59.1 Clinical Features
and Laboratory Investigations Megalencephalic leukoencephalopathy with subcorti- cal cysts (MLC) is a rare leukoencephalopathy with an autosomal recessive mode of inheritance. The disease is relatively prevalent among Turkish people and in a certain Asian-Indian community, the Agarwal ethnic group. Macrocephaly is present at birth or, more frequently, develops during the first year of life. The degree of macrocephaly is variable and is impressive in some of the patients. After the first year of life the head growth rate normalizes and growth follows a line parallel to the 98th percentile, usually several centimeters above it. Initial mental and motor devel- opment is normal in most cases, mildly delayed in some of the patients. Apart from progressive macro- cephaly, the first clinical sign is usually a delay in walking. Walking is often unstable and the child falls frequently. After an interval of several years, a slow deterioration of motor function is noted with devel- opment of axial ataxia and ataxia of the extremities.
Signs of pyramidal dysfunction are late and minor, and are as a rule dominated by the signs of cerebellar ataxia. Muscle tone tends to be low, apart from some ankle hypertonia. Reflexes become high and Babinski signs become apparent. Gradually the ability to walk independently is lost, and most children become completely wheelchair-dependent at the end of the first decade or in the second decade of life. Almost all patients have epilepsy from early on, usually easily controlled with medication. Mental deterioration is late and mild. Decreasing school performance be- comes evident during the later years of primary school. In a minority of patients, intellectual capaci- ties are mildly decreased from the beginning. A rela- tively late and slow decrease in intelligence is also noted in these patients. Speech becomes increasingly dysarthric and the patients may also develop dyspha- gia. Some patients display extrapyramidal movement abnormalities with dystonia and athetosis. Minor head trauma has been reported to induce temporary deterioration in some patients, most often with seizures or status epilepticus, prolonged uncon- sciousness, or acute motor deterioration with gradual improvement.
Some patients have a more severe clinical course and maintain the ability to walk independently only
for a few years or never achieve independent walking.
Some patients have a more benign clinical course. As a teenager they may have normal mental and motor function and only have borderline macrocephaly.
Some patients still walk independently in their for- ties.As the disease has been known for only a relative- ly short time, little information exists about average life span. Some patients have died in their teens or twenties, but others are alive in their forties.
In extensive laboratory investigations no abnor- malities are found. CSF protein is normal. Peripheral motor and sensory nerve conduction velocities and electromyogram are normal. Evoked potentials are initially normal in most patients. BAEPs remain nor- mal, but VEPs and SSEPs deteriorate over the years with prolongation of latencies and abnormal cortical responses. EEG is initially normal. Subsequently, background slowing occurs and abnormalities are seen such as sharp waves, spikes, and spike-wave complexes with variable location. Abnormal photo- paroxysmal responses are seen in some of the pa- tients but not in all.
Presently, the diagnosis is MRI-based. Analysis of the MLC1 gene can be performed, and abnormalities are found in 60–70% of the patients with typical MRI findings. Some families without mutations in MLC1 exclude linkage to the MLC1 locus, implying that there must be another gene or genes related to MLC.
Prenatal diagnosis is possible in families with known mutations in MLC1.
59.2 Pathology
Brain biopsy was performed in one patient (van der Knaap et al. 1996). The cortex was normal. A status spongiosus of the cerebral white matter was found with presence of innumerable vacuoles. Myelin sheaths had a normal thickness and density and there were only minor signs of myelin breakdown. The white matter showed intense fibrillary astrogliosis.
Electron microscopy revealed splitting of myelin sheaths at the intraperiod line with intramyelinic vac- uole formation. The splitting involved only the outer lamellae of the myelin sheaths; the vacuoles were cov- ered by only one or two myelin layers. There was no evidence of axonal degeneration or loss. The cerebral cortex was normal.
Megalencephalic Leukoencephalopathy
with Subcortical Cysts
59.3 Pathogenetic Considerations
There is one gene known to be related to MLC: MLC1, formerly called KIAA0027, located on chromosome 22qtel. Mutations in MLC1 are found in approximate- ly 70% of the MLC patients. Different mutations have been found. Within the Agarwal ethnic group, the patients are homozygous for the same founder mutation. Among Turkish patients, however, different mutations are found and there is no evidence for a founder mutation among them. There is no evident genotype–phenotype correlation. Some families without mutations in MLC1 exclude linkage to the MLC1 locus, implying that there must be another gene or other genes related to MLC.
MLC1 encodes a membrane protein of unknown function with eight transmembrane domains. The MLC1 protein is highly conserved throughout evolu- tion in a variety of different vertebrate species that produce myelin. Orthologues are not found in eu- karyotes that do not produce myelin, suggesting an as yet undiscovered fundamental function of MLC1 re- lated to myelin. Sequence analysis of the MLC1 pro- tein does not reveal any similarity to known proteins or protein domains. Most proteins with eight trans- membrane domains have a transport function. Both the C- and the N-terminus of MLC1 are located with- in the cytoplasm. MLC1 is expressed in the brain and all types of blood leukocytes. Within the brain, the MLC1 protein is specifically expressed in astrocytic endfeet in perivascular, subependymal, and subpial regions. Astrocytic endfeet form part of the blood–
brain barrier. This localization suggests a possible role for MLC1 in a transport process across the blood–brain barrier. The blood–brain barrier is a dif- fusion barrier for the exchange of molecules and is formed by seamlessly joined endothelial cells of the capillary wall, the basal lamina, and astroglial end- feet. The role of astrocytes in the blood–brain barrier is not well defined. They are separated from the endothelial cells by the basal lamina and do not con- tribute directly to the physical barrier. Perivascular astroglial endfeet contain many transport proteins, including transporters of monocarboxylates, glucose, glutamate, and water.
Given the presence of vacuoles in the outer layer of the myelin sheaths in MLC, the role of astrocytic end- feet in water homeostasis in the brain is of special interest. Different water channel proteins or aquapor- ins are present in the brain. Aquaporin-4 shows a lo- calization in the astroglial endfeet similar to MLC1.
Aquaporin-4 is associated with the dystrophin-asso- ciated glycoprotein complex (DAGC). This complex links the actin cytoskeleton to the extracellular ma- trix. Interestingly, some congenital muscular dystro- phies, which are caused by mutations in members of the dystrophin-associated glycoprotein complex, also
show white matter abnormalities on MRI. Especially the MRI pattern of merosin-deficient congenital muscular dystrophy is very similar to that of MLC.
Myelin vacuolation is seen in both MLC and merosin- deficient congenital muscular dystrophy. Another possibility is that MLC1 is involved in transporting molecules that are essential for oligodendrocytes or myelin. Mutations in MLC1 may affect myelin sheath formation or compaction. An argument in favor of this possibility is the fact that the rapidly increasing macrocephaly of MLC develops during the period of most rapid myelin formation, the first year of life, whereas head growth rate slows down and becomes normal in the second year of life. It is probable that the myelin vacuoles arise during the myelin deposi- tion. In agreement with this, Schmitt et al. (2003) show that MLC1 mRNA expression in the murine brain peaks during a transitional period of astrocytic specialization that occurs in white matter during myelination, suggesting a role for MLC1 in myelin formation.
The white matter has a very abnormal aspect on MRI at an early age (the youngest child was 1.5 years old when imaging was performed), when neurologi- cal examination is still normal or near-normal and evoked responses are normal. Thus, despite its highly abnormal appearance, the white matter is functional- ly intact or largely intact during these early years. Ap- parently the presence of the vacuoles in the outer part of the myelin sheaths permits normal function. Over the years, MRI shows some decrease in white matter swelling and some enlargement of lateral ventricles and subarachnoid spaces, a process accompanied by clinical deterioration. The basis of the deterioration is not known.
The gene KIAA0027/MLC1 has also been implicat- ed in catatonic schizophrenia. However, this has so far not been substantiated. Among patients and family members known to be carriers, the incidence of psy- chiatric illness is not increased.
59.4 Therapy
So far all attempts at treatment have failed. Patients have been treated with diuretics and acetazolamide, but neither the clinical symptoms nor the white matter swelling improved. Treatment with creatine monohy- drate did not lead to objective improvement either.
59.5 Magnetic Resonance Imaging
In MLC the cerebral hemispheric white matter is dif- fusely abnormal and swollen (Figs. 59.1–59.6). The swelling is most marked during the first years of life, with obliteration of peripheral CSF spaces and nar-
59.5 Magnetic Resonance Imaging 443 059_Valk_Megalencephalic 08.04.2005 16:15 Uhr Seite 443
Fig. 59.1.
rowing of ventricles (Fig. 59.1). In older children and adults the hemispheric white matter swelling is less severe, peripheral CSF spaces are more prominently visible, and the ventricular system becomes enlarged (Fig. 59.3 and 59.4). On FLAIR images parts of the cerebral white matter may have a slightly lower signal intensity than the remainder of the abnormal white matter, related to the very high water content of the
white matter. The external and extreme capsules are prominently involved. The central white matter struc- tures, including the corpus callosum, anterior limb of the internal capsule, posterior limb of the internal capsule (in part), and a periventricular rim of occipi- tal white matter are relatively spared. The posterior limb of the internal capsule shows either a double line of abnormal signal intensity over its whole length
59.5 Magnetic Resonance Imaging 445
Fig. 59.1. (continued). MRI series of a 6-year-old girl with MLC.
The upper row of T1-weighted sagittal images show the swollen white matter and the cysts in the frontal and temporal region. The U fibers in the posterior region of the cerebral hemispheres, corpus callosum, brain stem, and cerebellum are relatively normal in signal intensity. The second and third rows shows these features on axial T2-weighted images. A large cavum septi pellucidi and cavum Vergae are visible.The corpus
callosum is largely spared. The posterior limb of the internal capsule contains two lines of abnormal signal with a line of normal signal in between. The midbrain, pontine tegmentum, pyramidal tracts in the basis of the pons, and cerebellar white matter are mildly abnormal in signal but not swollen. The fourth and fifth rows contain the proton density images, which reveal the many subcortical cysts
Fig. 59.2. Three ADC maps of the same patient as in Fig. 59.1.
ADC values are highly elevated within the cerebral hemispher- ic white matter, for instance 2.06–2.47 ¥ 10–3mm2/s in the frontal white matter (normal white matter ADC 0.85–0.95).
ADC values are normal in the basal ganglia (0.74–0.94 ¥ 10–3mm2/s) and mildly elevated within the cerebellar white matter (1.10–1.32 ¥ 10–3mm2/s)
059_Valk_Megalencephalic 08.04.2005 16:15 Uhr Seite 445
(Figs. 59.1 and 59.3) or a signal abnormality mainly in its distal part (Fig. 59.4). Some sparing of arcuate fibers may be seen, most often in the occipital area (Figs. 59.3 and 59.4). In the majority of patients, the cerebellar white matter shows only a mild abnormal- ity in signal intensity and no swelling (Figs. 59.1, 59.3 and 59.4). In some patients minor abnormalities are
seen in the brain stem, especially the pyramidal tracts (Fig. 59.1). There are almost invariably subcortical cysts in the anterior temporal region, often also in the frontal and parietal subcortical regions (Figs. 59.1 and 59.3–59.6). The cysts are bilateral. So far, the anterior temporal cysts have only been found to be lacking in some young infants and children with
Fig. 59.3. An 18-year-old boy with MLC. The cerebral white matter is diffusely abnormal and mildly swollen, but less so than in the previous patient. Note again the sparing of the cor- pus callosum and the presence of a double line of high signal
from the posterior limb of the internal capsule. There are mild signal abnormalities in the cerebellar white matter. There are cystic lesions in the anterior temporal and frontal regions
MLC. The cysts tend to become larger with age and may increase in number. In some patients they be- come very large (Fig. 59.5). The signal intensity of the contents of the cysts is always similar to that of CSF. In accordance with this, T
1and T
2of cyst contents and CSF are also similar. A patent and enlarged cavum septi pellucidi and cavum Vergae are often present (Figs. 59.1 and 59.3). Cortical gray matter structures and basal nuclei are always normal.
Since the gene for the disease has been found, less prominent white matter abnormalities have been documented in patients with clinically mild disease (Fig. 59.6). Early MRI may show the typical diffuse cerebral white matter abnormalities with swelling (Fig. 59.6a), whereas follow-up MRI may show that the cerebral white matter now has a normal signal intensity in large areas and is less swollen (Fig. 59.6b).
It is mainly the subcortical white matter that remains
59.5 Magnetic Resonance Imaging 447
Fig. 59.4. A 20-year-old woman, showing that some atrophy has now developed 059_Valk_Megalencephalic 08.04.2005 16:15 Uhr Seite 447
abnormal. Still, the characteristic subcortical cysts are present.
MRS has revealed a reduction of all signals per vol- ume, indicative of the high water content of the brain.
Relative to creatine, N-acetylaspartate is decreased and myo-inositol is increased, suggesting axonal damage and gliosis. Diffusion tensor imaging shows increased ADC values in the cerebral white matter and reduced anisotropy (Fig. 59.2).
Similar white matter changes with swelling have been reported in Canavan disease, Alexander disease,
L
-2-hydroxyglutaric aciduria, and merosin-deficient congenital muscular dystrophy. However, in Canavan disease, as a rule, MRI demonstrates additional involvement of the thalamus and globus pallidus, not found in MLC patients. Special MRI findings in Alexander disease are a more prominent sparing of parieto-occipital white matter and often also sparing
Fig. 59.5. A 5-year-old girl with MLC. The subcortical cysts are huge. Courtesy of Dr. J. Wolf, Biochemical Genetics Clinic, Universi- ty of Wisconsin–Madison, Madison, Wisconsin, USA
of the U fibers throughout. Basal ganglia and brain stem structures are typically involved. Contrast en- hancement of certain brain structures is typically present. Cavitation starts in the deep frontal white matter. None of these features is present in MLC. In
L
-2-hydroxyglutaric aciduria MRI shows additional involvement of caudate nuclei, putamen, dentate
nuclei, and severe atrophy of the cerebellar vermis, not observed in MLC. The MRI abnormalities ob- served in merosin-deficient congenital muscular dys- trophy are very similar to those observed in MLC.
Subcortical cysts were observed in one patient with a later-onset variant of muscular dystrophy with leukoencephalopathy and swelling.
59.5 Magnetic Resonance Imaging 449
Fig. 59.6 a. Girl with DNA-confirmed MLC. The first MRI (a) was obtained at the age of 5 years; the second (b) at the age of 11 years. Whereas the first images show a classical pattern
of abnormalities (a), the white matter looks much more nor- mal than usual for MLC on the follow-up MRI (b).The subcorti- cal cysts, however, remain present
059_Valk_Megalencephalic 08.04.2005 16:15 Uhr Seite 449
Fig. 59.6 b. (continued).
