megalencephalic leukoencephalopathy with subcortical cysts is clinically characterized by macrocephaly , mild motor developmental delay , and seizures . later in life
a combination of clinical features and mri features is required for arriving at the diagnosis .
the condition is inherited in an autosomal recessive pattern and the gene locus has been mapped as mlc 1 gene at chromosome 22q . the condition has been originally reported from india . in a meeting in japan in 1991 , singhal et al . described 18 patients with megalencephalic leukodystrophy from india .
group from netherlands later published a series of eight patients and described the clinical and mri features .
their description earned them the eponym van der knaap disease first used by cavalcanti and nogueira . a turkish study of 12 patients soon followed and established the genetic nature of the disease with autosomal recessive inheritance and a locus at 22q . from india ,
gorospe , singhal and co - workers did detailed genetic analysis and established this disease as a distinct clinicopathological entity with common locus at mlc 1 gene in all the 31 patients described in the agarwal community .
there was marked diversity in clinical presentation and striking similarity in mri findings of these patients .
a 16-year - old boy presented with seizures and difficulty in walking since four years [ table 1 ] .
he had complex partial seizures with semiology suggestive of right temporal lobe with secondary generalization around 80% of the times . at the time of presentation ,
he had decline of the mental ability with a progressive loss of acquired knowledge and he had to be withdrawn from school .
developmental history was normal in the first few years , except an increased head size noted during infancy .
clinical and mri characteristics of the four patients ( a ) axial t2 w image of case 1 showing multiple subcortical cysts and hyperintense white matter changes .
( b ) sagittal t2w images of case 2 showing multiple temporal and frontal cysts and white matter changes .
( c ) axial t1w image of case 3 showing characteristic cystic subcortical white matter appearing hypointense on t1 a 5-year - old girl presented with progressive difficulty in walking and tightness of all limbs [ table 1 ] .
she had mild developmental delay in the form of delayed sitting and walking and she could never run or climb stairs .
she had seizures of simple partial motor type beginning with right lower limb jerking and followed by generalization since 8 months of age .
the child had moderate impairment of cognitive and language abilities and could not go to school .
the motor system examination was suggestive of severe spasticity with grade 4 power of all limbs .
she had severe incoordination much more than could be attributed to the mild limb weakness .
her mri [ figure 1b ] showed temporal polar subcortical cysts along with other characteristic features suggestive of the disease . a 9-year - old boy presented with her sister ( detailed above ) [ table 1 ] .
he had two episodes of generalized tonic clonic seizures at the age of 5 years .
his motor examination was suggestive of mild spasticity , normal power , and hyperreflexia with flexor planter response .
cerebellar signs were present bilaterally and were suggestive of dysmetria , past pointing , intention tremor , and dysdiadochokinesia . his mri is shown in figure 1c . a 34-year - old man presented with a history of depressed mood since 6 months interfering with his work [ table 1 ] .
he had a history of generalized tonic clonic seizures since 8 years of age , well controlled on divalproex .
his developmental milestones were delayed and a large head size was noted by the parents since childhood . on examination , he had a head circumference of 59.5 cm .
there was no evident cognitive dysfunction and his mini mental status examination ( mmse ) score was 28/30 .
a 16-year - old boy presented with seizures and difficulty in walking since four years [ table 1 ] .
he had complex partial seizures with semiology suggestive of right temporal lobe with secondary generalization around 80% of the times . at the time of presentation ,
he had decline of the mental ability with a progressive loss of acquired knowledge and he had to be withdrawn from school .
developmental history was normal in the first few years , except an increased head size noted during infancy .
clinical and mri characteristics of the four patients ( a ) axial t2 w image of case 1 showing multiple subcortical cysts and hyperintense white matter changes .
( b ) sagittal t2w images of case 2 showing multiple temporal and frontal cysts and white matter changes .
( c ) axial t1w image of case 3 showing characteristic cystic subcortical white matter appearing hypointense on t1
a 5-year - old girl presented with progressive difficulty in walking and tightness of all limbs [ table 1 ] .
she had mild developmental delay in the form of delayed sitting and walking and she could never run or climb stairs .
she had seizures of simple partial motor type beginning with right lower limb jerking and followed by generalization since 8 months of age .
the child had moderate impairment of cognitive and language abilities and could not go to school .
the motor system examination was suggestive of severe spasticity with grade 4 power of all limbs .
she had severe incoordination much more than could be attributed to the mild limb weakness .
her mri [ figure 1b ] showed temporal polar subcortical cysts along with other characteristic features suggestive of the disease .
a 9-year - old boy presented with her sister ( detailed above ) [ table 1 ] .
he had two episodes of generalized tonic clonic seizures at the age of 5 years .
his motor examination was suggestive of mild spasticity , normal power , and hyperreflexia with flexor planter response .
cerebellar signs were present bilaterally and were suggestive of dysmetria , past pointing , intention tremor , and dysdiadochokinesia . his mri is shown in figure 1c .
a 34-year - old man presented with a history of depressed mood since 6 months interfering with his work [ table 1 ] .
he had a history of generalized tonic clonic seizures since 8 years of age , well controlled on divalproex .
his developmental milestones were delayed and a large head size was noted by the parents since childhood . on examination , he had a head circumference of 59.5 cm .
there was no evident cognitive dysfunction and his mini mental status examination ( mmse ) score was 28/30 .
the age at onset of symptoms ranges from birth to 25 years , with a median age at onset of 6 months .
the patient who presented to us at 33 years of age was surprisingly well preserved .
the most consistent feature is macrocephaly which has been demonstrated in all the genetically proven cases .
the macrocephaly is usually present at birth and after the first year follows the normal growth pattern .
they are usually well controlled with one or two drugs and uncontrolled epilepsy is unusual .
seizures have been reported in half of the patients ( 49% ) by singhal et al . and
mental retardation and cognitive regression is reported to be mild , though late progression may be noted .
significant disability due to motor as well as cognitive and language impairment was present in only one of our patients .
the presentation of case 4 is unique as depression has not been reported in literature to the best of our knowledge .
the mild course with near - normal motor and cognition functioning at 34 years of age is also remarkable .
the extensive white - matter changes in the brain with temporal subcortical cysts , sparing of the deeper structures have been considered the mri hallmarks of the disorder .
subcortical cysts are present in the anterior temporal region most commonly and often in the frontoparietal region .
though alexander disease , canavan disease , and glutaric aciduria have been considered as differential diagnosis of megalencephalic leukoencephalopathy with subcortical cysts , these conditions are quite unlikely to have such a mild clinical course .
none of these conditions have subcortical cysts on mri and all of these involve basal ganglia unlike megalencephalic leukoencephalopathy with subcortical cysts .
indian reports emphasize the existence of this disorder more commonly among a certain community belonging to haryana state .
we report four cases of megalencephalic leukoencephalopathy with subcortical cysts with some usual and a few unusual features such as neuropsychiatric features in one and seizures in all four patients .
one of our patients was not from the predisposed ethnicity and this highlights that the possibility of mlc should not be limited to these families in india .
we believe that characteristic mri features , large head size , ethnicity , pyramidal and cerebellar features , with a discrepantly mild clinical course are the key to diagnosing this disease in practice .
 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 
 . it usually presents with pyramidal and cerebellar signs . 
 megalencephaly is usually detected early . 
 seizures may be present but are usually easily controlled . 
 it has been reported commonly from a certain ethnicity of northern indian origin , but its presence is global . 
 we encountered four patients and describe the clinical and radiological features of these patients . 
 seizures though reported to be uncommon were seen in all our patients . 
 neuropsychiatric features have not been described as presentation so far but one of our patients had moderately severe depression . 
 all the patients were diagnosed by mri features and they responded well to symptomatic treatment . 
Introduction
Case Reports
Case 1
Case 2
Case 3
Case 4
Discussion
Conclusion