Metachromatic leukodystrophy: Difference between revisions
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==Differentiating {{PAGENAME}} from Other Diseases== | ==Differentiating {{PAGENAME}} from Other Diseases== | ||
==Differential diagnosis== | |||
Metachromatic leukodystrophy must be differentiated from other diseases that cause neurological manifestations in infants. | |||
{| | |||
|- style="background: #4479BA; color: #FFFFFF; text-align: center;" | |||
! rowspan="2" |Diseases | |||
! colspan="4" |Type of motor abnormality | |||
! rowspan="2" |Clinical findings | |||
! rowspan="2" |Laboratory findings and diagnostic tests | |||
! rowspan="2" |Radiographic findings | |||
|- style="background: #4479BA; color: #FFFFFF; text-align: center;" | |||
!Spasticity | |||
!Hypotonia | |||
!Ataxia | |||
!Dystonia | |||
|- | |||
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Leigh syndrome]] | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" |<nowiki>+</nowiki> | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* Progressive [[psychomotor]] regression | |||
* [[Seizures]] | |||
* External [[ophthalmoplegia]] | |||
* [[Lactic acidosis]] | |||
* [[Vomiting]] | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* Increased [[lactate]] levels in [[blood]] and [[CSF]] | |||
* Genetic testing | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* MRI: abnormal [[white matter]] signal in the [[putamen]], [[basal ganglia]], and [[brainstem]] on T2 images | |||
|- | |||
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Niemann-Pick]] disease type C | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* Progressive [[neurodegeneration]] | |||
* [[Hepatosplenomegaly]] | |||
* Systemic involvement of [[liver]], [[spleen]], or [[lung]] preceedes [[neurologic]] symptoms | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* Abnormal [[liver]] function tests | |||
* [[Fibroblast]] cell culture with filipin staining | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* MRI: | |||
**[[Cerebral]] and [[cerebellar]] [[atrophy]] | |||
**Thinning of the [[corpus callosum]] | |||
|- | |||
| style="background: #DCDCDC; padding: 5px; text-align: center;" |Infantile Refsum disease | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* Abnormalities of the [[optic nerve]] and disc | |||
* [[Retinitis pigmentosa]] | |||
* [[Sensorineural]] hearing loss | |||
* [[Hepatomegaly]] and [[cirrhosis]] | |||
* [[Neurologic]] deterioration is slower than in [[Zellweger syndrome]] or ALD | |||
| style="background: #F5F5F5; padding: 5px;" |Elevated plasma VLCFA levels | |||
| style="background: #F5F5F5; padding: 5px; text-align: center;" |-- | |||
|- | |||
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Adrenoleukodystrophy]] | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* [[Cognitive]] and behavioral abnormalities | |||
* [[Adrenal insufficiency]] | |||
* [[Hyperpigmented]] skin | |||
* [[Gonadal dysfunction]] | |||
* [[Neurologic]] deterioration progresses at a variable rate | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* Elevated plasma VLCFA levels | |||
* Molecular [[genetic testing]] for mutations in the ABCD1 gene | |||
| style="background: #F5F5F5; padding: 5px; text-align: center;" |-- | |||
|- | |||
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Zellweger syndrome]] | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* [[Craniofacial]] dysmorphism | |||
* [[Hepatomegaly]] | |||
* Neonatal [[seizures]] | |||
* Profound developmental delay | |||
* [[MRI]] findings include [[cortical]] and [[white matter]] abnormalities | |||
* [[Neurologic deterioration]] is rapid and infants rarely survive beyond six months of age | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* Elevated plasma VLCFA levels | |||
* Elevated levels of [[phytanic acid]], pristanic acid, and pipecolic acid in plasma and [[fibroblasts]] | |||
* Reduced plasmalogen in [[erythrocytes]] | |||
* Molecular [[genetic]] testing for [[mutations]] in the PEX1 or PEX6 genes | |||
| style="background: #F5F5F5; padding: 5px; text-align: center;" |-- | |||
|- | |||
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Pyruvate dehydrogenase deficiency]] | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* [[Lactic acidosis]] | |||
* [[Seizures]] | |||
* [[Intellectual disability]] | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* Elevated [[lactate]] and pyruvate levels in [[blood]] and CSF | |||
* Abnormal PDH enzymatic activity in cultured fibroblasts | |||
| style="background: #F5F5F5; padding: 5px; text-align: center;" |-- | |||
|- | |||
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Arginase deficiency]] | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* [[Hyperammonemia]] | |||
* [[Encephalopathy]] | |||
* [[Respiratory alkalosis]] | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* Elevated [[ammonia]] level | |||
* Elevated [[arginine]] level | |||
| style="background: #F5F5F5; padding: 5px; text-align: center;" |-- | |||
|- | |||
| style="background: #DCDCDC; padding: 5px; text-align: center;" |Holocarboxylase synthetase deficiency | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* [[Ketoacidosis]] | |||
* [[Dermatitis]] | |||
* [[Alopecia]] | |||
* [[Seizures]] | |||
* [[Developmental delay]] | |||
| style="background: #F5F5F5; padding: 5px;" |Elevated levels of: | |||
* Beta-hydroxyisovalerate | |||
* Beta-methylcrotonylglycine | |||
* Beta-hydroxypropionate | |||
* Methylcitrate | |||
* Tiglylglycine | |||
| style="background: #F5F5F5; padding: 5px; text-align: center;" |-- | |||
|- | |||
| style="background: #DCDCDC; padding: 5px; text-align: center;" |Glutaric aciduria type 1 | |||
| style="background: #F5F5F5; padding: 5px;" |<nowiki>-</nowiki> | |||
| style="background: #F5F5F5; padding: 5px;" |<nowiki>-</nowiki> | |||
| style="background: #F5F5F5; padding: 5px;" |<nowiki>-</nowiki> | |||
| style="background: #F5F5F5; padding: 5px;" |<nowiki>+</nowiki> | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* Episodes of [[metabolic decompensation]] and [[encephalopathy]] often precipitated by [[infection]] and [[fever]] | |||
* Rarely presents in the newborn period | |||
* Microencephalic [[macrocephaly]] | |||
* [[Seizures]] (approximately 20 percent) | |||
* [[Cognitive function]] is preserved | |||
| style="background: #F5F5F5; padding: 5px;" |Elevated levels of: | |||
* [[glutaric acid]] | |||
* 3-hydroxyglutaric acid | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* MRI: | |||
**[[Frontal]] and [[temporal]] [[atrophy]] | |||
|- | |||
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Ataxia telangiectasia]] | |||
| style="background: #F5F5F5; padding: 5px;" |<nowiki>-</nowiki> | |||
| style="background: #F5F5F5; padding: 5px;" |<nowiki>-</nowiki> | |||
| style="background: #F5F5F5; padding: 5px;" |<nowiki>+</nowiki> | |||
| style="background: #F5F5F5; padding: 5px;" |<nowiki>-</nowiki> | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* Progressive [[cerebellar]] [[ataxia]] | |||
* Abnormal eye movements | |||
* [[Oculocutaneous]] [[telangiectasias]] | |||
* Immune deficiency | |||
* Increased risk of [[malignancy]] | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* Elevated serum alpha-fetoprotein level | |||
* Low [[IgA]] and [[IgG]] levels | |||
* [[Lymphopenia]] | |||
* Genetic testing for [[mutation]] in the ATM gene | |||
| style="background: #F5F5F5; padding: 5px; text-align: center;" |-- | |||
|- | |||
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Pontocerebellar]] [[hypoplasias]] | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* Progressive muscle [[atrophy]] | |||
* [[Microcephaly]] | |||
* [[Developmental delay]] | |||
| style="background: #F5F5F5; padding: 5px;" |[[Genetic]] testing for PCH gene mutations | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* MRI : | |||
**Small [[cerebellum]] and [[brainstem]] including the [[pons]] | |||
|- | |||
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Metachromatic leukodystrophy]] | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* Regression of motor skills | |||
* [[Seizures]] | |||
* [[Optic atrophy]] | |||
* Reduced or absent [[deep tendon reflexes]] | |||
* [[Intellectual disability]] | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* Deficient arylsulfatase A enzyme activity in [[leukocytes]] or cultured skin fibroblasts | |||
| style="background: #F5F5F5; padding: 5px; text-align: center;" |-- | |||
|- | |||
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Pelizaeus-Merzbacher]] | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* [[Nystagmus]] | |||
* [[Cognitive impairment]] | |||
* Onset in infancy | |||
* Slowly progressive | |||
* Language development may be normal | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* [[Genetic]] testing for [[mutations]] in PLP1 gene | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
*MRI: | |||
**[[White matter]] abnormalities | |||
|- | |||
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Angelman syndrome]] | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* Profound [[intellectual disability]] | |||
* Postnatal [[microcephaly]] | |||
* Typical abnormal behaviors (paroxysmal laughter, easily excitable) | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* Methylation studies and [[chromosome]] microarray to detect chromosome 15 anomalies and UBE3A mutations | |||
| style="background: #F5F5F5; padding: 5px; text-align: center;" |-- | |||
|- | |||
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Rett syndrome]] | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* Occurs almost exclusively in females | |||
* Normal development during first six months followed by regression and loss of milestones | |||
* Loss of speech capability | |||
* Stereotypic hand movements | |||
* [[Seizures]] | |||
* [[Autistic]] features | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* Clinical diagnosis | |||
* [[Genetic]] testing for MECP2 mutations | |||
| style="background: #F5F5F5; padding: 5px; text-align: center;" |-- | |||
|- | |||
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Lesch-Nyhan syndrome]] | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* [[Self-mutilating]] behavior | |||
* [[Urinary]] stones due to [[hyperuricemia]] | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* Elevated [[uric acid]] level | |||
* Abnormal enzymatic activity of HPRT in cultured fibroblasts | |||
* [[Genetic]] testing for HPRT gene [[mutations]] | |||
| style="background: #F5F5F5; padding: 5px; text-align: center;" |-- | |||
|- | |||
| style="background: #DCDCDC; padding: 5px; text-align: center;" |Miller-Dieker lissencephaly | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* [[Lissencephaly]] | |||
* [[Microcephaly]] | |||
* [[Dysmorphic]] features | |||
* [[Seizures]] | |||
* Failure to thrive | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* Cytogenetic testing for 17p13.3 microdeletion | |||
| style="background: #F5F5F5; padding: 5px; text-align: center;" |-- | |||
|- | |||
| style="background: #DCDCDC; padding: 5px; text-align: center;" |Dopa-responsive [[dystonia]] | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* Onset in early childhood | |||
* Symptoms worsen with [[fatigue]] and exercise | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
* Positive response to a trial of [[levodopa]] | |||
| style="background: #F5F5F5; padding: 5px; text-align: center;" |-- | |||
|} | |||
==Epidemiology and Demographics== | ==Epidemiology and Demographics== |
Revision as of 16:00, 9 October 2017
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
Synonyms and keywords: Arylsulfatase A deficiency
Overview
Metachromatic leukodystrophy is the most common form of a family of genetic diseases known as the leukodystrophies, diseases which affect the growth and/or development of myelin, the fatty covering which acts as an insulator around nerve fibres throughout the central and peripherial nervous systems .
Historical Perspective
Classification
Pathophysiology
Gene Therapy
- two trials are in the planning stages in Europe, one in Italy and one in France
Clinical trial updates provided by the MLD Foundation
Causes
MLD is directly caused by a deficiency of the enzyme arylsulfatase A. Without this enzyme, sulfatides build up in many tissues of the body, eventually destroying the myelin of the nervous system.
Differentiating Metachromatic leukodystrophy from Other Diseases
Differential diagnosis
Metachromatic leukodystrophy must be differentiated from other diseases that cause neurological manifestations in infants.
Diseases | Type of motor abnormality | Clinical findings | Laboratory findings and diagnostic tests | Radiographic findings | |||
---|---|---|---|---|---|---|---|
Spasticity | Hypotonia | Ataxia | Dystonia | ||||
Leigh syndrome | - | - | + | + |
|
| |
Niemann-Pick disease type C | - | - | + | + |
|
|
|
Infantile Refsum disease | - | + | + | - |
|
Elevated plasma VLCFA levels | -- |
Adrenoleukodystrophy | + | - | - | - |
|
|
-- |
Zellweger syndrome | - | + | - | - |
|
|
-- |
Pyruvate dehydrogenase deficiency | + | + | + | - | -- | ||
Arginase deficiency | + | - | - | - | -- | ||
Holocarboxylase synthetase deficiency | - | + | - | - | Elevated levels of:
|
-- | |
Glutaric aciduria type 1 | - | - | - | + |
|
Elevated levels of:
|
|
Ataxia telangiectasia | - | - | + | - |
|
|
-- |
Pontocerebellar hypoplasias | - | + | - | - |
|
Genetic testing for PCH gene mutations |
|
Metachromatic leukodystrophy | - | + | + | - |
|
|
-- |
Pelizaeus-Merzbacher | + | - | + | - |
|
| |
Angelman syndrome | - | - | + | - |
|
|
-- |
Rett syndrome | + | - | - | + |
|
-- | |
Lesch-Nyhan syndrome | + | - | - | + |
|
-- | |
Miller-Dieker lissencephaly | + | + | - | - |
|
|
-- |
Dopa-responsive dystonia | + | - | - | + |
|
|
-- |
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications, and Prognosis
Natural History
Complications
Prognosis
Diagnosis
Diagnostic Criteria
History and Symptoms
Like many other genetic disorders that affect lipid metabolism, there are several forms of MLD, which are late infantile, juvenile, and adult.
In the late infantile form, which is the most common form MLD, affected children begin having difficulty walking after the first year of life. Symptoms include muscle wasting and weakness, muscle rigidity, developmental delays, progressive loss of vision leading to blindness, convulsions, impaired swallowing, paralysis, and dementia. Children may become comatose. Untreated, most children with this form of MLD die by age 5, often much sooner.
Children with the juvenile form of MLD (onset between 3-10 years of age) usually begin with impaired school performance, mental deterioration, and dementia and then develop symptoms similar to the late infantile form but with slower progression. Age of death is variable, but normally within 10 to 15 years of symptom onset.
The adult form commonly begins after age 16 as a psychiatric disorder or progressive dementia. Adult-onset MLD progresses more slowly than the late infantile and juvenile forms, with a protracted course of a decade or more.
In rare cases the body can compensate for the deficiency and the person will exhibit no symptoms.
Physical Examination
Laboratory Findings
Imaging Findings
Other Diagnostic Studies
Treatment
There is no cure for MLD, nor a standard form of treatment. Children with advanced juvenile or adult onset, and late infantile patients displaying symptoms have treatment limited to pain and symptom management. Presymptomatic late infantile MLD patients, as well as those with juvenile or adult MLD that are either presymptomatic or displaying mild to moderate symptoms, have the option of bone marrow transplantation (including stem cell transplantation), which may slow down the progression of the disease, or stop its progression in the central nervous system, however results in the peripheral nervous system have been less dramatic.
Treatment options for the future that are currently being investigated include gene therapy and enzyme replacement therapy (ERT), and potentially a enzyme enhancement therapy (EET).
Medical Therapy
Surgery
Prevention
Future or Investigational Therapies
Clinical Trials
Enzyme Replacement Therapy
- Phase II clinical trials are underway in Europe by a Danish company, Zymenex, using Metazym, (updated August 2007)
- Shire Human Genetics is proposing an enzyme replacement therapy
See also
External links
- Large portions of this article are courtesy of the public domain text available at the National Institute of Neurological Disorders and Stroke [2]
- Further information regarding MLD, treatments, genetics, and current research projects, can be found at:
- eMedicine article about MLD by Theodore Moore, MD.
- mld at NIH/UW GeneTests
References
Template:Metabolic pathology fi:Metakromaattinen leukodystrofia