatic leukodystrophy
• Sphingomyelinase deficiency

Although distinguishing Krabbe disease from the disorders mentioned above can be challenging, a definitive diagnosis can be made based on targeted metabolic and molecular genetic testing.[33]

Prognosis

The average lifespan in patients with infantile Krabbe disease is 13 months. Most patients with late infantile disease die within two years of disease onset. The progression of disease and lifespan reduction vary in both juvenile-onset and adult-onset Krabbe disease. HSCT markedly improves short-term survival for individuals treated while asymptomatic during the early neonatal period.[30][35]

Complications

The disease is usually fatal. Most infantile cases die by two years of age, late infantile within two years of disease onset, and juvenile cases within ten years of diagnosis. It has a multitude of complications that debilitate the patient, including:

• Deafness
• Vision loss
• Rigid posture
• Cognitive deterioration
• Aspiration leading to infections
• Respiratory failure due to poor muscle tone