Megalencephalic leukoencephalopathy with subcortical cysts

Megalencephalic leukoencephalopathy with subcortical cysts, also known as Van der Knaap disease, refers to a rare inherited autosomal recessive disease characterized by diffuse subcortical leukoencephalopathy associated with white matter cystic degeneration. 

Epidemiology

The age at symptoms manifestations ranges from birth to 25 years, with a median age of 6 months ⁵.

In the Indian population, there is an association with the Aggarwal community and thus this condition is sometimes also referred to as Aggarwal's disease ⁸.

Clinical presentation

Patients typically present with megalencephaly during the first year of life associated with mild motor developmental delay and seizures ⁵. There is also a gradual onset of ataxia, spasticity, dysarthria, and sometimes extrapyramidal findings. Mild mental deterioration can be observed late in life. 

Pathology

It is sometimes classified as a megalencephalic leukoencephalopathy.

Genetics

It is thought to carry an autosomal recessive inheritance, and the gene locus has been mapped as MLC1 gene at chromosome 22q ^4,5.

Serology

Elevated levels of glycine have been reported in CSF ¹.

Radiographic features

MRI brain

The hallmarks of radiological diagnosis are the following features: 

• megalencephaly

• diffuse, bilateral and symmetric T2-weighted hyperintensity and T1-weighted hypointensity in the cerebral white matter, giving a characteristic 'swollen' appearance

  • there may also be abnormal diffusion signal on DWI

• subcortical white matter involved early in course of disease with involvement of the subcortical U-fibers

• relative sparing of the deep and cerebellar white matter

• bilateral subcortical cysts of CSF intensity affecting the anterior temporal regions and frontoparietal lobes

• eventual cerebral atrophy with increase in size of the subcortical cysts

Treatment and prognosis

The disease is managed by treating the manifestations with antiseizure medications to control epileptic seizures and physical therapy to improve motor function.

History and etymology

Although Bhim Sen Singhal (1933-), an Indian neurologist, initially described a megalencephalic leukodystrophy series of cases in 1991 ^5,6, it is sometimes named after Marjo S van der Knaap (1958-), a Dutch pediatric neurologist, who detailed another series with clinical and radiological features in 1995 ^4,7. 

Differential diagnosis

• cystic leukoencephalopathy without megalencephaly

• metachromatic leukodystrophy

• others causes of megalencephaly

• other leukoencephalopathies