A case of megalencephalic leukoencephalopathy with subcortical cysts ( Van der Knaap disease )

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare neurodegenerative disorder first described by Van der Knaap in 1995 1 . It is characterized by early onset macrocephaly which is an invariable feature. Slow degeneration of motor functions and mild mental deterioration are late findings 1 . Some patients have lived up to their 2nd or 3rd decades 1 . To the best of our knowledge this is the first reported case in Sri Lanka.


Megalencephalic
leukoencephalopathy with subcortical cysts (MLC) is a rare neurodegenerative disorder first described by Van der Knaap in 1995 1 .It is characterized by early onset macrocephaly which is an invariable feature.Slow degeneration of motor functions and mild mental deterioration are late findings 1 .Some patients have lived up to their 2nd or 3rd decades 1 .To the best of our knowledge this is the first reported case in Sri Lanka.

Case report
A 3 year old girl, born to non consanguineous parents, with an uneventful birth history following a normal pregnancy, presented with progressive enlargement of the head size from early months of life.According to the Child Health Development Record (CHDR) the head circumference (HC) was normal at birth, exceeded the 2SD limit for age at 6 months and after 9 months of age followed above and parallel to the 98th percentile (Figure1).The child had achieved age appropriate milestones up to the age of 9 months.She had developed unsteady gait and urinary incontinence at the age of 2 years.At the age of 3 years, she developed seizures which were easily controlled with sodium valproate.
On examination, there was macrocephaly (HC 56cm, >98 th percentile), unsteady gait, slurring of speech, extra-pyramidal signs and cerebellar ataxia.Magnetic resonance imaging (MRI) of the brain showed bilaterally symmetrical "swollen white matter" which was hypo-intense on T1 weighted sequences (Figure 1) and hyper-intense in T2 weighted sequences and FLAIR sequences suggestive of diffuse white matter degeneration.Characteristic subcortical cysts were seen in both temporal regions, both parietal regions and right frontal region.Deep structures and cerebellum were spared.Cerebral cortex was uninvolved.There was no enhancement following contrast administration.

Discussion
MLC is an autosomal recessive disorder due to mutations in MLC1 gene 2 .The disease is more commonly found in some ethnicities like the Agrawal community in India, Libyan Jews and Turks where consanguinity is common 3,4 .In our case consanguinity was not present.
Macrocephaly may be present at birth but more frequently develops during the first year of life 1 .The degree of macrocephaly is variable and can be as much as 4 to 6 standard deviations (SDs) above the mean 5 .The HC in this child was normal at birth and there was rapid growth since early months of life.all patients have early onset epilepsy 1 .This child too had seizures which were easily controlled.Other clinical symptoms that may be present are cerebellar ataxia, dysarthria and extrapyramidal symptoms like dystonia and athetosis 1 .Unsteady gait, slurring of speech, extra-pyramidal signs and cerebellar ataxia were present in our patient.
MLC can be diagnosed confidently by MRI which shows diffuse white matter changes and subcortical cysts 1 .Subcortical cysts are almost invariably present in the anterior temporal region and often in the frontoparietal region 1 .Over time the white matter swelling decreases and cerebral atrophy ensues 1 .Gray matter and deep white matter structures like corpus callosum, internal capsule and brain stem are relatively spared..Typical MRI features were seen in our patient.
The differential diagnosis of macrocephaly and leukoencephalopathy includes Canavan disease, Alexander disease, infantile-onset GM2 and GM1 gangliosidosis.In contrast to MLC these diseases have a rapidly progressive course of deterioration.In Canavan disease 6 , MRI shows involvement of cerebral white matter, thalamus and globus pallidus, which are spared in MLC.There is marked increase in the N-acetylaspartate.Alexander disease 7 leads to a megalencephaly and leukoencephalopathy with frontal predominance of MRI abnormalities and contrast enhancement of particular brain structures, which is not a feature of MLC.Cystic degeneration may occur in Alexander's disease, but deep frontal white matter is mainly affected 7 .MLC characteristically has an early onset and slow progression, whereas Canavan and Alexander disease have rapid progression.MRI in infantile GM2 gangliosidosis is characterized by prominent involvement of the basal ganglia and thalami in addition to the white matter abnormalities 8 .MRI features in infantile GM1 gangliosidosis are very similar to those of GM2 gangliosidosis.Demonstration of deficiency of beta galactosidase activity in leukocytes confirms the diagnosis.