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Globoid Cell Leukodystrophy

Krabbe disease

Globoid cell leukodystrophy is a rare, degenerative disease associated with progressive demyelination; symptom onset typically occurs in infancy. Globoid cell leukodystrophy may also be referred to as Krabbe disease.


Presentation

Patients suffering from type 1 GLC generally present during the first six months of their life. Parents may report feeding difficulties, vomiting, irritability, and developmental arrest, i.e., the infant initially shows normal development, but then development remains stagnant at a certain level. Physical examination generally reveals hyperesthesia and spasticity. Symptoms aggravate rapidly and within weeks or few months, affected infants lose the ability to control their movements, develop opisthotonus and reflex disturbances. They may suffer from epileptic seizures, lose their eyesight and hearing ability. Eventually, they present decerebrate posturing and die [10].

Late-onset GLC is also characterized by normal development until symptom onset. Type 2 GLC patients present before attaining the age of three years. Type 3 GLC may be diagnosed in pediatric patients that have not yet reached puberty. Later onset is considered type 4 GLC and progressive motor disturbance and visual impairment are often noted as first symptoms [11], but complaints described for type 1 GLC may also be experienced such as psychomotor arrest, deterioration, sensory disorders, spasticity, and seizures. Disease progression is usually much slower than in infantile GLC.

Feeding Difficulties
  • Symptoms begin between the ages of 3 and 6 months with irritability, fevers, limb stiffness, seizures, feeding difficulties, vomiting, and slowing of mental and motor development.[en.wikipedia.org]
  • Initial signs and symptoms typically include irritability, muscle weakness, feeding difficulties, episodes of fever without any sign of infection, stiff posture, and delayed mental and physical development.[ghr.nlm.nih.gov]
  • Symptoms of early-onset Krabbe disease are: Changing muscle tone from floppy to rigid Hearing loss that leads to deafness Failure to thrive Feeding difficulties Irritability and sensitivity to loud sounds Severe seizures (may begin at a very early age[nlm.nih.gov]
  • Symptoms include irritability, unexplained fever, limb stiffness, seizures, feeding difficulties, vomiting, and slowing of mental and motor development. Other symptoms include muscle weakness, spasticity, deafness, and blindness.[centogene.com]
Developmental Delay
  • The classic presentation includes excessive irritability, muscle hypertonicity, developmental delay, failure to thrive, peripheral neuropathy, seizures, and optic nerve atrophy.[ncbi.nlm.nih.gov]
  • Early developmental delay, however, occurred in 71% of patients with seizures and in only 6% of those without seizures. Patients with a later seizure onset also had a lower incidence of developmental delay and fewer special education needs.[emedicine.medscape.com]
  • Locations Specialties & Treatments Center for Autism Clinical Evaluation, Diagnosis And Treatment Clinical Trials Consultation and Long-term Care Department of Pediatric Neurology & Neurosurgery Diagnostic Genetic Evaluation of Developmental Delay Pediatric[my.clevelandclinic.org]
  • Some physicians advocate earlier surgery for seizures in order to protect against refractory seizures, developmental delays, cognitive dysfunction, and hemiparesis.[rarediseases.org]
  • These usually begin in the first few years of life and are often associated with developmental delay and hemispheric symptoms including hemiplegia/hemiparesis and hemianopsia.[radiopaedia.org]
Multiple Congenital Anomalies
  • Winter and Michael Baraitser, A catalogue of multiple congenital anomaly syndromes, Multiple Congenital Anomalies, 10.1007/978-1-4899-3109-2_1, (1-672), (1991). P. J. Willems, C. A. Garcia, M. C. H. Smedt, R. Martin‐Jimenez, J. K. Darby, D. A.[doi.org]
Irritability
  • The classic presentation includes excessive irritability, muscle hypertonicity, developmental delay, failure to thrive, peripheral neuropathy, seizures, and optic nerve atrophy.[ncbi.nlm.nih.gov]
  • Researchers are studying the use of low-dose morphine to help control marked irritability often associated with Krabbe disease. Initial results demonstrated that low-dose morphine treatment resulted in improvement of irritability.[rarediseases.org]
  • On examination, she was awake but irritable. She had poor visual fixation and tracking, but complete spontaneous extraocular movements. Mild optic atrophy and hyperactive gag reflex were noted.[neurology.org]
  • Parents may claim feeding difficulties, vomiting, and irritability. While development until symptom onset has been normal, infants suffering from GLC may manifest failure to thrive.[symptoma.com]
Ataxia
  • Clinically, the patient showed a remitting course marked by seizures, ataxia, white-matter disease on computed tomographic scan, and reduced conduction velocities of peripheral nerves. Symptoms improved somewhat around the age of 10 years.[ncbi.nlm.nih.gov]
  • The early symptoms include rotary movements of the head and eyes, which may vanish later in life, usually followed by spasticity of the legs and arms, cerebellar ataxia, dementia, and parkinsonian tremor.[icd9data.com]
  • The globoidcell leucodystrophy manifests itself in affected dogs at the age of 1-3 months, beginning with ataxia and paresis of the hind legs. During the progress of the disease, muscular atrophy and neurological degeneration oocur.[shop.labogen.com]
  • Patients with later onset forms usually present with ataxia, weakness, blindness, spastic paraparesis, behavioral problems, and dementia.[mhmedical.com]
Peripheral Neuropathy
  • The classic presentation includes excessive irritability, muscle hypertonicity, developmental delay, failure to thrive, peripheral neuropathy, seizures, and optic nerve atrophy.[ncbi.nlm.nih.gov]
  • Peripheral neuropathy is present in the infantile form and may be the only presenting abnormality in the later-onset forms ( Adachi et al 2016 ).[medlink.com]
  • Peripheral neuropathy is almost always detectable. Patients rarely survive the second year. While the infantile form is the most common, later onset forms are also recognized.[mhmedical.com]
  • The infantile (early and late) forms of Krabbe's disease show increased CSF proteins and delayed nerve conduction, whereas in the juvenile form, CSF findings remain normal with minimal peripheral neuropathy [1] .[ijri.org]
Tremor
  • They include blindness, tremors, incontinence and severe hind leg weakness. MRI findings are abnormal. References: McGraw, R.A., and Carmichael, K.P. (2006). Molecular basis of globoid cell leukodystrophy in Irish setters.[animalabs.com]
  • Postural tremor of limbs. Spasticity. Hyperreflexia. Clonus. Pyramidal paresis of limb or limbs. Extensor plantar responses. Unsteadiness of gait. Psychomotor retardation. Dysphagia. Deafness.[patient.info]
  • Both showed neurological signs mainly characterized by progressive pelvic limb ataxia, paraplegia with loss of deep pain perception in the pelvic limb, and intentional tremors of the thoracic limbs.[ncbi.nlm.nih.gov]
  • The early symptoms include rotary movements of the head and eyes, which may vanish later in life, usually followed by spasticity of the legs and arms, cerebellar ataxia, dementia, and parkinsonian tremor.[icd9data.com]
Spastic Paraplegia
  • paraplegia from the middle of the second decade, and all patients had diminished GALC activity in their leukocytes.[ncbi.nlm.nih.gov]
  • Late-onset krabbe disease (lokd) has first symptoms at ages 5 to 10 years, consisting of focal neurological signs, hemiparesis, cerebellar ataxia, cortical blindness, and spastic paraplegia, followed by mental and physical deterioration.[icd10data.com]

Workup

Neurological anomalies may prompt a strong suspicion of GLC, particularly in a patient with a familial history of leukodystrophy. Neuroimaging, lumbar puncture, measurement of GALC activity and genetic screens may be performed to confirm that tentative diagnosis.

In a GLC patient, magnetic resonance imaging or computed tomography of the head will reveal progressive cerebral atrophy. This pathologic process comprises both hemispheres, generally in a symmetric manner. Optic atrophy is another frequent finding. With regards to the preferred technique, demyelination is better visualized by magnetic resonance imaging.

Analysis of cerebrospinal fluid typically yields elevated levels of total protein and albumin as well as abnormal concentrations of distinct types of globulin.

GALC activity is measured in cell lysates from blood; activity levels are below 5% of physiological values. According to current practice, no differentiation between distinct types of GLC is possible on the basis of measured GALC activity. It has recently been proposed that evaluation of GALC activity in the lysosomal fraction may allow for such a distinction [12]. Of note, GALC activity may also be measured in amniocytes or chorionic villi and thus, prenatal diagnosis is feasible.

Genetic screens are required to identify carriers since heterozygous individuals will neither show neurological symptoms nor reduced GALC activity. Such analysis is of importance to determine carriers within a family and predict the risk of future offspring to inherit mutated alleles.

Cerebrospinal Fluid Abnormality
  • A lumbar puncture can be done to sample the cerebrospinal fluid. Abnormally high protein levels can indicate the disease. For a child to be born with the condition, both parents must carry the mutated gene — located on chromosome 14.[verywell.com]

Treatment

The only known therapeutic approach to infantile GLC is a hematopoietic stem cell transplantation, but its efficacy seems to be limited to patients who have not yet developed any symptoms. In these patients, symptom onset may be prevented or at least delayed. Life quality and life expectancy seem to increase after stem cell transplantation. In patients with late-onset GLC, psychomotor deterioration may be partially reversed [8]. Due to the risks associated with the procedure, clear criteria need to be established to decide whether an asymptomatic child who tested positive in genetic screens for GALC mutations should be subjected to stem cell transplantation.[9].

Otherwise, the treatment of GLC is mainly supportive and should be adjusted according to the needs of each individual patient.

Prognosis

Prognosis depends on the age of symptom onset. Type 1 GLC is diagnosed during the first six months of life and is associated with a life expectancy of little more than one year; patients diagnosed with type 2 GLC usually die within two years of onset of first symptoms. In general, patients affected by type 3 or 4 GLC live considerably longer.

Prognosis may be improved by hematopoietic stem cell transplantation if this procedure is carried out in neonates before symptom onset [8]. However, treatment of an asymptomatic child is not without risks and the possibility of false-positive results of genetic screens should seriously be considered [9].

Etiology

Mutations of the gene encoding for GALC account for all GLC cases described so far. This gene is located on the long arm of chromosome 14, position 31. It comprises 19 exons and more than 70 mutations distributed throughout the whole sequence have been related to GLC [3]. They may render GALC catalytically inactive or interfere with protein trafficking and hinder its transport to the lysosome. Although the disease is generally described as being inherited with an autosomal recessive trait, it may not always be possible to directly correlate the genotype of a patient with the course of the disease. Compound patterns of heterozygous and homozygous polymorphisms further complicate the issue.

Additional factors contributing to the etiology of GLC cannot be ruled out. Such an assumption is supported by the fact that individuals with identical sequences of the GALC gene may show different clinical presentations [3].

Epidemiology

The overall incidence of GLC has been estimated to be approximately 1 per 100,000 inhabitants. The incidence rate in certain ethnic minorities significantly deviates from the average. In the highly inbred community of Israeli Druze, for instance, GLC incidence rates are as high as 6 per 1,000 individuals [4].

Sex distribution
Age distribution

Pathophysiology

As has been indicated above, all genetic defects related to GLC affect GALC function. This lysosomal enzyme is essential for myelin metabolism, namely in the degradation of sphingolipids. Its substrates are galactocerebroside, psychosine, and other galactose-containing cerebrosides. Galactocerebroside and psychosine are synthesized via galactosylation of ceramide and sphingosine, respectively, and constitute considerable shares of the myelin sheaths that encompass the majority of axons in the central and peripheral nervous system.

Myelination is not a one-off matter and in fact, myelin formation and degradation continue throughout life. The turnover rates vary, though, and are highest during infancy. They decline during childhood and adolescence and finally reach a steady state in the third decade of life. An important step in myelin degradation is hydrolysis of galactocerebroside and psychosine to ceramide, sphingosine, and galactose, respectively. This step is catalyzed by GALC and consequently, functional deficits of this enzyme will manifest in early life.

The low catalytic activity of GALC causes an accumulation of its substrates and these are assumed to mediate cytotoxic effects. Thus, myelination is not only impaired by disturbances in turnover, but also by a reduced production of white matter. According to current knowledge, psychosine is the main trigger of oligodendrocyte and Schwann cell apoptosis [5].

Also, neuroinflammation may contribute to GCL progression. On the one hand, psychosine may directly trigger the release of proinflammatory cytokines [6]. On the other hand, macrophages take up GALC substrates by phagocytosis and turn into globoid cells. To date, it is not clear how neuroinflammation affects the course of the disease, but with regards to diagnosis, globoid cells are of major importance.

The molecular mechanisms behind demyelination and neurodegeneration are only incompletely understood, but phospholipase A2 activation has been suggested as a possible intermediate step and may eventually be considered in drug development [7].

Prevention

Affected families may benefit from genetic counseling. Additionally, neonatal screens for GLC-related gene mutations have been proposed as a possible measure to identify children who are likely to develop the disease. Here, hematopoietic stem cell transplantation may be carried out prior to symptom onset. However, the high rates of false-positive screening results, the risks associated with repeated testing and stem cell transplantation itself as well as the uncertain usefulness of this procedure argue against population-wide neonatal screens for GALC mutations [9]. Genetic testing is indicated, though, in children born to families with a known history of GLC.

Summary

Globoid cell leukodystrophy (GCL) is a rare, degenerative disease caused by mutations affecting the gene encoding for the enzyme galactocerebrosidase (GALC; also designated galactosylceramidase). This enzyme plays a major role in myelin metabolism, it degrades sphingolipids like galactocerebroside (also referred to as galactosylceramide) and psychosine (also termed galactosyl sphingosine). Consequently, functional impairment of GALC leads to an abnormal accumulation of these lipids. This interferes with myelin turnover and subsequent myelin synthesis. Additionally, cytotoxic effects - presumably mediated by psychosine - are observed in GCL patients. Myelin-forming cells undergo apoptosis, which further diminishes myelin production.

Galactocerebroside and psychosine are synthesized by both oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system and thus, the afore-described anomalies may be observed in any nervous tissue. The morphologic equivalents of this pathophysiological development are a loss of myelin and myelin-forming cells, reactive astrogliosis, and infiltration of affected sites with multi-nucleated macrophages, which are designated globoid cells and have given this white matter disease its name [1]. Of note, myelin synthesis itself is not disturbed and while myelin quantities are significantly decreased in GCL patients, myelin quality is unaltered.

The disease was first described by the Danish neurologist Knud Krabbe who documented a progressive neurologic disorder characterized by irritability, seizures and psychomotor deterioration in infants [2]. These symptoms are still considered typical for GLC and in most cases, they are first observed in infants aged less than two years. However, additional cases of late symptom onset have been reported by now. Four types of the disease can be distinguished:

Types 2, 3 and 4 are often referred to as late-onset GLC.

Symptoms differ only slightly between all these types of GLC, but disease progression is less pronounced in those individuals with advanced age at symptom onset. While type 1 GLC is generally fatal within one year, individuals affected by late-onset GLC may live for several years. Nevertheless, life expectancy is considerably reduced for all GLC patients.

Treatment consists of hematopoietic stem cell transplantation - the earlier, the better. Best effects are achieved if stem cell transplantation is carried out before symptom onset in early infancy. Thus, neonatal screening for GLC-related genetic defects may be the only chance for an affected child to receive their therapy in a timely manner. In some places, such screenings have already been implemented.

Patient Information

Globoid cell leukodystrophy (GLC) is a rare genetic disorder. In order to understand the pathophysiology of the disease, certain background knowledge regarding nerve function is required. Nerve cells consist of a small body or soma and a rather long appendix or tail referred to as an axon. In fact, the soma may measure only a few micrometers in diameter, but the axon of a nerve cell may measure up to one meter. Most axons are insulated by a myelin sheath which is important for signal conduction. In GLC, myelin sheaths of axons pertaining to the central and peripheral nerve systems degenerate progressively.

Causes

Specialized cells, namely oligodendrocytes and Schwann cells, produce myelin. However, myelin formation is not a one-off matter and a considerable turnover can be observed during the first years of life. In fact, myelin turnover reaches its peak within the first two years of life and subsequently declines until a steady state is reached in the third decade of life.

In GLC patients, myelin degradation is strongly inhibited due to defective synthesis of an essential enzyme. The name of that enzyme is galactocerebrosidase. It's functional impairment results in accumulation of cytotoxic metabolites, oligodendrocyte and Schwann cell death, demyelination and neurodegeneration.

Symptoms

In most cases, GLC-associated symptoms manifest during the first six months of a child's life. Parents may claim feeding difficulties, vomiting, and irritability. While development until symptom onset has been normal, infants suffering from GLC may manifest failure to thrive. Their muscle tone is altered, they may lose the ability to control their movements. Epileptic seizures, blindness, and deafness are also observed. Symptoms aggravate rapidly.

Similar symptoms may indicate GLC onset in later years of life, but disease progression is usually slower in these cases.

Diagnosis

Diagnosis is based on neurological examination, magnetic resonance imaging or computed tomography scans of the head, measurement of enzymatic activity in blood cells, as well as genetic screens.

Neuroimaging typically reveals progressive, bilateral cerebral atrophy and optic atrophy. Galactocerebrosidase activity is strongly reduced. Of note, this test may also be carried out in amniocytes or chorionic villi and thus, prenatal diagnosis is feasible. This option should be considered in families with a known medical history of GLC. These families may also benefit from genetic screens.

Treatment

There is no curative treatment for GLC and the prognosis is poor. Most patients suffering from infantile GLC die within one or two years of symptom onset. Those individuals presenting with late-onset GLC, i.e., symptoms manifesting after the third year of life, may live for a few years longer. However, progressive exacerbation of symptoms is to be expected.

To date, the only treatment known to be effective in GLC is a hematopoietic stem cell transplantation. This procedure should be carried out before an infant develops any symptoms and is therefore based on early diagnosis by means of measurement of enzymatic activity and genetic screens. Repeated testing and hematopoietic stem cell transplantation itself is not without risks. Pros and cons should be thoroughly considered before taking that measure.

References

Article

  1. Suzuki K. Globoid cell leukodystrophy (Krabbe's disease): update. J Child Neurol. 2003; 18(9):595-603.
  2. Krabbe K. A new familial, infantile form of diffuse brain sclerosis. Brain. 1916;39:74.
  3. Deane JE, Graham SC, Kim NN, et al. Insights into Krabbe disease from structures of galactocerebrosidase. Proc Natl Acad Sci U S A. 2011; 108(37):15169-15173.
  4. Zlotogora J, Regev R, Zeigler M, Iancu TC, Bach G. Krabbe disease: increased incidence in a highly inbred community. Am J Med Genet. 1985; 21(4):765-770.
  5. Hill CH, Graham SC, Read RJ, Deane JE. Structural snapshots illustrate the catalytic cycle of beta-galactocerebrosidase, the defective enzyme in Krabbe disease. Proc Natl Acad Sci U S A. 2013; 110(51):20479-20484.
  6. Giri S, Jatana M, Rattan R, Won JS, Singh I, Singh AK. Galactosylsphingosine (psychosine)-induced expression of cytokine-mediated inducible nitric oxide synthases via AP-1 and C/EBP: implications for Krabbe disease. Faseb J. 2002; 16(7):661-672.
  7. Giri S, Khan M, Rattan R, Singh I, Singh AK. Krabbe disease: psychosine-mediated activation of phospholipase A2 in oligodendrocyte cell death. J Lipid Res. 2006; 47(7):1478-1492.
  8. Krivit W, Shapiro EG, Peters C, et al. Hematopoietic stem-cell transplantation in globoid-cell leukodystrophy. N Engl J Med. 1998; 338(16):1119-1126.
  9. Lantos JD. Dangerous and expensive screening and treatment for rare childhood diseases: the case of Krabbe disease. Dev Disabil Res Rev. 2011; 17(1):15-18.
  10. Bernardi B, Fonda C, Franzoni E, Marchiani V, Della Guistina E, Zimmerman RA. MRI and CT in Krabbe's disease: case report. Neuroradiology. 1994; 36(6):477-479.
  11. Lyon G, Hagberg B, Evrard P, Allaire C, Pavone L, Vanier M. Symptomatology of late onset Krabbe's leukodystrophy: the European experience. Dev Neurosci. 1991; 13(4-5):240-244.
  12. Shin D, Feltri ML, Wrabetz L. Altered Trafficking and Processing of GALC Mutants Correlates with Globoid Cell Leukodystrophy Severity. J Neurosci. 2016; 36(6):1858-1870.

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Last updated: 2019-07-11 20:22