Metachromatic leukodystrophy: Difference between revisions

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{{SI}}
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{{CMG}}; {{AE}}
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{{SK}} Arylsulfatase A deficiency
{{SK}} Arylsulfatase A deficiency
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'''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 nervous system|central]] and [[Peripheral nervous system|peripherial]] [[nervous system]]s .   
'''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 nervous system|central]] and [[Peripheral nervous system|peripherial]] [[nervous system]]s .   


==Historical Perspective==
==Classification==
Based on the age of onset, Metachromatic Leukodystrophy is classified into three types.
 
Types:
 
- Late infantile onset (before 30 months)
 
- Juvenile onset ( 2.5 years to 16 years)
 
- Adult onset


==Classification==


==Pathophysiology==
==Pathophysiology==
===Gene Therapy===
Metachromatic leukodystrophy is caused by deficiency of Arylsulfatase A (ASA), an autosomal recessive disorder.
* two trials are in the planning stages in Europe, one in Italy and one in France


''Clinical trial updates provided by the [http://www.mldfoundation.org/research MLD Foundation]''
==Causes==
Disease name] may be caused by [cause1], [cause2], or [cause3].


==Causes==
OR
MLD is directly caused by a deficiency of the enzyme [[arylsulfatase A]]. Without this enzyme, [[sulfatide]]s build up in many tissues of the body, eventually destroying the myelin of the nervous system.
 
Common causes of [disease] include [cause1], [cause2], and [cause3].
 
OR
 
The most common cause of [disease name] is [cause 1]. Less common causes of [disease name] include [cause 2], [cause 3], and [cause 4].
 
OR
 
The cause of [disease name] has not been identified. To review risk factors for the development of [disease name], click [[Pericarditis causes#Overview|here]].
 
==Differentiating Metachromatic leukodystrophy from other Diseases==
[Disease name] must be differentiated from other diseases that cause [clinical feature 1], [clinical feature 2], and [clinical feature 3], such as [differential dx1], [differential dx2], and [differential dx3].
 
OR


==Differentiating {{PAGENAME}} from Other Diseases==
[Disease name] must be differentiated from [[differential dx1], [differential dx2], and [differential dx3].
==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==
The incidence/prevalence of [disease name] is approximately [number range] per 100,000 individuals worldwide.
OR
In [year], the incidence/prevalence of [disease name] was estimated to be [number range] cases per 100,000 individuals worldwide.
OR
In [year], the incidence of [disease name] is approximately [number range] per 100,000 individuals with a case-fatality rate of [number range]%.
Patients of all age groups may develop [disease name].
OR
The incidence of [disease name] increases with age; the median age at diagnosis is [#] years.
OR
[Disease name] commonly affects individuals younger than/older than [number of years] years of age.
OR
[Chronic disease name] is usually first diagnosed among [age group].
OR
[Acute disease name] commonly affects [age group].
There is no racial predilection to [disease name].
OR
[Disease name] usually affects individuals of the [race 1] race. [Race 2] individuals are less likely to develop [disease name].
[Disease name] affects men and women equally.
OR
[Gender 1] are more commonly affected by [disease name] than [gender 2]. The [gender 1] to [gender 2] ratio is approximately [number > 1] to 1.
The majority of [disease name] cases are reported in [geographical region].
OR
[Disease name] is a common/rare disease that tends to affect [patient population 1] and [patient population 2].


==Risk Factors==
==Risk Factors==
There are no established risk factors for [disease name].
OR
The most potent risk factor in the development of [disease name] is [risk factor 1]. Other risk factors include [risk factor 2], [risk factor 3], and [risk factor 4].
OR
Common risk factors in the development of [disease name] include [risk factor 1], [risk factor 2], [risk factor 3], and [risk factor 4].
OR
Common risk factors in the development of [disease name] may be occupational, environmental, genetic, and viral.


==Screening==
==Screening==
There is insufficient evidence to recommend routine screening for [disease/malignancy].
OR
According to the [guideline name], screening for [disease name] is not recommended.
OR
According to the [guideline name], screening for [disease name] by [test 1] is recommended every [duration] among patients with [condition 1], [condition 2], and [condition 3].


==Natural History, Complications, and Prognosis==
==Natural History, Complications, and Prognosis==
===Natural History===
If left untreated, [#]% of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].


===Complications===
OR


===Prognosis===
Common complications of [disease name] include [complication 1], [complication 2], and [complication 3].
 
OR
 
Prognosis is generally excellent/good/poor, and the 1/5/10-year mortality/survival rate of patients with [disease name] is approximately [#]%.


==Diagnosis==
==Diagnosis==
===Diagnostic Criteria===
===Diagnostic Study of Choice===
The diagnosis of [disease name] is made when at least [number] of the following [number] diagnostic criteria are met: [criterion 1], [criterion 2], [criterion 3], and [criterion 4].
 
OR
 
The diagnosis of [disease name] is based on the [criteria name] criteria, which include [criterion 1], [criterion 2], and [criterion 3].
 
OR
 
The diagnosis of [disease name] is based on the [definition name] definition, which includes [criterion 1], [criterion 2], and [criterion 3].
 
OR
 
There are no established criteria for the diagnosis of [disease name].


===History and Symptoms===
===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.
The majority of patients with [disease name] are asymptomatic.
 
OR
 
The hallmark of [disease name] is [finding]. A positive history of [finding 1] and [finding 2] is suggestive of [disease name]. The most common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3]. Common symptoms of [disease] include [symptom 1], [symptom 2], and [symptom 3]. Less common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3].
 
===Physical Examination===
Patients with [disease name] usually appear [general appearance]. Physical examination of patients with [disease name] is usually remarkable for [finding 1], [finding 2], and [finding 3].


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 [[coma]]tose. Untreated, most children with this form of MLD die by age 5, often much sooner.
OR


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.
Common physical examination findings of [disease name] include [finding 1], [finding 2], and [finding 3].


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.
OR


In rare cases the body can compensate for the deficiency and the person will exhibit no symptoms.
The presence of [finding(s)] on physical examination is diagnostic of [disease name].


===Physical Examination===
OR
 
The presence of [finding(s)] on physical examination is highly suggestive of [disease name].


===Laboratory Findings===
===Laboratory Findings===
An elevated/reduced concentration of serum/blood/urinary/CSF/other [lab test] is diagnostic of [disease name].
OR
Laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3].
OR
[Test] is usually normal among patients with [disease name].
OR
Some patients with [disease name] may have elevated/reduced concentration of [test], which is usually suggestive of [progression/complication].
OR
There are no diagnostic laboratory findings associated with [disease name].
===Electrocardiogram===
There are no ECG findings associated with [disease name].
OR
An ECG may be helpful in the diagnosis of [disease name]. Findings on an ECG suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].


===Imaging Findings===
===X-ray===
There are no x-ray findings associated with [disease name].
 
OR
 
An x-ray may be helpful in the diagnosis of [disease name]. Findings on an x-ray suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
 
OR
 
There are no x-ray findings associated with [disease name]. However, an x-ray may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].
 
===Echocardiography or Ultrasound===
There are no echocardiography/ultrasound  findings associated with [disease name].
 
OR
 
Echocardiography/ultrasound  may be helpful in the diagnosis of [disease name]. Findings on an echocardiography/ultrasound suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
 
OR
 
There are no echocardiography/ultrasound  findings associated with [disease name]. However, an echocardiography/ultrasound  may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].
 
===CT scan===
There are no CT scan findings associated with [disease name].
 
OR
 
[Location] CT scan may be helpful in the diagnosis of [disease name]. Findings on CT scan suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
 
OR
 
There are no CT scan findings associated with [disease name]. However, a CT scan may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].
 
===MRI===
There are no MRI findings associated with [disease name].
 
OR
 
[Location] MRI may be helpful in the diagnosis of [disease name]. Findings on MRI suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
 
OR
 
There are no MRI findings associated with [disease name]. However, a MRI may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].
 
===Other Imaging Findings===
There are no other imaging findings associated with [disease name].
 
OR
 
[Imaging modality] may be helpful in the diagnosis of [disease name]. Findings on an [imaging modality] suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].


===Other Diagnostic Studies===
===Other Diagnostic Studies===
There are no other diagnostic studies associated with [disease name].
OR
[Diagnostic study] may be helpful in the diagnosis of [disease name]. Findings suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
OR
Other diagnostic studies for [disease name] include [diagnostic study 1], which demonstrates [finding 1], [finding 2], and [finding 3], and [diagnostic study 2], which demonstrates [finding 1], [finding 2], and [finding 3].


==Treatment==
==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.
===Medical Therapy===
There is no treatment for [disease name]; the mainstay of therapy is supportive care.
 
OR
 
Supportive therapy for [disease name] includes [therapy 1], [therapy 2], and [therapy 3].
 
OR
 
The majority of cases of [disease name] are self-limited and require only supportive care.
 
OR
 
[Disease name] is a medical emergency and requires prompt treatment.
 
OR
 
The mainstay of treatment for [disease name] is [therapy].
 
OR
 
The optimal therapy for [malignancy name] depends on the stage at diagnosis.
 
OR


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).
[Therapy] is recommended among all patients who develop [disease name].
===Medical Therapy===
 
OR
 
Pharmacologic medical therapy is recommended among patients with [disease subclass 1], [disease subclass 2], and [disease subclass 3].
 
OR
 
Pharmacologic medical therapies for [disease name] include (either) [therapy 1], [therapy 2], and/or [therapy 3].
 
OR
 
Empiric therapy for [disease name] depends on [disease factor 1] and [disease factor 2].
 
OR
 
Patients with [disease subclass 1] are treated with [therapy 1], whereas patients with [disease subclass 2] are treated with [therapy 2].


===Surgery===
===Surgery===
Surgical intervention is not recommended for the management of [disease name].
OR
Surgery is not the first-line treatment option for patients with [disease name]. Surgery is usually reserved for patients with either [indication 1], [indication 2], and [indication 3]
OR
The mainstay of treatment for [disease name] is medical therapy. Surgery is usually reserved for patients with either [indication 1], [indication 2], and/or [indication 3].
OR
The feasibility of surgery depends on the stage of [malignancy] at diagnosis.
OR
Surgery is the mainstay of treatment for [disease or malignancy].
===Primary Prevention===
There are no established measures for the primary prevention of [disease name].
OR
There are no available vaccines against [disease name].
OR
Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3].
OR
[Vaccine name] vaccine is recommended for [patient population] to prevent [disease name]. Other primary prevention strategies include [strategy 1], [strategy 2], and [strategy 3].
===Secondary Prevention===
There are no established measures for the secondary prevention of [disease name].
OR
Effective measures for the secondary prevention of [disease name] include [strategy 1], [strategy 2], and [strategy 3].


===Prevention===


===Future or Investigational Therapies===
====Clinical Trials====
====Clinical Trials====
Enzyme Replacement Therapy
Enzyme Replacement Therapy
*Phase II clinical trials are underway in Europe by a Danish company, [http://www.zymenex.com Zymenex], using Metazym, ''(updated August 2007)''
*Phase II clinical trials are underway in Europe by a Danish company, [http://www.zymenex.com Zymenex], using Metazym, ''(updated August 2007)''
*[http://www.shire.com/shire/Pipeline/projects.jsp Shire Human Genetics] is proposing an enzyme replacement therapy
*[http://www.shire.com/shire/Pipeline/projects.jsp Shire Human Genetics] is proposing an enzyme replacement therapy
   
   
==See also==
==See also==
*[http://www.evanoskyfoundation.org The Evanosky Foundation]
*[http://www.evanoskyfoundation.org The Evanosky Foundation]
*[http://www.MLDfoundation.org The MLD Foundation]
*[http://www.MLDfoundation.org The MLD Foundation]
Line 378: Line 362:
*[[The Stennis Foundation]]
*[[The Stennis Foundation]]


== External links ==
==External links==
 
*Large portions of this article are courtesy of the public domain text available at the [[National Institute of Neurological Disorders and Stroke]] [http://ninds.nih.gov/disorders/metachromatic_leukodystrophy/metachromatic_leukodystrophy.htm]
*Large portions of this article are courtesy of the public domain text available at the [[National Institute of Neurological Disorders and Stroke]] [http://ninds.nih.gov/disorders/metachromatic_leukodystrophy/metachromatic_leukodystrophy.htm]
*Further information regarding MLD, treatments, genetics, and current research projects, can be found at:
*Further information regarding MLD, treatments, genetics, and current research projects, can be found at:
**[http://www.MLDfoundation.org The MLD Foundation]
**[http://www.MLDfoundation.org The MLD Foundation]
**[http://www.stennisfoundation.org. The Stennis Foundation]
**[http://www.stennisfoundation.org. The Stennis Foundation]
**[http://www.evanoskyfoundation.org/1267/3071.html The Evanosky Foundation]
**[http://www.evanoskyfoundation.org/1267/3071.html The Evanosky Foundation]


*[http://www.emedicine.com/ped/topic2893.htm eMedicine article] about MLD by Theodore Moore, MD.
*[http://www.emedicine.com/ped/topic2893.htm eMedicine article] about MLD by Theodore Moore, MD.
* {{GeneTests|mld}}
*{{GeneTests|mld}}
 


==References==
==References==

Latest revision as of 12:29, 14 November 2021

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chiranjeevi Sainatham, M.B.B.S[2]

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 .

Classification

Based on the age of onset, Metachromatic Leukodystrophy is classified into three types.

Types:

- Late infantile onset (before 30 months)

- Juvenile onset ( 2.5 years to 16 years)

- Adult onset


Pathophysiology

Metachromatic leukodystrophy is caused by deficiency of Arylsulfatase A (ASA), an autosomal recessive disorder.

Causes

Disease name] may be caused by [cause1], [cause2], or [cause3].

OR

Common causes of [disease] include [cause1], [cause2], and [cause3].

OR

The most common cause of [disease name] is [cause 1]. Less common causes of [disease name] include [cause 2], [cause 3], and [cause 4].

OR

The cause of [disease name] has not been identified. To review risk factors for the development of [disease name], click here.

Differentiating Metachromatic leukodystrophy from other Diseases

[Disease name] must be differentiated from other diseases that cause [clinical feature 1], [clinical feature 2], and [clinical feature 3], such as [differential dx1], [differential dx2], and [differential dx3].

OR

[Disease name] must be differentiated from [[differential dx1], [differential dx2], and [differential dx3].

Epidemiology and Demographics

The incidence/prevalence of [disease name] is approximately [number range] per 100,000 individuals worldwide.

OR

In [year], the incidence/prevalence of [disease name] was estimated to be [number range] cases per 100,000 individuals worldwide.

OR

In [year], the incidence of [disease name] is approximately [number range] per 100,000 individuals with a case-fatality rate of [number range]%.


Patients of all age groups may develop [disease name].

OR

The incidence of [disease name] increases with age; the median age at diagnosis is [#] years.

OR

[Disease name] commonly affects individuals younger than/older than [number of years] years of age.

OR

[Chronic disease name] is usually first diagnosed among [age group].

OR

[Acute disease name] commonly affects [age group].


There is no racial predilection to [disease name].

OR

[Disease name] usually affects individuals of the [race 1] race. [Race 2] individuals are less likely to develop [disease name].


[Disease name] affects men and women equally.

OR

[Gender 1] are more commonly affected by [disease name] than [gender 2]. The [gender 1] to [gender 2] ratio is approximately [number > 1] to 1.


The majority of [disease name] cases are reported in [geographical region].

OR

[Disease name] is a common/rare disease that tends to affect [patient population 1] and [patient population 2].

Risk Factors

There are no established risk factors for [disease name].

OR

The most potent risk factor in the development of [disease name] is [risk factor 1]. Other risk factors include [risk factor 2], [risk factor 3], and [risk factor 4].

OR

Common risk factors in the development of [disease name] include [risk factor 1], [risk factor 2], [risk factor 3], and [risk factor 4].

OR

Common risk factors in the development of [disease name] may be occupational, environmental, genetic, and viral.

Screening

There is insufficient evidence to recommend routine screening for [disease/malignancy].

OR

According to the [guideline name], screening for [disease name] is not recommended.

OR

According to the [guideline name], screening for [disease name] by [test 1] is recommended every [duration] among patients with [condition 1], [condition 2], and [condition 3].

Natural History, Complications, and Prognosis

If left untreated, [#]% of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].

OR

Common complications of [disease name] include [complication 1], [complication 2], and [complication 3].

OR

Prognosis is generally excellent/good/poor, and the 1/5/10-year mortality/survival rate of patients with [disease name] is approximately [#]%.

Diagnosis

Diagnostic Study of Choice

The diagnosis of [disease name] is made when at least [number] of the following [number] diagnostic criteria are met: [criterion 1], [criterion 2], [criterion 3], and [criterion 4].

OR

The diagnosis of [disease name] is based on the [criteria name] criteria, which include [criterion 1], [criterion 2], and [criterion 3].

OR

The diagnosis of [disease name] is based on the [definition name] definition, which includes [criterion 1], [criterion 2], and [criterion 3].

OR

There are no established criteria for the diagnosis of [disease name].

History and Symptoms

The majority of patients with [disease name] are asymptomatic.

OR

The hallmark of [disease name] is [finding]. A positive history of [finding 1] and [finding 2] is suggestive of [disease name]. The most common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3]. Common symptoms of [disease] include [symptom 1], [symptom 2], and [symptom 3]. Less common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3].

Physical Examination

Patients with [disease name] usually appear [general appearance]. Physical examination of patients with [disease name] is usually remarkable for [finding 1], [finding 2], and [finding 3].

OR

Common physical examination findings of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

The presence of [finding(s)] on physical examination is diagnostic of [disease name].

OR

The presence of [finding(s)] on physical examination is highly suggestive of [disease name].

Laboratory Findings

An elevated/reduced concentration of serum/blood/urinary/CSF/other [lab test] is diagnostic of [disease name].

OR

Laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3].

OR

[Test] is usually normal among patients with [disease name].

OR

Some patients with [disease name] may have elevated/reduced concentration of [test], which is usually suggestive of [progression/complication].

OR

There are no diagnostic laboratory findings associated with [disease name].

Electrocardiogram

There are no ECG findings associated with [disease name].

OR

An ECG may be helpful in the diagnosis of [disease name]. Findings on an ECG suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

X-ray

There are no x-ray findings associated with [disease name].

OR

An x-ray may be helpful in the diagnosis of [disease name]. Findings on an x-ray suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no x-ray findings associated with [disease name]. However, an x-ray may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

Echocardiography or Ultrasound

There are no echocardiography/ultrasound findings associated with [disease name].

OR

Echocardiography/ultrasound may be helpful in the diagnosis of [disease name]. Findings on an echocardiography/ultrasound suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no echocardiography/ultrasound findings associated with [disease name]. However, an echocardiography/ultrasound may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

CT scan

There are no CT scan findings associated with [disease name].

OR

[Location] CT scan may be helpful in the diagnosis of [disease name]. Findings on CT scan suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no CT scan findings associated with [disease name]. However, a CT scan may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

MRI

There are no MRI findings associated with [disease name].

OR

[Location] MRI may be helpful in the diagnosis of [disease name]. Findings on MRI suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no MRI findings associated with [disease name]. However, a MRI may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

Other Imaging Findings

There are no other imaging findings associated with [disease name].

OR

[Imaging modality] may be helpful in the diagnosis of [disease name]. Findings on an [imaging modality] suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

Other Diagnostic Studies

There are no other diagnostic studies associated with [disease name].

OR

[Diagnostic study] may be helpful in the diagnosis of [disease name]. Findings suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

Other diagnostic studies for [disease name] include [diagnostic study 1], which demonstrates [finding 1], [finding 2], and [finding 3], and [diagnostic study 2], which demonstrates [finding 1], [finding 2], and [finding 3].

Treatment

Medical Therapy

There is no treatment for [disease name]; the mainstay of therapy is supportive care.

OR

Supportive therapy for [disease name] includes [therapy 1], [therapy 2], and [therapy 3].

OR

The majority of cases of [disease name] are self-limited and require only supportive care.

OR

[Disease name] is a medical emergency and requires prompt treatment.

OR

The mainstay of treatment for [disease name] is [therapy].

OR   The optimal therapy for [malignancy name] depends on the stage at diagnosis.

OR

[Therapy] is recommended among all patients who develop [disease name].

OR

Pharmacologic medical therapy is recommended among patients with [disease subclass 1], [disease subclass 2], and [disease subclass 3].

OR

Pharmacologic medical therapies for [disease name] include (either) [therapy 1], [therapy 2], and/or [therapy 3].

OR

Empiric therapy for [disease name] depends on [disease factor 1] and [disease factor 2].

OR

Patients with [disease subclass 1] are treated with [therapy 1], whereas patients with [disease subclass 2] are treated with [therapy 2].

Surgery

Surgical intervention is not recommended for the management of [disease name].

OR

Surgery is not the first-line treatment option for patients with [disease name]. Surgery is usually reserved for patients with either [indication 1], [indication 2], and [indication 3]

OR

The mainstay of treatment for [disease name] is medical therapy. Surgery is usually reserved for patients with either [indication 1], [indication 2], and/or [indication 3].

OR

The feasibility of surgery depends on the stage of [malignancy] at diagnosis.

OR

Surgery is the mainstay of treatment for [disease or malignancy].

Primary Prevention

There are no established measures for the primary prevention of [disease name].

OR

There are no available vaccines against [disease name].

OR

Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3].

OR

[Vaccine name] vaccine is recommended for [patient population] to prevent [disease name]. Other primary prevention strategies include [strategy 1], [strategy 2], and [strategy 3].

Secondary Prevention

There are no established measures for the secondary prevention of [disease name].

OR

Effective measures for the secondary prevention of [disease name] include [strategy 1], [strategy 2], and [strategy 3].


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


References

Template:Metabolic pathology fi:Metakromaattinen leukodystrofia


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