Krabbe disease (KD) is a rare, debilitating disorder of the brain with a poor prognosis that primarily affects young children. Newborn screening for KD is a valuable tool that can be utilised to ensure early diagnosis and early treatment of affected individuals. However, it remains inconsistent throughout the world, making this an unmet medical need for many KD-affected individuals. This article will review KD and newborn screening, as well as the challenges that some countries face with screening implementation.

Understanding Krabbe disease

KD is found in about 1 in 100,000 people worldwide, making it a rare disease. KD is inherited in an autosomal recessive pattern, i.e. both parents have to carry at least one disease-causing mutation for KD to manifest in their child.

Krabbe disease is part of a group of brain disorders called leukodystrophies that affect the white brain matter and are associated with a deficiency of an enzyme known as galactocerebrosidase (GALC) due to mutations in the GALC gene. GALC is a lysosomal enzyme, which means that Krabbe disease can also be classified as a lysosomal storage disease, similar to Pompe disease, Gaucher disease, and Niemann-Pick disease. White brain matter is composed of many nerve fibres and plays an important role in the transmission of signals between the brain and the body. Nerve fibres have an outer lipid cover known as myelin, which allows electrical signals to travel more efficiently from one end to another. Myelin is produced by specialised nerve cells known as glial cells. Deficiency of the GALC enzyme leads to impaired lipid metabolism in glial cells and accumulation of toxic galactolipids like psychosine, which cause the apoptosis of affected cells and progressive destruction of myelin. With time, this leads to degeneration of white brain matter and the manifestation of a wide range of neurological symptoms and early death.

Based on the age of onset, KD can be classified into 3 group types: infantile, which manifests before 3 years of age; juvenile, which manifests in the age range 3 to 16 years; and adult KD, which manifests after 16 years of age. Infantile KD make up about 90% of all cases. Earlier onset of symptoms is also associated with more rapid progression of disease and increased risk of childhood mortality.¹

Most KD-affected individuals carry one or two copies of the 30kbdel mutation in the GALC gene, which is a deletion of 30 thousand DNA base pairs in the GALC gene, resulting in significantly reduced or completely diminished enzyme activity. Individuals carrying two 30kbdel mutations (i.e. 30kbdel homozygotes) usually have the earliest onset of symptoms and the most severe disease presentation. Enzymatic activity is partially conserved if a person has one 30kbdel mutation and a second disease-causing mutation with residual function (i.e. compound heterozygotes). Some individuals don’t carry any 30kbdel mutations and usually have milder symptoms and a later onset of the disease. Examples of such less severe genetic defects include the c.1841G>A and c.857G>A single-nucleotide substitutions, resulting in moderately reduced function of the GALC enzyme.¹

Newborn screening for Krabbe disease

What is Newborn screening?

Newborn screening is a national health technology that can help identify babies at high risk of developing certain congenital diseases. In newborn screening, every baby is tested upon birth for a panel of diseases. Usually, a midwife or a nurse will prick a baby’s heel and sample blood from it on a screening card in the form of dried blood spots. The cards are transferred to the screening laboratories, where the blood is further used to perform biochemical and genetic testing. A baby will usually have its blood sampled once, however, if there is any suspicion of a disease being present, the parents might have to return to the maternity ward for follow-up tests. This process should be explained to parents in advance.

Countries have different disease panels for newborn screening - some countries like Italy screen for over 40 diseases at once, while others don’t have newborn screening programs at all or screen for only a few diseases.² Early diagnosis is associated with a slower disease progression and a more favourable prognosis for affected individuals. It allows people to start appropriate treatment before any symptoms have developed and helps preserve organ function.

How is Krabbe disease detected through newborn screening?

Newborn screening for any disease usually consists of multiple consecutive steps. The first step for KD screening usually involves tandem MS detection of GALC enzyme levels in a dried blood spot. Babies with GALC levels under the normal threshold are at a higher risk of developing KD. Positive GALC testing has to be verified through a second screening step, which in most cases is genetic testing for the most common mutation in the GALC gene - 30kbdel. An alternative to screening for a single mutation is to sequence the entire GALC gene. Gene sequencing can be performed as an additional step to 30kbdel screening if only one or no 30kbdel mutations are found in individuals carrying less common GALC mutations. Alternatively, gene sequencing can be performed immediately after a positive enzymatic test, however, this algorithm is more costly.³ Genotyping can also help prognose the clinical severity of Krabbe disease and the age at onset of symptoms.

Some countries/states go for additional testing of psychosine levels (the toxic galactolipid mentioned earlier) in a dried blood spot. Psychosine accumulates in the body of KD-affected individuals, and its levels strongly correlate with the severity of KD disease. Some laboratories perform psychosine testing as an alternative to genetic testing, while others prefer to test for psychosine as a third step after positive 30kbdel or gene sequencing to confirm the diagnosis. Psychosine testing can be a valuable too,l especially in babies carrying mutations with unknown clinical significance, to confirm the disease, i.e. it’s considered more of a confirmatory test than a primary screening test.⁴

After positive newborn screening, further testing of newly identified KD-affected individuals can be performed to assess the disease stage and severity of complications, such as using MRI to look for white brain matter lesions indicative of KD.⁵

Early treatment of Krabbe disease

Available treatments for Krabbe disease

Practically the only therapy available to KD-affected individuals is hematopoietic stem cell transplantation (HSCT). This procedure involves the transfer of stem cells from a healthy donor’s bone marrow into KD-affected individuals in the form of intravenous infusion. Stem cells can differentiate into different cell types, including healthy glial cells. This way, stem cells can repopulate the damaged white brain matter and slow down the progression of KD. HSCT has indeed been shown to impede the manifestation of both cognitive and motor symptoms of KD, especially in infantile individuals. A downside of HSCT therapy is that there is a need for conditioning procedures to deplete the host’s immune system and minimise the risk of graft rejection.¹ Early initiation of HSCT therapy solidifies the importance of newborn screening for KD.

Ongoing research of Krabbe disease therapy

• Novel stem cell therapies - currently, several stem cell platforms are being researched for the treatment of KD. For instance, HSCT with the cell therapy candidate MGTA-456⁶ as well as umbilical cord blood transplantation with the cell therapy candidate HSC835.⁷ Another research field for KD cell therapies of interest are novel conditioning procedures for transplantation recipients. Currently, there is research on novel so-called reduced intensity conditioning combinations between chemotherapy with lowered toxicity and drugs with anti-oxidant and anti-inflammatory properties that may potentially reduce the side effects of cell transplantation and assure a smoother procedure⁸
• Gene therapy - correcting faulty mutations in the GALC gene can potentially cure KD. Gene therapy in itself brings many biological and ethical risks that have to be addressed before reaching human application. PBKR03 is an adeno-associated viral vector carrying a healthy GALC gene that is currently in a global multicenter Phase 1/2 clinical trial in people aged 1-9 months with infantile KD. It’s administered as a solution for intrathecal injection directly into the brain. This trial is expected to end in 2030.⁹ FBX-101 is another experimental adeno-associated virus-based gene therapy based on a healthy GALC gene that is studied for intravenous use in infantile KD in a Phase 1/2 trial after a run-in period of HSCT therapy. The trial is expected to end in 2026¹⁰

Challenges and considerations

Ethical considerations in newborn screening

Newborn screening raises several ethical questions, such as: 

• Informed consent from parent
• Should parents be asked for consent to perform a heel-prick test on their babies? 
• Should babies be genetically tested only for specific gene mutations or have whole genome sequencing performed instead, with the risk of discovering other potential disease-causing mutations?
• Should the child have the right to know about its mutations only after transitioning into adulthood?
• Data privacy
• How should screening data be handled to ensure data privacy?
• Who should have access to this information?
• Can external authorities be involved with this data in case of urgency, e.g. if the parents refuse to have follow-up tests for their child after a positive screening result?
• Potential psychological impact
• How should positive screening results be communicated to the parents to ensure compliance?
• How should clinics proceed with false negative results, which can create a false state of reassurance and lead to delayed diagnosis and further disease progression?

Cost and resource implications for healthcare systems

Costs are a major constraint for employing new health technologies, and newborn screening is no different. A newborn screening program needs to have an optimal cost-benefit ratio, i.e. offer benefits to the community at a feasible cost. Some countries consider only the short-term costs for a health technology and don’t look at the broader picture: early diagnosis of a disease allows affected individuals to receive timely treatment and avoid complications and associated costs such as hospitalisations and additional symptomatic treatment.

Importance of public awareness

Patient advocacy groups (PAGs) are a major stakeholder in public awareness, especially when talking about rare diseases. PAGs should engage in public campaigns to raise awareness about the burden of living with KD and the benefits newborn screening can bring to affected individuals.

Summary

Currently, newborn screening for KD is restricted to some US states and has not been integrated into most European countries’ national screening programs. Only some countries, like Italy, have recently started pilot projects for KD screening.¹¹ The inclusion of KD in newborn screening programs can improve early diagnosis and allow for the timely initiation of stem cell therapies and, potentially in the future, gene therapies as well. Multiple organisations, such as governments, PAGs, scientific and medical institutions, and healthcare providers, should unite and advocate for the establishment of a patient-centric infrastructure.