A distinct phenotype of childhood leukodystrophy presenting as absence seizure.

Leukoencephalopathy refers to any disease of the white matter including hereditary as well as acquired and toxic causes. Inherited leukodystrophies are diseases of myelin including abnormal myelin development, hypomyelination, or degeneration of myelin. We report a 6-year old female who presented with absence seizure at the age of 4 years. Cerebral magnetic resonance imaging (MRI) of the brain showed bilateral periventricular confluent high signal intensity. The seizure responded to anticonvulsant therapy, and the clinical course was characterized by normal development and neurological examination.

Introduction

The leukodystrophies are a heterogeneous group of genetic diseases involving dysmyelination of brain white matter as a result of substrate accumulation due to enzymatic defects.[1] Recognition of leukodystrophies has been revolutionized by MRI technology because of its increased sensitivity compared to CT scan and because of its ability in some cases to reveal disease-specific features that can lead to a diagnosis.[23] Most leukodystrophies manifest themselves during childhood or adolescence.[24] The onset of clinical disease is often insidious or intermittent and their signs and symptoms are often non-specific. These symptoms may include delay in attaining milestones, growth retardation, seizure, spasticity, ataxia, or movement disorders.[4] Some clinical features may be more specific to one or more disorders and can help orient the diagnostic investigations. An example would be the presence of macrocephaly, which is typically seen in Alexander, Canavan, and megalencephalic leukoencephalopathy with subcortical cysts (MLC).[5] Here, we report a 6-year old Palestinian girl who presented at the age of 4 years with absence seizure that responded to valproate therapy. Cerebral MRI on two occasions showed diffuse leukodystrophy.

Case Report

A 6-year-old Palestinian girl was born to non-consanguineous parents after uneventful pregnancy and labor. She had normal early development. At the age of 4 years, she developed episodes of sudden loss of activities and unresponsiveness to voice, each lasting only for few seconds followed by altered awareness for few minutes then she resumed her activities. The episodes were noted by the parents several times in 6 months. On examination, her head circumference was 51 cm (50th centile). She had no neurocutaneous markers, hepatosplenomegaly, skeletal abnormalities, or dysmorphic features. She had normal neurological examination including normal gait, cranial nerves, muscle strength and tone, deep tendon reflexes, and planter response. She had also normal cerebellar and fundus examination.

Metabolic workup, including serum ammonia and lactic acid levels were normal. Urine organic acid chromatography, plasma amino acid chromatography, and very long-chain fatty acids (VLCFA) were also normal. Other normal studies included normal arylsulfatase A activity in leukocytes and serum biotinidase assay. Electroencephalogram (EEG) showed normal background activity with bilateral generalized epileptiform discharges. Cerebral MRI showed diffuse symmetric high signal intensity in the periventricular white matter [Figure 1].

Figure 1

T2-weighted MR images showing symmetric confluent high signal intensities of the periventricular white matter

The seizures resolved after several weeks of treatment with valproic acid. Co-enzyme Q10 and B vitamins were also supplemented for the hope of treating one of several rare genetic vitamin-responsive disorders. Cerebral MRI repeated 8 months later showed the same findings [Figure 2].

Figure 2

T2-weighted MR images obtained after 8 months of treatment with B vitamins and co-enzyme Q10 showing the same high signal intensities of periventricular white matter

At last follow up at the age of 6 years, the patient had normal development and neurological examination including gait, cranial nerves, muscle tone, strength, deep tendon reflexes, and coordination. She had good school performance and social activities.

Discussion

In recent years, the use of magnetic resonance techniques has facilitated the characterization of several new forms of white matter disorders in children.[6] A pattern recognition program was used to identify cases with common features among the unclassified leukoencephalopathies, in which 7 major categories could be distinguished and 2 new entities were described: Megalencephalic leukoencephalopathy with cysts (MLC) and vanishing white matter disease (VWMD).[67] Demyelinating leukodystrophies are characterized by prominent hyperintensity of the white matter in T2-weighted images and prominent hypointensity in T1-weighted images compared with gray-white matter structures.[25]

The clinical presentation of the different leukodystrophies is often similar for a given age group.[5] Neurological symptoms of leukodystrophies consist of progressive motor symptoms and changes in cognition and language, but recalcitrant seizures are an unusual feature of disorders mainly affecting brain white matter.[25] Some clinical features may be more specific to one or more disorders and can help orient the investigations as macrocephaly in Alexander disease, Canavan disease, MLC, and VWMD.[57] Rare presentations of childhood leukodystrophy of unknown origin were reported including inattention and behavioral problems resembling bipolar disorder.[8] The adolescent or adult presentations are usually characterized by cognitive regression and psychiatric manifestations while the motor symptoms are typically more subtle.[59]

The patient we present in this article has typical demyelinating leukodystrophy presenting with seizure as the sole manifestation, which, to our knowledge, has not been described in previous reports.

Neurometabolic workup excluded many entities in this patient such as L2-Hydroxyglutaric aciduria, adrenoleukodystrophy, metachromatic leukodystrophy, and Canavan disease. Serum biotinidase enzyme assay was also normal excluding this entity as a rare cause of white matter disease. Alexander disease was not considered as a diagnostic possibility in the patient due to the absence of macrocephaly and the lack of its typical recognition pattern on cerebral MRI.

Conclusion

Our patient has a leukodystrophy with a distinct phenotype further expanding the clinical spectrum and adding to the increasingly recognized evidence that the clinical features of childhood leukodystrophy are extremely variable.