A 3 year old female, larger head relative to rest of the body.
Product of non consanguineous marriage.
Clinical and neurological examination shows delayed milestones, walking imbalance.
History of similar illness in elder sister.
MRI study of brain shows:
Diffuses cerebral white matter involvement. Early involvement of sub cortical white matter. Sub cortical white matter cysts iso intense to Csf representing white matter paucity in temporal regions.
Basal ganglia and internal capsules spared.
Cerebral cortical atrophy.
Minimal involvement of Cerebellar white matter.
On MRS reduced NAA and slightly raised Choline peak.
Impression:
Imaging findings of bilateral diffuse white matter disease, involvement sub cortical white matter with cysts, sparing basal ganglia and internal capsules with Macrocephaly clinically goes in favour of Van der Knaap disease.
Vander Knaap Leukoencephalopathy
Abbreviations and Syn:
1. MLC: Megaloencephalic leukoencephalopathy with subcortical cysts, formerly known as Vacuolating megaloencephalic leukoencephalopathy with benign, slowly progressive course.
2. VWM: Leukoencephalopathy with Vanishing white matter (WM), Alternatively called CACH (Childhood ataxia central hypomyelination)
3. WML: White matter disease with lactate.
4. H-ABC: Hypomyelination with atrophy of the basal ganglia (BG) and cerebellum.
Imaging findings and diagnostic clues:
MLC:
Swollen WM involvement is diffuse, includes subcortical U-fibers.
Subcortical cysts makred in anterior temporal and fronto parietal white matter.
Spares internal capsules, BG, thalami
Cerebellar involvement subtle.
VWM:
WM replaced by CSF signal, involvement is diffuse WM, includes subcortical U-fibers.
BG and thalami not involved.
Trackt-like ventral trigeminothalamic and central tegmental tract demyelination in brain stem
Cerebellar WM involved.
WML:
Diffuse periventricular, deep cerebral WM.
Spared subcortical U-fibers.
Posterior corpus callosum and posterior limb of internal capsule involved.
In Brainstem cerebral Peduncles, pyramidal tracts, medial lemniscus, intraparenchymal trajectories of trigeminal nerves, anterior spinocerebellar tracts involved.
Cerebellar WM involved later, but then notably abnormal.
Spinal involvement an important feature. In spine dorsal columns and lateral corticospinal tracts involvement is typical.
H-ABC:
Atrophy of BG and cerebellum.
Diffuse hypomyelination of cerebral WM.
Subcortical U-fibers involved.
CT
In all varieties involved WM show reduced attenuation. No contrast-enhancement.
MRI
In all involved WM show decreased signal on Tl WI and increased signal on T2WI
In MLC: Anterotemporal and frontoparietal subcortical cysts approximate CSF signal.
In VWM: Involved WM approximates CSF signal.
DWI: both MLC and WML on DTI shows decreased anisotropy and increased ADC values
No contrast-enhancement on post contrast study.
On MR spectroscopy in MLC all metabolites decreased in cystic regions with reduced NAA in
WM, +/- lactate. In VWM: All metabolites of affected WM disappear as the WM disappears; +/-lactate , glucose signals. In WML: Positive lactate peak; normal to mildly increased Cho,
reduced NAA, increased myo-inositol. In H-ABC: Increased Myo-inositol and creatine (gliosis) in WM;reduced frontal NAA, but otherwise NAA relatively normal
Differential Diagnosis:
DDs of macrocephaly with diffuse leukoencephalopathy is limited includes Canavan disease, Alexander disease, infantile-onset GM2 gangliosidosis and laminin alpha-2 (merosin) deficiency.
Laminin alpha 2 deficiency: The white matter disease in laminin alpha-2 deficiency most closely resembles that observed in MLC; however, the typical subcortical cysts of van der Knaap are lacking. Individuals with laminin alpha-2 deficiency have prominent weakness and hypotonia, not seen with MLC - van der Knaap. Molecular genetic testing will be confirmative.
Canavan disease: Typically shows involvement of the thalamus and globus pallidus with relative sparing of Putamen and caudate nucleus. The globus pallidus and thalamus are not involved in MLC. The white matter may be cystic in Canavan disease, but the typical subcortical cysts seen in MLC are lacking. Confrmation of Canavan disease possible by demonstration of very high concentration of NAA in the urine and/or molecular genetic testing of ASPA.
Alexander disease: Megalencephaly and leukoencephalopathy with frontal predominance on MRI is typical with contrast enhancement of particular brain structures not a feature of MLC. Cystic degeneration may occur in Alexander disease, but the location of the cysts is frontal. Alexander disease can be confirmed by molecular genetic testing of GFAP.
Infantile GM2 gangliosidosis: MRI characterized by prominent involvement of the basal ganglia and thalami in addition to the white matter abnormalities. Demonstration of assaying hexosaminidase A and B in serum, leukocytes, or cultured skin fibroblast will be confirmtative.
General Features: None have systemic or other organ involvement
Genetics:
MLC: Autosomal recessive; gene localized on chr22q(tel); 26 different mutations of MLCI gene. Encodes putative CNS membrane transporter
VWM: Recessive inheritance; gene on 3q27,mutations in genes that encode eIF2B subunits: EIF2Bl-S.
WML: Autosomal recessive inheritance likely.
H-ABC: Unknown, 7 cases in literature (no sibling pairs, so inheritance unknown)
Etiology:
All are inborn genetic errors
Epidemiology
All are extremely rare
MLC and VWM rare, but carrier rate is high in some communities with high levels consanguinity.
Common MLC mutations in specific Indian community (Agarwal), Libyan Jewish, and Turkish populations due to founder effect.
Common VWM mutations in certain regions of Netherlands.
Age
MLC: Macrocephaly before the age of 1year
VWM: Young children (slower progression of older onset of symptoms)
WML: Older children, adolescents, young adults
H-ABC: 1-20 years.
Clinical Presentation
Most common signs/symptoms
MLC: Macrocephaly. Delayed onset slow motor deterioration. Slower cognitive decline.Cerebellar ataxia and pyramidal tract involvement, motor deterioration, seizures.
VWM: Episodes of major deterioration and coma following infection or minor head trauma. Relatively preserved cognition.
WML: Slowly progressive pyramidal, cerebellar and dorsal column dysfunction. Spasticity and ataxia. preserved cognitionr
H-ABC: Progressive extrapyramidal symptom like ataxia.
Management
Establish the extent of disease in an individual diagnosed with megalencephalic leukoencephalopathy with subcortical cysts (MLC) by
• Neurologic examination
• Brain MRI
• Physical therapy/occupational therapy assessment
• Assessment of cognitive dysfunction (neuropsychological testing)
Supportive therapy includes the following:
• Antiepileptic drugs (AED) if epileptic seizures are present
• Physical therapy to improve motor function
• Special education
• Speech therapy as needed
Prevention of Secondary Complications from minor head trauma.
Evaluation of Relatives at Risk with Genetic Counseling.
Reference : Diagnostic Imaging Osborn.
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