BIOCHEMISTRY (EHBC 123)

METABOLIC DISEASE OR DISORDER

(KRABBE DISEASE)
ASSIGNMENT REPORT
2021
BY

BANUGAA THURAI RAJ (BEHP20046080 – COHORT 15)

PETER CHIONG (BEHP20046090 – COHORT 15)
 TABLE OF CONTENT

CONTENT
What is Krabbe Disease?

Krabbe Disease in Malaysia

The cause of Krabbe Disease

Risk Factor of Krabbe Disease

The Signs & Symptoms of Krabbe Disease

Treatments and Preventions

Malaysian’s Institute For Medical Research

References
WHAT IS KRABBE DISEASE?

Krabbe (KRAH-buh) disease is a type of inherited disorder. It is a rare condition where

the protective coating (myelin) of nerve cells in the brain and throughout the nervous systems is
destroyed.
Krabbe disease is common in babies and in most cases, the signs and symptoms
can be seen within the period of 6 months of age. Babies who developed this disease usually died
by the age of 2. There are also cases in older children and adults, the course of the disease can
vary greatly.
There is no known cure for the Krabbe disease and treatment can only be done by
focusing on supportive care of its signs and symptoms. The Krabbe disease is also known as globoid
cell leukodystrophy.
KRABBE DISEASE IN MALAYSIA

There are no exact numbers of Krabbe disease occurrence in Malaysia. It is an

extremely rare disease. However, it is reported affects about 1 in 100,000 people in the United
States. This disease is also reportedly occurred in a few isolated communities in Israel at which 6
cases per 1,000 people.
CAUSES OF KRABBE DISEASE

Krabbe disease is caused by the inheritance of two copies of an altered (mutated)

gene – one copy from each parent. How this affects? Well, a gene act as a blueprint to produce
proteins and when this malfunctions or there’s an error, the protein product will no work properly as
intended. In the case of Krabbe disease, the two mutated copies of a particular gene result in the
lack or no production of enzyme called galactocerebrosidase (GALC).
The enzyme GALC are responsible for breaking down certain substances in a cell’s
recycling centre (lysosome). In the case of Krabbe disease, the short supply of GALC enzymes will
results in the accumulation of certain types of fats called galactolipids.
Galactolipids normally present in cells that produce and maintain the protective coating
of nerve cells (myelin). If the galactolipids is abundance, it causes a toxic effect. Some galactolipids
trigger myelin-forming cells to self-destruct.
Other galactolipids are taken up by specialized debris-eating cells in the nervous
system called microglia. The process of cleaning up excessive galactolipids will create an abnormal,
toxic cells called globoid cells, which then cause myelin-damaging inflammation.
The subsequent loss of myelin (demyelination) prevents nerve cells from sending and
receiving messages.
RISK FACTOR

The only risk factors for the occurrence of this disease is mutated gene. This disease
is categorized in the autosomal recessive disorder as it is the result from two mutated copies of
gene. If each parent has one mutated copy of the gene, the risk for a child would be as follows:
 A 25% chance of inheriting two mutated copies, which would result in the disease.
 A 50% chance of inheriting only mutated copy, which would result in the child being carrier
of the mutation but would not result in the disease itself.
 A 25% chance of inheriting two normal copies of the gene.

Genetic Testing

It is always a good preparation and planning to run genetic testing to better understand
the risk of having a child with Krabbe disease. It is advisable to have genetic testing in below
situations:
 If one or both parents are likely carriers of a GALC gene mutation because of a known family
history of Krabbe disease, a couple may want to have tests to understand the risks in their
own family.
 If one child is diagnosed with Krabbe disease, a family may consider genetic tests to identify
other children who could develop the disease later in life.
 If the parents are known carriers, they may request a prenatal genetic test to determine if
their child is likely to develop the disease.
 Known carriers, who are using in vitro fertilization, may request a genetic test with fertilized
eggs before implantation.
SIGNS & SYMPTOMS OF KRABBE DISEASE

Krabbe disease appear in babies during their first 2 to 5 months of life. The symptoms
then gradually and progressively worsen. The signs and symptoms vary in infants, older children and
adults.

1.1 Infants (early symptoms)

i Feeding difficulties
ii Unexplained crying
iii Extreme irritability
iv Fever with no sign of infection
v Declines in alertness
vi Delays in typical developmental milestones
vii Muscle spasms
viii Loss of head control
ix Frequent vomiting

1.2 Infants (severe symptoms)

i Seizures
ii Loss of developmental abilities
iii Progressive loss of hearing and sight
iv Rigid, constricted muscles
v Stiff, fixed posture
vi Progressive loss of ability to swallow and breathe

The signs and symptoms become vary in later childhood or during adulthood. The
symptoms include progressive loss of vision, difficulty walking (ataxia), decline in thinking skills, loss
of manual dexterity, and muscle weakness.
Krabbe disease in infants are a lot deadlier than in older children and adults. The
progress is faster and the symptoms is often severe. There are reportedly that some people
diagnosed during adolescence or adulthood may have less severe symptoms, with muscle weakness
as a primary condition. They may have no impairment of their thinking skills.
TREATMENT AND PREVENTION

Treatment

a. CORD BLOOD TRANSFUSION

There is a study of treatment using umbilical cord blood stem cells for infants with inherited Krabbe
disease conducted in 2005, reported in the New England Journal of Medicine. The study showed
positive outcomes for 100% of the infants who had umbilical cord stem cells implanted before they
began showing symptoms of the disease.
According to the study, “infants who underwent transplantation before the development of
symptoms showed progressive central myelination and continued gains in development skills, and
most had age-appropriate cognitive function and receptive language skills, but a few had mild-to-
moderate delays in expressive language and mild-to-severe delays in gross motor function.”
However, for infants who were already symptomatic before they received the treatment, the survival
rate was 43%.
Since then, the cord blood has become a standard treatment option for Krabbe disease if caught
pre-symptom. It may also be beneficial in older cases if the symptoms are mild. In either case, the
treatment uses allogeneic hematopoietic stem cell transplantation (HSCT), meaning the cord blood
would need to come from healthy sibling or matched unrelated donor.

b. BONE MARROW TRANSPLANTATION

This treatment requires the transplantation that replaces the patient’s bone marrow with a donor.
This will help introduce healthy cells into the body which can cure the deficiencies which cause the
disease. The bone marrow cells are haematopoietic – blood forming. This will become possible to
reconstitute an entire blood system using bone marrow cells.

Prevention

Early diagnosis is the best prevention method for Krabbe disease. It is important to know if there is
a family history of Krabbe disease. This piece of information can help in planning for pregnancy or
marriage and to discuss further with health care providers.
MALAYSIAN’S INSTITUTE FOR MEDICAL RESEARCH

Biochemistry Unit of the Institute for Medical Research, Ministry of Health

Malaysia have well established in the development of new diagnostic methods and provision of
specialised diagnostics services in particular for Inborn Error of Metabolism (IEM). The unit
conducts research projects in the field of IEM and related diseases where one of the objectives
is determining the incidence of various types of IEM in Malaysian Children. The unit is a reference
centre for IEM that provides consultation services, technology transfer and training on IEM and
Biochemical Genetic Testing.

There are numerous achievements that this institute has achieved such as
developed and set up more than 25 types of Biochemical Genetic Testing and become the
Referral Laboratory for Diagnosis of IEM by providing confirmatory testing for
 Amino acids disorders
 Organic acid disorders
 Carbohydrate disorders
 Peroxisomal diseases
 Lysosomal storage diseases
 Fatty acid oxidation defects

The institute also setting up Rapid screening of IEM in dried blood spot using
Tandem Mass Spectrometry (TMS);
 Method development for rapid screening
using TMS
 Establishment of reference ranges and
cut-off values
 An estimate of prevalence and incidence
of IEM in newborn in Malaysia
 Logistics and feasibility of newborn
screening programme
Figure 1 Tandem Mass Spectrometry For Rapid IEM Screening
 Newborn and high risk babies screening
test to screen/identify amino acid disorders, organic acid disorders and fatty acid oxidation
defects using Tandem Mass Spectrometry (LCMS/MS)
 They also setting up screening test and enzyme assay for Lysosomal Storage
Disorders;
 Mucopolysaccharidosis (MPS)
 Oligosaccharidosis
 Fabry disease
 Pompe disease
 Gaucher disease
 Krabbe disease
 Niemann-Pick disease

Private hospital can send their request for IEM screening with the form provided as below.

Figure 2 Newborn Screening For IEM (Source: https://www.imr.gov.my/index.php/en/sdc/55-biochemistry-unit/175-

objectives?profile=default)
Figure 3 Diagnostic Services (Source: https://www.imr.gov.my/en/sdc/55-english-content/centre/sdc/biochemistry-unit/173-activities-of-
biochemistry-unit)
References
Escolar, M. L., Poe, M. D., Provenzale, J. M., Richards, K. C., Allison, J., Wood, S., Wenger, D. A.,
Pietryga, D., Wall, D., Champagne, M., Morse, R., Krivit, W., & Kurtzberg, J. (2005).
Transplantation of Umbilical-Cord Blood in Babies with Infantile Krabbe’s Disease. New England
Journal of Medicine, 352(20), 2069–2081. https://doi.org/10.1056/nejmoa042604
How Cord Blood Transfusions can treat Krabbe Disease | Cells4Life. (n.d.). Retrieved January 30,
2021, from https://cells4life.com/2018/10/how-cord-blood-transfusions-can-treat-krabbe-disease/
Institute for Medical Research, Malaysia - Activities of Biochemistry Unit. (n.d.). Retrieved January 30,
2021, from https://www.imr.gov.my/en/sdc/55-english-content/centre/sdc/biochemistry-unit/173-
activities-of-biochemistry-unit
Institute for Medical Research, Malaysia - Objectives of Biochemistry Unit. (n.d.). Retrieved January
30, 2021, from https://www.imr.gov.my/en/sdc/55-english-content/centre/sdc/biochemistry-
unit/175-objectives-of-biochemistry-unit
Krabbe disease - Symptoms and causes - Mayo Clinic. (n.d.). Retrieved January 30, 2021, from
https://www.mayoclinic.org/diseases-conditions/krabbe-disease/symptoms-causes/syc-20374178
Treatment of Krabbe Disease with Umbilical Cord Stem Cells. (n.d.). Retrieved January 30, 2021,
from https://www.cordbloodbank.com/krabbe-disease-umbilical-cord-stem-cells/