megalencephalic leukoencephalopathy with subcortical cysts 1

Megalencephalic Leukoencephalopathy with Subcortical Cysts: A Rare Inherited Brain Disorder

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare inherited brain disorder that affects the development and function of the brain. It is characterized by two distinct phenotypes: classic MLC and improving MLC.

Key Features of MLC:

• Macrocephaly: Individuals with MLC often have an abnormally large head size due to excessive brain growth.
• Mild Motor Developmental Delay: Affected infants may experience mild delays in motor development, such as delayed crawling or walking.
• Seizures: Seizures are a common symptom of MLC, occurring in both classic and improving phenotypes.
• Infantile-Onset: MLC typically presents in infancy, with symptoms becoming apparent within the first few years of life.

Genetic Basis:

MLC is caused by mutations in the MLC1 gene, which plays a crucial role in maintaining normal brain structure and function. The disorder is inherited in an autosomal recessive pattern, meaning that affected individuals inherit two copies of the mutated gene (one from each parent).

References:

• [1] Megalencephalic leukoencephalopathy with subcortical cysts is a progressive condition that affects brain development and function. [1]
• [4] Megalencephalic leukoencephalopathy with subcortical cysts, also known as Van der Knaap disease, refers to a rare inherited autosomal recessive disease. [4]
• [9] Megalencephalic leukoencephalopathy with subcortical cysts is a rare inherited brain disorder characterized by mutations in the MLC1 gene, leading to abnormal brain growth and development. [9]

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Early Signs and Symptoms

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) typically presents with a combination of clinical signs and symptoms. The first symptom is often an increase in head circumference in the first year of life [3]. This is due to the enlargement of the brain, which is evident at birth or within the first year of life [1].

Motor Delay

Delayed walking is usually the first clinical sign, with children experiencing unstable gait and frequent falls [2]. Motor functions may deteriorate over time, leading to ataxia (loss of coordination) and spasticity (increased muscle tone) [6].

Neurological Deterioration

As the condition progresses, patients may experience seizures, which are usually easily controlled [4]. However, cognitive decline is a significant concern, with patients showing deterioration in mental functions over time [6].

Other Symptoms

Subcortical cysts and diffusely abnormal white matter can be observed on brain magnetic resonance imaging (MRI) scans [5]. These findings are characteristic of MLC.

Delayed Onset

In some cases, the onset of symptoms may be delayed until later in childhood or even adolescence. When this occurs, patients typically experience motor problems, epilepsy, and slow cognitive decline [7].

Key Points:

• Increased head circumference in the first year of life
• Delayed walking with unstable gait and frequent falls
• Motor deterioration leading to ataxia and spasticity
• Seizures (usually easily controlled)
• Cognitive decline over time
• Subcortical cysts and abnormal white matter on MRI scans

References:

[1] Mar 1, 2015 — Individuals with this condition typically have an enlarged brain (megalencephaly) that is evident at birth or within the first year of life. [2] by R Min · 2023 · Cited by 3 — Apart from macrocephaly, the first clinical sign is usually delayed walking. Walking is often unstable, and the child falls frequently. [3] In most patients, the first symptom is an increase in head circumference in the first year of life. [4] by A Batla · 2011 · Cited by 24 — It usually presents with pyramidal and cerebellar signs. Megalencephaly is usually detected early. Seizures may be present but are usually easily controlled. [5] Brain magnetic resonance imaging reveals diffusely abnormal and mildly swollen white matter as well as subcortical cysts in the anterior temporal and... [6] Clinically, patients show deterioration of motor functions with ataxia and spasticity, seizures and mental decline. [7] by EMJ Passchier · 2024 · Cited by 2 — With delayed onset, patients typically experience motor problems, epilepsy and slow cognitive decline.

Diagnostic Tests for Megalencephalic Leukoencephalopathy with Subcortical Cysts

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare genetic disorder that can be diagnosed through various tests. Here are some of the diagnostic tests used to confirm MLC:

• Brain MRI: A brain MRI scan shows evidence of severe white matter involvement and cysts in the tips of the temporal lobes, as well as diffuse signal abnormalities of the cerebral hemispheric white matter [8][13].
• Genetic testing: Genetic testing of a blood sample can often confirm the diagnosis by identifying mutations in the MLC1 gene or other genes associated with MLC [6][10].
• Sequence analysis and deletion/duplication analysis: These tests may be used to identify pathogenic variants in the MLC1 gene, although they may also be inconclusive [4].

Other Diagnostic Tests

In addition to these specific tests, a diagnosis of MLC can often be established through a combination of clinical findings and characteristic abnormalities identified on brain MRI examination. This includes abnormal and swollen cerebral hemispheric white matter and subcortical cysts in the anterior temporal and frontoparietal regions [10].

References

[1] Megalencephalic leukoencephalopathy with subcortical cysts (MLC, or Van der Knaap disease) is a form of hereditary CNS demyelinating disease.

[4] Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. Note: If no pathogenic ...

[6] The diagnosis can often be confirmed by genetic testing of a blood sample. But these tests may also be inconclusive because other genes that have not been ...

[8] by X Chen · 2023 · Cited by 1 — Magnetic resonance imaging (MRI) of the brain shows evidence of severe white matter involvement and cysts in the tips of the temporal lobes, as ...

[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 ...

[13] Megalencephalic leukoencephalopathy with subcortical cysts is an infantile-onset inherited disorder characterized by cerebral white matter edema. 1 – 3 MRI shows diffuse signal abnormalities of the cerebral hemispheric white matter.

Treatment Options for Megalencephalic Leukoencephalopathy with Subcortical Cysts (MLC)

Megalencephalic leukoencephalopathy with subcortical cysts is a progressive condition that affects brain development and function. While there is no definitive therapy for MLC, various treatments can help manage its symptoms.

Medications

• Anti-seizure medication: Medications such as phenobarbital, valproate, or levetiracetam may be prescribed to control seizures, which are a common symptom of MLC [5].
• Other medications: In some cases, other medications like benzodiazepines or muscle relaxants may be used to manage symptoms like muscle spasms or agitation [9].

Therapeutic Approaches

• Physical therapy: Physical therapy can help improve motor function and mobility in individuals with MLC [1].
• Speech therapy: Speech therapy may be necessary to address communication difficulties associated with the condition [1].
• Special education: Special education programs can provide support for children with MLC, helping them develop skills and adapt to their condition [5].

Gene Therapy

• A gene therapy approach has been designated as an orphan drug by the European Medicines Agency (EMA) to treat MLC [4]. However, this treatment is still in its early stages, and more research is needed to fully understand its potential.

It's essential to note that while these treatments can help manage symptoms, there is no cure for the underlying cause of MLC. A multidisciplinary approach involving healthcare professionals from various fields may be necessary to provide comprehensive care for individuals with this condition.

The differential diagnosis for megalencephalic leukoencephalopathy with subcortical cysts (MLC) includes several conditions that present with similar symptoms. Some of these conditions are:

• Canavan disease: This is a genetic disorder that affects the nervous system and causes progressive damage to the brain, leading to macrocephaly (increased head size), ataxia, spasticity, and epilepsy [9].
• Alexander disease: This is another rare genetic disorder that affects the nervous system and causes progressive damage to the brain, leading to symptoms such as megalencephaly, seizures, and developmental delay [1].
• Infantile-onset GM2 gangliosidosis: This is a rare genetic disorder that affects the nervous system and causes progressive damage to the brain, leading to symptoms such as macrocephaly, ataxia, spasticity, and epilepsy [9].

These conditions can be difficult to distinguish from MLC based on clinical presentation alone. However, MRI findings can help differentiate between these conditions. For example, Canavan disease is characterized by a "swiss cheese" appearance of the brain on MRI due to cystic changes in the white matter [1]. In contrast, MLC is characterized by abnormal swelling of the white matter and subcortical cysts [7].

It's worth noting that the diagnosis of MLC is based on clinical and MRI criteria, and a comprehensive evaluation by a multidisciplinary team of healthcare professionals is necessary to accurately diagnose this condition [5].