Krabbe disease (KD) (also known as globoid cell leukodystrophy
or galactosylceramide lipidosis) is a rare and often fatal
lysosomal storage disease
Lysosomal storage diseases (LSDs; ) are a group of over 70 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other ...
that results in progressive
damage to the nervous system. KD involves
dysfunctional metabolism of sphingolipids and is inherited in an
autosomal recessive pattern. The disease is named after the Danish
neurologist
Neurology (from el, νεῦρον (neûron), "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the brain, the spinal c ...
Knud Krabbe (1885–1961).
Signs and symptoms
Symptoms in asymptomatic infantile-onset (<12 months after birth) and later-onset Krabbe disease present themselves differently. Of individuals with infantile-onset Krabbe disease, 85–90% display progressive neurologic deterioration in infancy and death before the age of two.
Symptoms include
irritability
Irritability (also called as crankiness) is the excitatory ability that living organisms have to respond to changes in their environment. The term is used for both the physiological reaction to stimuli and for the pathological, abnormal or excessi ...
,
fever
Fever, also referred to as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using val ...
s, limb stiffness,
seizure
An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with l ...
s,
feeding difficulties
Dysphagia is difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, in some contexts it is classified as a disease#Terminology, condition in its own right.
It may be a sensation that suggests difficulty in the passag ...
(like
GERD Gerd or GERD may refer to:
* Gerd (given name), a list of people with the given name or nickname
* Gerd (moon), a moon of Saturn
* Gerd Island, South Orkney Islands, Antarctica
* Gastroesophageal reflux disease, a chronic symptom of mucosal damage ...
),
vomiting
Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose.
Vomiting can be the result of ailments like food poisoning, gastroenteri ...
, staring episodes, and slowing of mental and motor
development
Development or developing may refer to:
Arts
*Development hell, when a project is stuck in development
*Filmmaking, development phase, including finance and budgeting
*Development (music), the process thematic material is reshaped
* Photograph ...
. In the first stages of the disease, doctors often mistake the symptoms for those of
cerebral palsy
Cerebral palsy (CP) is a group of movement disorders that appear in early childhood. Signs and symptoms vary among people and over time, but include poor coordination, stiff muscles, weak muscles, and tremors. There may be problems with sens ...
. Other symptoms include
muscle weakness,
spasticity
Spasticity () is a feature of altered skeletal muscle performance with a combination of paralysis, increased tendon reflex activity, and hypertonia. It is also colloquially referred to as an unusual "tightness", stiffness, or "pull" of muscles ...
,
deafness
Deafness has varying definitions in cultural and medical contexts. In medical contexts, the meaning of deafness is hearing loss that precludes a person from understanding spoken language, an audiological condition. In this context it is written ...
,
optic atrophy Optic neuropathy is damage to the optic nerve from any cause. The optic nerve is a bundle of millions of fibers in the retina that sends visual signals to the brain.
Damage and death of these nerve cells, or neurons, leads to characteristic featu ...
, optic nerve enlargement, blindness, paralysis, and
difficulty when swallowing. Prolonged weight loss may also occur.
10–15% of individuals with later-onset Krabbe disease have a much slower disease progression. These individuals may also display symptoms such as
esotropia
Esotropia is a form of strabismus in which one or both eyes turns inward. The condition can be constantly present, or occur intermittently, and can give the affected individual a "cross-eyed" appearance. It is the opposite of exotropia and usual ...
, slurred speech, and slow development or loss of motor milestones.
Causes
Krabbe disease is caused by
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA replication, DNA or viral repl ...
s in the ''
GALC
Galactosylceramidase (or galactocerebrosidase) is an enzyme that in humans is encoded by the ''GALC'' gene. Galactosylceramidase is an enzyme which removes galactose from ceramide derivatives ( galactosylceramides).
Galactosylceramidase is a lys ...
''
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
located on
chromosome 14
Chromosome 14 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 14 spans about 107 million base pairs (the building material of DNA) and represents between 3 and 3.5% of the total DNA ...
(14q31), which is inherited in an
autosomal recessive manner. Mutations in the ''GALC'' gene cause a deficiency of an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
called
galactosylceramidase. In rare cases, it may be caused by a lack of active saposin A (a derivative of
prosaposin
Prosaposin, also known as PSAP, is a protein which in humans is encoded by the ''PSAP'' gene.
This highly conserved glycoprotein is a precursor for 4 cleavage products: saposins A, B, C, and D. Saposin is an acronym for Sphingolipid Activator Pr ...
).
The buildup of unmetabolized
lipid
Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids includ ...
s adversely affects the growth of the nerve's protective
myelin sheath
Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be l ...
(the covering that insulates many
nerves) resulting in
demyelination
A demyelinating disease is any disease of the nervous system in which the myelin sheath of neurons is damaged. This damage impairs the conduction of signals in the affected nerves. In turn, the reduction in conduction ability causes deficiency i ...
and severe progressive degeneration of motor skills. As part of a group of disorders known as
leukodystrophies
Leukodystrophies are a group of usually inherited disorders characterized by degeneration of the white matter in the brain. The word ''leukodystrophy'' comes from the Greek roots ''leuko'', "white", ''dys'', "abnormal" and ''troph'', "growth". Th ...
, Krabbe disease results from the imperfect growth and development of myelin.
Galactosylceramidase deficiency also results in a buildup of a
glycosphingolipid
Glycosphingolipids are a subtype of glycolipids containing the amino alcohol sphingosine. They may be considered as sphingolipids with an attached carbohydrate. Glycosphingolipids are a group of lipids (more specifically, sphingolipids) and are a ...
called
psychosine, which is toxic to
oligodendrocyte
Oligodendrocytes (), or oligodendroglia, are a type of neuroglia whose main functions are to provide support and insulation to axons in the central nervous system of jawed vertebrates, equivalent to the function performed by Schwann cells in the ...
s, a type of non-neuronal cell found in the nervous system, collectively termed
neuroglia.
Diagnosis
There are a few ways to help pinpoint the presence of Krabbe disease. Newborn screening for Krabbe disease includes
assaying dried blood cells for
GALC
Galactosylceramidase (or galactocerebrosidase) is an enzyme that in humans is encoded by the ''GALC'' gene. Galactosylceramidase is an enzyme which removes galactose from ceramide derivatives ( galactosylceramides).
Galactosylceramidase is a lys ...
enzyme activity and molecular analysis for evidence of GALC enzyme mutations. Infants displaying low enzyme activity and/or enzyme mutations should be referred for additional diagnostic testing and neurological examination. 0-5% GALC enzyme activity is observed in all symptomatic individuals with Krabbe disease.
High concentration of
psychosine in dried blood spots may also be identified as a marker for Krabbe disease. A 2011 study discovered that individuals with Krabbe disease, more so in later-onset individuals, tend to have an abnormal increase in CSF protein concentration.
The disease may be diagnosed by its characteristic grouping of certain cells (multinucleated globoid cells), nerve demyelination and degeneration, and destruction of brain cells. Special stains for
myelin
Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be ...
(e.g.,
luxol fast blue
Luxol fast blue stain, abbreviated LFB stain or simply LFB, is a commonly used stain to observe myelin under light microscopy, created by Heinrich Klüver and Elizabeth Barrera in 1953. LFB is commonly used to detect demyelination in the central ...
) may be used to aid diagnosis.
New York, Missouri and Kentucky include Krabbe in the
newborn screening
Newborn screening (NBS) is a public health program of screening in infants shortly after birth for conditions that are treatable, but not clinically evident in the newborn period. The goal is to identify infants at risk for these conditions e ...
panel. Indiana started screening in 2020.
Treatment
Although there is no known
cure for Krabbe disease,
bone marrow transplantation
Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produce ...
or
hematopoietic stem cell transplantation
Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produce ...
(HSCT) has been shown to benefit cases early in the course of the disease. Generally, treatment for the disorder is
symptomatic
Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showi ...
and
supportive.
Physical therapy may help maintain or increase
muscle tone and circulation.
A 15-year study on the developmental outcomes of children with Krabbe disease who underwent HSCT in the first seven weeks after birth found that patients have a better prognosis for both lifespan and functionality, with a slower progression of the disease. Even symptomatic individuals with later-onset Krabbe disease may benefit from HSCT if diagnosed early enough. Umbilical-cord blood is typically used as the source for the transplant stem cells.
Clinical trials for gene therapy are currently enrolling patients.
Management
Symptom management can be particularly difficult for individuals with infantile onset, as symptoms tend to progress rapidly.
Because there is no treatment for Krabbe disease, management of the condition is typically supportive and aimed at alleviating symptoms. Frequent evaluation is encouraged in order to anticipate the onset of, and preparation for, certain symptoms.
Physical therapy can help to alleviate motor difficulties and increase strength, mobility, and flexibility.
Gastrostomy tubes are used to circumvent feeding difficulties and prevent aspiration. A simultaneous gastrostomy tube insertion and
Nissen fundoplication
A Nissen fundoplication, or laparoscopic Nissen fundoplication when performed via laparoscopic surgery, is a surgical procedure to treat gastroesophageal reflux disease (GERD) and hiatal hernia. In GERD, it is usually performed when medical thera ...
procedure is commonly performed to prevent the need for a secondary surgical procedure.
Individuals with Krabbe disease with severe motor deficits tend to be more susceptible to overfeeding, as they require less calorie consumption and thus consume fewer calories than what caretakers may expect.
There is also evidence that routine vaccines may accelerate disease progression; many individuals with Krabbe disease tend to not follow traditional vaccination procedures.
Prognosis
In infantile Krabbe disease, death usually occurs in early childhood. A 2011 study found one-, two-, and three-year
survival rates of 60%, 26%, and 14%, respectively, with a few surviving longer. Patients with late-onset Krabbe disease tend to have a slower progression of the disease and live significantly longer.
Epidemiology
This disease does not only impact humans, but other animals such as monkeys, mice, and dogs have been observed to develop Krabbe disease as well. While certain gene deletions are more frequent than others, novel mutations resulting in Krabbe disease have been discovered worldwide. Most commonly, the underlying cause of the disease is a deletion of a GALC gene, which causes a deficiency in the GALC enzyme. This is the circumstance in 80% of patients who have European and Mexican origins.
The mortality rate of early infantile Krabbe disease is 90% before the age of two. Later onset of symptoms is associated with longer life expectancy, with older children generally surviving two to seven years after the initial diagnosis.
Krabbe disease occurs in about one in 100,000 births.
Because the disease is genetic, incidence rates vary widely from population to population.
The incidence rate is extremely low in Japan, with between 5 and 10 cases per 1,000,000 live births. In the United States, Krabbe disease occurs in approximately 1 out of every 100,000 live births.
Scandinavian countries
Scandinavia; Sámi languages: /. ( ) is a subregion in Northern Europe, with strong historical, cultural, and linguistic ties between its constituent peoples. In English usage, ''Scandinavia'' most commonly refers to Denmark, Norway, and Swede ...
report incidence rates of one in 50,000 births. In certain communities Krabbe disease is much more frequent, such as the
Druze community in Israel
Israeli Druze or Druze Israelis ( ar, الدروز الإسرائيليون; he, דְּרוּזִים יִשְׂרְאֵלִים) are an ethnoreligious minority among the Arab citizens of Israel. In 2019, there were 143,000 Druze people livin ...
, which has an incidence rate of 6 out of every 1,000 live births.
This higher rate is thought to be due in part to a high frequency of
consanguineous marriages. Almost 35% of all Druze marriages were found to be between first-cousin familial relations. There have been no reported cases of Krabbe disease among the Jewish community.
Time of onset also varies in frequency by location. Early infantile Krabbe Disease is the most common form of the disease overall, but Nordic communities tend to have even higher rates of early infantile onset Krabbe disease, while Southern European countries have higher incidences of late-onset cases. It is difficult to estimate the incidence of adult-onset Krabbe disease, due to discrepancies in classifying cases late-onset versus adult-onset.
Society and culture
Former
Buffalo Bills quarterback
Jim Kelly
James Edward Kelly (born February 14, 1960) is a former American football quarterback who played in the National Football League (NFL) for 11 seasons with the Buffalo Bills. He also spent two seasons with the Houston Gamblers of the United Stat ...
has been a leader in gaining recognition and research funding for Krabbe disease following the diagnosis of his son, Hunter, in 1997. Hunter Kelly died of the disease on August 5, 2005, at the age of eight. They create
Hunter's Hope- a foundation that seeks to advance Newborn Screening, research and treatments, and provides support to families of leukodystrophy children.
Family advocacy is a critical part of advancing newborn screening, and many Krabbe families have made significant advocacy progress in their states.
As an example, Cove Ellis is a child from
Georgia, United States
Georgia is a state in the Southeastern United States, Southeastern region of the United States, bordered to the north by Tennessee and North Carolina; to the northeast by South Carolina; to the southeast by the Atlantic Ocean; to the south by ...
who was diagnosed with the disease in early 2016. Ellis' family, along with her community, has worked to raise awareness of the disease and helped pass "Cove's Law", which provides parents the option to have
prenatal screening
Prenatal testing consists of prenatal screening and prenatal diagnosis, which are aspects of prenatal care that focus on detecting problems with the pregnancy as early as possible. These may be anatomic and physiologic problems with the health o ...
for the disease, which can, potentially, save the child from the morbidity and mortality of Krabbe disease.
Other animals
Krabbe disease is found in mice may also be found in cats
and in dogs, particularly the
West Highland White Terrier
The West Highland White Terrier, commonly known as the Westie, is a breed of dog from Scotland with a distinctive white harsh coat with a somewhat soft white undercoat. It is a medium-sized terrier, although with longer legs than other Scot ...
s and
Cairn Terrier
The Cairn Terrier is a terrier breed originating in the Scottish Highlands and recognized as one of Scotland's earliest working dogs. The breed was given the name Cairn because the breed's function was to hunt and chase quarry between the ca ...
s.
NYtimes.com
/ref>
See also
* Maria Luisa Escolar
* The Myelin Project
The Myelin Project is 501(c)(3) nonprofit organization established in 1989 by Augusto Odone and his wife, Michaela. Their son, Lorenzo, suffered from adrenoleukodystrophy (ALD), the most common of the leukodystrophies. The story of the Odones' s ...
* The Stennis Foundation The Stennis Foundation is a registered nonprofit organization based in the U.S. The foundation is primarily a fundraising organization, sending money to various research projects. Currently, the Stennis Foundation supports research at Duke, Kennedy ...
KrabbeConnect
The Legacy of Angels Foundation
Hunter's Hope Foundation
References
''This article incorporates public domain text from the United States National Library of Medicine
The United States National Library of Medicine (NLM), operated by the United States federal government, is the world's largest medical library.
Located in Bethesda, Maryland, the NLM is an institute within the National Institutes of Health. Its ...
and the National Institute of Neurological Disorders and Stroke.''
External links
GeneReviews/NCBI/NIH/UW entry on Krabbe disease
OMIM entries on Krabbe disease
{{DEFAULTSORT:Krabbe Disease
Leukodystrophies
Rare diseases
Lipid storage disorders
Autosomal recessive disorders
Demyelinating diseases of CNS
Neurological disorders in children