Krabbe disease is a genetically determined glycolipidosis that occurs with a predominant lesion of myelin fibers. The classic variant of pathology develops in the first half of life, manifests with hyperexcitability, febrile syndrome, muscle spasticity, seizures, delayed psychomotor development. Krabbe disease is diagnosed through cerebral MRI, ENMG, enzyme and molecular genetic studies. No specific therapy for the disease has been developed, stem cell transplantation may be effective at the pre-symptomatic stage, which allows slowing the progression of leukodystrophy.
General information
Krabbe disease (acute childhood leukodystrophy, globoid cell leukodystrophy, galactosylceramide lipidosis) is a rare hereditary pathology associated with a disorder of lipid metabolism and destruction of myelin in the peripheral nerves and central nervous system. It was first described by the German physician R. Beneke, but received its name in honor of the Danish neurologist K. Krabbe, who described in detail the symptoms and pathomorphology of the disease. In the population, it occurs with a frequency of 1:100,000 newborns (more often in Israeli Druze – 1:6000 and Scandinavians ‒ 1:50,000). No sexual differences were noted. The course of the disease is steadily progressing.
Causes
Krabbe disease occurs due to mutational changes in the GALC gene located in the genomic region 14q31. This gene encodes the enzyme galactosylceramidase, the deficiency of which in globoid cell leukodystrophy causes a violation of myelination of nerve fibers. In rarer cases, Krabbe disease is mediated by a genetic defect in the PSAP gene prosaposin located at the 10q22 locus.1. The disease has an autosomal recessive type of hereditary transmission.
Pathogenesis
The function of galactocerebrosidase is the cleavage of glycolipids. Enzyme deficiency leads to the accumulation of non-hydrolyzed lipids in the myelin substance of the peripheral and central NS. Possessing neurotoxicity, these compounds (in particular, psychosine) initiate apoptosis of oligodendrocytes, destruction of the myelin sheath, infiltration of neuroglia by globoid cells.
The process of demyelination of nerve fibers leads to a violation of the passage of nerve impulses, which is accompanied by a disorder of the patient’s motor skills. The involvement of the HLA complex in the pathogenesis of Crabbe disease is not excluded, as indicated by a systemic inflammatory reaction caused by a cytokine cascade.
During pathomorphological examination, a macroscopically determined decrease in the size of the brain due to pronounced atrophic processes. Microscopic examination of the preparations shows the death of oligodendrocytes, loss of myelin, accumulation of multinucleated globoid cells in demyelination sites.
Classification
Krabbe’s disease is characterized by polymorphism of clinical variants of the course. Depending on the age of the debut, 4 forms of the disease are differentiated:
- infantile – the classical form, which accounts for up to 90% of all cases. Develops at the age of 3-6 months.
- late infantile – the onset of the disease occurs in the age period from 6 months to 3 years.
- juvenile – signs of Krabbe disease appear from 3 to 12 years old.
- adult – clinical manifestation begins in the post-puberty period.
Symptoms
Infantile form
The initial signs of acute childhood leukodystrophy appear in the first half of a child’s life. The first symptoms are nonspecific. The child often cries, refuses to eat, constantly regurgitates, adds weight poorly. There is a high muscle tone, causeless episodes of hyperthermia. Already by 6-8 months, children begin to lag behind in psychophysical development: they stop holding their heads, turning over. Convulsions may join at this stage.
Often the described symptoms are taken by pediatric doctors for cerebral palsy, so the diagnosis of Krabbe disease is rarely made in a timely manner. Further progression of genetic pathology is accompanied by the disintegration of the child’s already existing motor skills, mental development arrest. There are myoclonia, opisthotonus, a sharp decrease in tendon reflexes. Develops atrophy of the optic nerves, deafness. Hypotrophy is noted, reaching the most extreme degree – cachexia.
At the terminal stage of Krabbe disease, bulbar paralysis develops, which leads to complete immobilization, loss of speech, and inability to swallow. Cerebral degeneration is progressing. Most children do not live to the age of 2.
Late infantile form
Debuts in early childhood (up to 3 years). Characterized by rapid atrophy of the optic nerve with the development of partial or absolute blindness. In the initial period, there is a gradual intellectual decline, a disorder of motor skills, ataxia. In the future, spastic tetraplegia and dementia are added. Death occurs before the age of 7.
Juvenile and adult forms
Krabbe disease with a late onset usually begins with a deterioration of visual function: hemianopia develops, visual agnosia. Patients have difficulty performing arbitrary movements. Over time, spastic rigidity of the muscles of the lower extremities increases, manifestations of cerebellar ataxia. Hemi- or paraparesis, peripheral polyneuropathy develops. The progression of galactosylceramide lipidosis is slower, but the prognosis is still disappointing.
Complications
The severe consequences of Krabbe disease are caused by a progressive decrease in motor and cognitive functions. As the immobilization increases, recurrent respiratory infections often occur. Dysphagia can lead to aspiration pneumonia. The formation of secondary hydrocephalus is possible. In the later stages of the disease, patients are bedridden, incapacitated, in the terminal stage they fall into a vegetative state. The death of patients usually occurs due to respiratory failure, infectious complications.
Diagnostics
Initially, patients usually turn to a neurologist with characteristic complaints of a violation of habitual movements and gait. At the initial reception, an increase in muscle tone of the spastic type, bilateral positive reflexes of Jacobson-Lask and Babinsky, coordination disorders, etc. are revealed. To confirm the diagnosis of Krabbe disease, a number of diagnostic tests are used – neuroimaging, electrophysiological, laboratory:
- Cerebral CT or MRI. Early markers are demyelination zones in the cerebellum, subcortical formations, and pyramidal pathways. In the late stage, atrophy of the large hemispheres and the corpus callosum is visualized on tomographic sections. Additional supporting information is obtained during MR spectroscopy.
- Electrophysiological diagnostics. The study of peripheral nerves using ENMG demonstrates a slowdown in the rate of nerve transmission due to demyelination. According to the EEG data, a violation or absence of the alpha rhythm is determined, indicating dementia. Auditory and visual evoked potentials are additionally investigated.
- Laboratory verification. Galactocerebrosidase activity is determined in blood leukocytes or skin fibroblasts. In Krabbe disease, the enzyme concentration is less than 5% of the norm. A high protein content (70 mg/dl) is determined in the cerebrospinal fluid. Molecular genetic diagnostics confirms mutations in GALC or PSAP genes.
All patients with suspected Krabbe disease are shown an oculist’s examination, a geneticist’s consultation. If there is an older child in the family with a similar diagnosis in subsequent pregnancies, it is recommended to perform prenatal diagnostics of chorionic villi or amniotic fluid. Preimplantation genetic screening (PGЫ) before IVF is possible.
Differential diagnosis
Krabbe disease should be suspected in infants with nervous hyperexcitability, causeless hyperpyrexia, myoclonus. The number of differentiable pathologies includes other diseases:
- cerebral palsy;
- Tay-Sachs disease;
- Batten disease;
- Canavan disease;
- Gaucher disease;
- optic nerve glioma in type I neurofibromatosis;
- metachromatic leukodystrophy, etc.
Treatment
Pathology is not curable, so all measures are symptomatic. Supportive anticonvulsant, dehydration, enzyme therapy is carried out. Therapeutic gymnastics and physiotherapy procedures are shown to improve motor function. In order to preserve self-service, occupational therapy classes are held.
If it is impossible to self-feed, feeding through a nasogastric probe or gastrostomy is adjusted. Severe respiratory insufficiency requires auxiliary respiratory support up to the imposition of a tracheostomy and a ventilator.
Experimental therapy
Early detection of laboratory markers of globoid cell leukodystrophy even before the development of the first clinical manifestations creates opportunities for attempts to treat pathology. Hematopoietic stem cell transplantation is used (the results are ambiguous), umbilical cord blood (according to 3-year follow-up, it leads to the normal course of myelination processes, normal psychomotor development of children).
Experimental developments are underway in the direction of gene therapy, the search for drugs that can activate the GALC gene. However, to date, there are no scientific reports on the success of such experimental therapy yet.
Prognosis and prevention
Krabbe disease is incurable, characterized by progressive motor disorders, cerebral atrophy. In infantile forms, death occurs at an early or preschool age. In juvenile and adult types, the disease develops more slowly, but also inevitably leads to fatal consequences.
The possibility to slow down the development of irreversible neurodegenerative changes exists only at the pre-manifest stage. Prevention of Krabbe disease consists in carrying out genetic diagnostics at the preimplantation stage or before delivery.