Krabbé disease
Krabbé disease (KD) is a rare progressive neurodegenerative disorder caused by mutations in the galactocerebrosidase (GALC) gene. This deficiency impairs the metabolism of specific sphingolipids, leading to demyelination of nerve fibers and the accumulation of toxic globoid cells. KD is classified within a group of conditions known as leukodystrophies, which affect the white matter of the brain and can severely impact motor and cognitive functions. It is an autosomal recessive disorder, affecting approximately 1 in 100,000 births, with a 25% chance of a child being affected if both parents are carriers of the gene.
Infantile KD progresses rapidly, with symptoms including irritability, motor delays, and severe neurological decline, often resulting in death by early childhood. In contrast, other phenotypes of KD may display milder symptoms and longer life spans. Diagnosis typically involves biochemical assays and genetic testing to confirm GALC deficiency. While hematopoietic cell transplantation can improve outcomes if performed before symptoms appear, treatment remains largely supportive, focusing on managing symptoms and providing care. Genetic counseling is recommended for at-risk families to understand the implications of the disease.
Krabbé disease
DEFINITION Krabbé disease (KD) is a progressive neurodegenerative disorder caused by mutations of the galactocerebrosidase (GALC) gene, resulting in deficiency of the GALC enzyme needed to metabolize the sphingolipids galactosylceremide and galactosylsphingosine (psychosine) and leading to demyelination of the myelin sheath surrounding the nerves and accumulation of large globoid cells containing psychosine.
ALSO KNOWN AS: Globoid cell leukoencephalopathy or leukodystrophy; galactocerebrosidase; galactocerebroside beta-galactosidase; or galactosylceramidase deficiency
Risk Factors
KD is an autosomal recessive disorder, occurring in approximately 1 out of every 100,000 births. It can be inherited only if both parents carry the defective gene. In every pregnancy, the risk of a baby inheriting both genes and being affected is 25 percent, and its risk of inheriting one gene and being a carrier is 50 percent. Genetic carrier testing is available for at-risk populations (Swedish or Ashkenazi Jewish) and families with a history of KD.
Etiology and Genetics
KD is one of the leukodystrophies, a group of inherited metabolic diseases causing demyelination of the central nervous system (CNS) and peripheral nervous system (PNS) and abnormal development of white matter in the brain. Each disorder has a separate gene abnormality that causes a different enzyme deficiency, resulting in a range of dysfunctions.
KD is caused by mutations of the GALC gene, resulting in a deficiency of galactocerebrosidase, a lysosomal enzyme needed to metabolize the sphingolipids galactosylceremide and galactosylsphingosine (psychosine). Galactosylceramide is found in nervous tissue and is a major constituent of CNS myelin-forming oligodendrocyte cells. (PNS myelin is made by Swann cells.) Psychosine is a lysolipid known to cause death in cells. Failure of the GALC enzyme to break down these two substrates causes demyelination of the myelin sheath and formation of large multinucleate globoid cells containing undegraded psychosine. The stored psychosine becomes toxic, inducing cell death in oligodendrocytes and thus preventing myelin from forming.
The myelin sheath is a fatty covering surrounding axons in the CNS and PNS and acts as an electrical insulator, allowing impulses to be transmitted quickly along the nerve cells. Without myelin, impulses leak out and nerves cannot function normally. Myelination is a step-by-step, ordered process that begins at about five months of gestation and continues until a child is two to three years old. In KD, this process becomes reversed, with myelin being progressively lost instead of gained. Infantile KD pathology is severe, with demyelination rapidly progressing until nearly all myelin and myelin-forming cells have disappeared.
The GALC gene is located on the long arm of chromosome 14 (14q24.3-q32.1) and is about 60 kilobases in size, consisting of 17 exons, 16 introns, and a 5 flanking region populated with GC sequences. Inhibitory sequences, plus a suboptimal nucleotide at position +4, may contribute to deficiency of the GALC protein.
More than seventy disease-causing mutations have been reported; many have been studied in the GALC protein-deficient twitcher mouse, the animal model used for Krabbé disease in humans. Alleles causing infantile KD are thought to have a large deletion, plus a point mutation involving a transition at nucleotide 502 (C502T) cDNA. Another mutation, a guanine-to-adenine substitution at nucleotide 809 (809GA), has been associated with late-onset KD.
Symptoms
Infantile KD is characterized by quickly progressing neurological dysfunction, leading to death by early childhood. In stage 1, infants experience excessive crying and irritability, stiffness, motor and mental delays and loss of already-learned skills, feeding problems, and occasionally seizures. In stage 2, babies exhibit extreme arching of the back, jerking motions of limbs, and further deterioration of mental and motor skills, and they require tube feeding. In stage 3, children lose nearly all motor and mental functions, become blind and deaf, and can no longer move or speak. Patients with the other KD phenotypes have milder, slower-progressing symptoms and longer life spans.
Screening and Diagnosis
In 2006 New York became the first state to institute universal screening for KD; Missouri did so in 2009, and Illinois in 2010.
The standard procedure for diagnosing KD is biochemical assay for GALC activity via blood sample/skin biopsy; levels at 0 to 5 percent of reference values indicate deficiency but do not distinguish infantile from other KD phenotypes. The definitive diagnosis for KD is DNA sequencing analysis of the GALC gene coding region for mutations. Pathological signs of demyelination can be detected using magnetic resonance imaging (MRI), brain MR spectroscopy, and/or diffusion tensor imaging. Other diagnostics test for cerebrospinal fluid (CSF) total protein, nerve conduction, and optic nerve damage.
Treatment and Therapy
The only available treatment for infantile KD is hematopoietic cell transplantation, using bone marrow or blood cells extracted from unrelated umbilical cord blood. However, this procedure is effective only before symptoms begin to manifest and requires a tissue match of human leukocyte antigens (HLAs) between donor and recipient. Other gene therapies have been studied in the twitcher mouse and hold promise. Treatment for this otherwise fatal disorder is symptomatic and supportive.
Prevention and Outcomes
There are no means of preventing KD, but genetic counseling/testing is available for parents who have the GLAC gene mutation. Many children with KD who have undergone transplants are living longer and fare much better neurologically, but continue to have motor and language dysfunctions.
Bibliography
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