Overview

A lysosomal storage disease called Krabbe disease is caused by the absence of the enzyme galactocerebrosidase (GALC).¹ Consequently, a harmful chemical called psychosine builds up, mostly in the central and peripheral nervous systems, triggering neurological effects.¹ In addition, galactosylceramide is the main lipid that GALC breaks down, and GALC also breaks down galactosyl sphingosine (psychosine), a glycolipid with significant cytotoxicity.² The buildup of psychosine caused by GALC deficiency attacks Schwann cells and oligodendrocytes.² Krabbe disease impacts adults and children with gene mutations that code for GALC.³

Since Krabbe disease is rare, it has been difficult to determine its prevalence.⁴ According to estimations based on incidence from genomic allele frequency forecasts, the current estimate of Krabbe disease is 1 in 12,080 live births. 

The WHO (World Health Organisation) defines palliative care as a treatment method that helps patients and their loved ones deal with issues related to a life-limiting disease, which is often progressive.⁵ Through early detection, accurate evaluation, pain management and other issues, it avoids and lessens suffering.⁵ Therefore, palliative care can be applied to patients suffering from Krabbe disease to improve their quality of life. 

Causes of Krabbe disease

A gene is responsible for the inheritance of Krabbe illness in biological offspring. The pattern of inheritance for Krabbe disease is autosomal recessive, suggesting that each cell's two copies of the gene have mutations.⁶ The absence of GALC occurs from mutations in the GALC gene, leading to Krabbe disease. This enzyme is necessary for your body to metabolise galactocerebroside, a part of myelin, the coating that protects your neurons.⁶ As a result, when this enzyme is absent, myelin sheaths are degraded, causing neurological symptoms.⁶

Symptoms of Krabbe disease

The infantile type of Krabbe disease, which is the most prevalent kind, typically manifests before the age of 1.⁷ Irritability, muscular weakness, feeding issues, fever instances without any infection-related symptoms, stiffness, and stunted mental and physical development are common initial symptoms ⁷. Muscle weakness increases as the condition worsens, impairing the infant's mobility, chewing, swallowing, and breathing.⁷ Individuals suffering from the infantile type of Krabbe disease rarely live past the age of 2 due to its severity. 

The infantile type impacts 85% of all cases. The main feature of the infantile type is a normal starting development that quickly and severely deteriorates.⁸ In contrast, when Krabbe disease develops later in life, neurological performance declines more slowly and the average survival time is extended to 8 years from the beginning of symptoms.⁸ Despite having substantial neurologic damage, adults with Krabbe disease can live for 30 to 50 years after being diagnosed.⁸ Later-onset symptoms generally involve delayed progress, impairment in motor function, decline in previously learned abilities, issues with vision, and spasticity of muscles.⁸

Role of palliative care in Krabbe disease

Palliative care is a speciality of medicine that aims to relieve pain and other signs and symptoms associated with a chronic illness ⁹. Palliative care providers work to make patients and their families feel more comfortable and to enhance their quality of life. Moreover, it is beneficial in managing symptoms such as pain, fatigue, and breathing difficulties.⁹

Krabbe disease has no known treatment and ultimately leads to death. Since Krabbe disease has no known cure and only worsens with time, supportive care such as palliative care is the primary form of treatment.⁶ The actions in the palliative care programme are intended to manage symptoms and enhance comfort and overall health.⁹

Management and treatment of Krabbe disease

The usual course of treatment for Krabbe disease is hematopoietic stem cell transplantation (HSCT).⁸ It is a stem cell transplant that aids in the body's replacement of damaged cells with normal or healthy ones.⁶ Hematopoietic cells are undeveloped cells that can differentiate into all blood cell types. In HSCT, the hematopoietic cells from a healthy donor are transplanted to a child with Krabbe disease but it is ideal to perform this treatment before the development of symptoms to maximise efficacy.⁶ Additionally, most patients benefitting from HSCT are asymptomatic; they first develop almost normally with small motor delays.⁸ Despite this, most patients receive palliative care. 

There are also therapies for children who have trouble eating, are irritable, have discomfort, or stiffness in their muscles, or have seizures.¹⁰ Among these therapies are: 

• Pain and irritation medications, like gabapentin¹⁰
• Drugs that ease muscular tension, like baclofen¹⁰
• Physical treatment to support flexibility and motion¹⁰
• Antiepileptic drugs¹⁰
• Feeding tubes for assistance with drinking and eating¹⁰

Diagnosis of Krabbe disease

Chorionic villus sampling and amniocentesis are two prenatal screening techniques that can be used to determine Krabbe disease in fetuses.¹¹ In certain areas of the United areas, standard newborn screening tests can detect Krabbe disease after birth. Additionally, physicians do DNA analysis tests and examine the concentrations of GALC beta-galactosidase in skin cells, or both.¹¹

Future directions of research

Even though lysosomal enzymes are found inside organelles that are bound by internal membranes, a cell can produce them and have neighbouring cells absorb them.¹² Originally known as "cross-correction," this procedure is currently the foundation of several lysosomal storage disease (LSD) therapy methods. After bone marrow transplantation, it is speculated that donor-derived cells of hematopoietic origin may enter various systems of the body, including the central nervous system (CNS), and provide host cells with therapeutic concentrations of lysosomal enzymes.¹²

Research into different treatment options is important because bone marrow transplantation has limitations. These consist of graft rejection, graft vs host illness, the challenge of finding matching donors and identifying pre-symptomatic patients with infantile Krabbe disease.¹² Lastly, clinical information from children undergoing this treatment indicates that the transplantation is ineffective.¹² Therefore, safer and more potent treatments for Krabbe disease are required. 

Summary

Overall, Krabbe disease is a rare lysosomal storage disease with no cure. It is a progressive condition that gives rise to neurological symptoms due to its impact on myelin sheaths. This occurs due to a deficiency in GALC enzyme due to GALC mutations. Fortunately, palliative care is effective in managing symptoms since it provides long-term care to patients, however, it does not cure Krabbe disease. Therefore, future research directions are necessary to explore alternative therapies to hematopoietic stem cell transplantation (HSCT), as this approach may not be efficacious in all cases.