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megalencephalic leukoencephalopathy with subcortical cysts
ICD-10 Codes
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Description
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare genetic disorder that affects the brain's white matter, leading to progressive neurological symptoms and cyst formation.
Characteristics of MLC:
- Macrocephaly: Individuals with MLC typically have an enlarged brain (megalencephaly) that is evident at birth or within the first year of life [4][14].
- Progressive condition: MLC is a progressive condition that affects brain development and function, leading to worsening neurological symptoms over time [13][14].
- Cyst formation: The disorder is characterized by the formation of cysts in the subcortical regions of the brain, which can lead to further complications [1][12].
Causes and Genetics:
- Genetic mutation: MLC is caused by mutations involving the MLC1 gene, which provides instructions for producing a protein that is made primarily in the brain [10].
- Autosomal-recessive inheritance: The disease is inherited in an autosomal-recessive pattern, meaning that both parents must be carriers of the mutated gene to pass it on to their offspring [2][5].
Symptoms and Diagnosis:
- Neurological symptoms: Individuals with MLC may experience progressive neurological symptoms, including seizures, developmental delay, and lack of muscular coordination [1][11].
- MRI abnormalities: The diagnosis of classic MLC is established through characteristic abnormalities identified on brain MRI examination, including abnormal and swollen cerebral hemispheric white matter and subcortical cysts [12].
References:
[1] - Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is an inherited disease that causes seizures and developmental delay in affected infants... (Search result 3) [2] - Megalencephalic leukoencephalopathy with subcortical cysts, also known as Van der Knaap disease, refers to a rare inherited autosomal recessive disease. (Search result 4) [10] - Mutations in the MLC1 gene cause megalencephalic leukoencephalopathy with subcortical cysts type 1; this type accounts for 75 percent of all cases... (Search result 10) [11] - Megalencephalic leukoencephalopathy with subcortical cysts (MLC, or Van der Knaap disease) is a form of hereditary CNS demyelinating disease. (Search result 11) [12] - Diagnosis/testing. The diagnosis of classic MLC is established in individuals with suggestive clinical findings and characteristic abnormalities identified on brain MRI examination... (Search result 12) [13] - Megalencephalic leukoencephalopathy with subcortical cysts is a rare genetic disorder affecting the brain's white matter, leading to progressive neurological symptoms and cyst formation. (Search result 13) [14] - Megalencephalic leukoencephalopathy with subcortical cysts Description Megalencephalic leukoencephalopathy with subcortical cysts is a progressive condition that affects brain development and function... (Search result 14)
Additional Characteristics
- Macrocephaly
- Megalencephalic leukoencephalopathy with subcortical cysts
- Progressive neurological symptoms and cyst formation
- Cyst formation in the subcortical regions of the brain
- Genetic mutation involving the MLC1 gene
- Autosomal-recessive inheritance
- Neurological symptoms including seizures, developmental delay, and lack of muscular coordination
- MRI abnormalities including abnormal and swollen cerebral hemispheric white matter and subcortical cysts
Signs and Symptoms
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare genetic disorder characterized by the progressive enlargement of the brain, leading to various neurological symptoms. The signs and symptoms of MLC can be divided into two main categories: early-onset and delayed-onset.
Early-Onset Symptoms
- Macrocephaly: Enlargement of the head circumference, evident at birth or within the first year of life [1]
- Mild motor developmental delay: Delayed walking and unstable gait, with frequent falls [2]
Delayed-Onset Symptoms
- Progressive deterioration of motor functions:
- Ataxia (loss of coordination)
- Spasticity (increased muscle tone)
- Seizures
- Mental decline [5]
- Other symptoms may include:
- Poor ambulation
- Falls
- Increasing seizures and epilepsy [5]
Clinical Characteristics
- The first symptom is often an increase in head circumference in the first year of life [4]
- Patients typically experience a gradual worsening of motor functions, leading to significant disability [6]
- There are three types of MLC, distinguished by their signs and symptoms, as well as genetic cause [7]
Prognosis
- Unfortunately, no treatment is available for MLC [9]
- With delayed onset, patients typically experience motor problems, epilepsy, and slow cognitive decline [9]
Additional Symptoms
- Macrocephaly
- Seizures
- Falls
- Mild motor developmental delay
- Mental decline
- Poor ambulation
- Increasing seizures and epilepsy
- ataxia
- spasticity
Diagnostic Tests
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare genetic disorder that affects the brain. Diagnostic tests for MLC are crucial in confirming the diagnosis and ruling out other conditions.
Diagnostic Criteria The diagnosis of classic MLC is established in individuals with suggestive clinical findings and characteristic abnormalities identified on brain MRI [3]. A negative test result does not rule out a diagnosis of MLC since a mutation may not be detected by genetic testing [4].
Brain MRI Findings Brain MRI findings seen in affected individuals include diffusely abnormal and mildly swollen cerebral hemispheric white matter [1]. Subcortical cysts are also visible on brain scans, which is a characteristic feature of the condition [7].
Genetic Testing The diagnosis can often be confirmed by genetic testing of a blood sample. Defects in one of two genes, MLC1 and HEPACAM, have been reported in the majority of patients with a clinical diagnosis and MRI findings suggestive of MLC [9]. Genetic testing starts with Sanger sequencing of MLC1, followed by Sanger sequencing of GLIALCAM if no potentially pathogenic variants are found [8].
Other Diagnostic Tests While not explicitly mentioned as diagnostic tests for MLC, other imaging studies such as CT scans may be used to rule out other conditions that present with similar symptoms.
In summary, the diagnostic tests for megalencephalic leukoencephalopathy with subcortical cysts include:
- Brain MRI: to identify characteristic abnormalities and subcortical cysts
- Genetic testing: to confirm the diagnosis by detecting defects in the MLC1 or HEPACAM genes
- Sanger sequencing of MLC1 and GLIALCAM: to further confirm the diagnosis
References: [1] - Context 1 [3] - Context 3 [4] - Context 4 [7] - Context 7 [8] - Context 8 [9] - Context 9
Additional Diagnostic Tests
- Genetic testing
- Brain MRI
- Sanger sequencing of MLC1 and GLIALCAM
Treatment
Treatment Overview
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare and inherited disorder that affects the brain, leading to various neurological complications. While there is no definitive therapy for MLC, symptomatic treatments and supportive care are available to manage its symptoms.
Symptomatic Treatments
- Medications: Medications such as carbamazepine can be used to control seizures in patients with MLC [6].
- Epilepsy management: Uncontrolled epilepsy is a common symptom of MLC, and medications like carbamazepine are often effective in controlling seizures [6].
- Supportive care: Supportive care, including physical therapy, occupational therapy, and speech therapy, can help manage the symptoms of MLC and improve quality of life.
Gene Therapy Approach
A gene therapy approach has been designated as an orphan drug by the European Medicines Agency (EMA) to treat megalencephalic leukoencephalopathy with subcortical cysts (MLC) [7, 12]. This approach has shown promise in reducing symptoms of MLC in preclinical mouse models [2].
Current Treatment Limitations
- No cure: There is no cure for the underlying cause of MLC.
- Limited treatment options: Currently, there are limited treatment options available for MLC, and symptomatic treatments are often used to manage its symptoms.
In summary, while there is no definitive therapy for megalencephalic leukoencephalopathy with subcortical cysts (MLC), symptomatic treatments such as medications and supportive care can help manage its symptoms. A gene therapy approach has shown promise in reducing symptoms of MLC in preclinical models.
References: [2] First gene therapy approach for MLC leukoencephalopathy designated as orphan drug. [6] Medications used to control seizures in patients with MLC. [7] Gene therapy approach designated as an orphan drug by the EMA. [12] Designation of a gene therapy approach as an orphan drug for MLC.
Recommended Medications
- gene therapy
- carbamazepine
- Carbamazepine
💊 Drug information is sourced from ChEBI (Chemical Entities of Biological Interest) database. Always consult with a healthcare professional before starting any medication. Click on any medication name for detailed information.
Differential Diagnosis
Differential Diagnosis of Megalencephalic Leukoencephalopathy with Subcortical Cysts
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare inherited disorder, and as such, it can be challenging to diagnose. However, there are several conditions that should be considered in the differential diagnosis of MLC.
Conditions to Consider:
- Canavan disease: This is another leukodystrophy that affects the brain's white matter, leading to progressive neurological symptoms and cyst formation. Canavan disease shows similar MRI features to MLC, making it a potential differential diagnosis.
- Alexander disease: This is a rare degenerative disorder of the central nervous system characterized by megalencephaly (enlarged brain), seizures, and developmental delay. Alexander disease can present with similar clinical features to MLC, such as macrocephaly and progressive neurological deterioration.
- Infantile-onset GM2 gangliosidosis: This is a rare genetic disorder that affects the metabolism of gangliosides in the brain, leading to megalencephaly, seizures, and developmental delay. Infantile-onset GM2 gangliosidosis can be considered in the differential diagnosis of MLC due to its similar clinical presentation.
Diagnostic Approach:
Establishing a differential diagnosis in patients with suspected leukodystrophies or genetic disorders will begin by identifying key clinical features, assessing neurologic and systemic symptoms, and then performing appropriate diagnostic investigations (i.e., genetic testing). In the case of MLC, the diagnosis is made based on suggestive clinical findings and characteristic abnormalities identified on brain MRI examination.
References:
- [9] Jan 16, 2023 — The differential diagnosis includes Canavan disease, Alexander disease, and infantile-onset GM2 gangliosidosis. Canavan disease shows similar MRI features to MLC.
- [10] Diagnosis/testing. The diagnosis of classic MLC is established in individuals with suggestive clinical findings and characteristic abnormalities identified on brain MRI examination, including abnormal and swollen cerebral hemispheric white matter and subcortical cysts in the anterior temporal and often frontoparietal regions; and/or biallelic loss-of-function variants in MLC1 or HEPACAM or a ...
- [14] Megalencephalic leukoencephalopathy with subcortical cysts is an inherited autosomal recessive disorder with characteristic MRI features and a variable but mild clinical course. Frontal and temporal subcortical cysts are the diagnostic hallmark. ... Canavan disease, and Glutaric aciduria have been considered as differential diagnosis of ...
Additional Differential Diagnoses
- hypomyelinating leukoencephalopathy
- Infantile-onset GM2 gangliosidosis
- Canavan disease
- Alexander disease
Additional Information
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- A leukodystorphy characterized by infantile-onset macrocephaly, often with mild neurologic signs at presentation (such as mild motor delay), which worse with time, leading to poor ambulation, falls, ataxia, spasticity, increasing seizures and cognitive decline.
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