Leukodystrophy with Megalencephaly
When this child was initially evaluated, a diagnosis of hydrocephalus seemed certain. Yet elements of the physical exam brought this diagnosis into question. Since the process was chronic, ventriculoperitoneal shunting was postponed until a differential for enlarging head circumference could be pursued. The differential diagnosis for this case was separated between two divergent categories: macrocephaly (large head) versus megalencephaly (large brain).
Macrocephaly involves an enlarged head circumference due to either a space occupying lesion, an increase in cerebral spinal fluid (CSF) spaces, an increase in cranial vascular volume, an increase in clavarium thickness, or an increase in the brain volume.
Though this child's tense, bulging anterior fontanel strongly suggested hydrocephalus, other elements of the physical exam did not fully support this conclusion, e.g. the child's level of consciousness was not significantly different from his baseline, he was not irritable, his feeding pattern remained the same, and he had not vomited. He did not exhibit papilledema or signs of increased tectal pressure ("setting sun"). Moreover, a prominent split metopic suture suggested a chronic rather than acute process. The opening pressure during the lumbar puncture (LP) was normal and the level of consciousness did not change following the LP.
A head CT did not show evidence of a space occupying lesion or bony abnormality. No mass effect, midline shift, or cystic structures were noted and the white matter signal was abnormal for a child this age. There was enlargement of the lateral, third, and fourth ventricles with a persistent cavum septum pellucidum, but no sulcal effacement. The degree of hydrocephalus was felt to be mild and not the primary cause for the very large head circumference. No evidence of a Chiari malformation, posterior fossa tumor, edema, or vascular malformation was seen. A head MRI showed white matter hypomyelination in the frontal, temporal, and occipital lobes, as well as the centrum semiovale.
While in the developing brain, a certain amount of hypomyelination is expected, the adult pattern is present by 18-24 months of age. Myelination occurs in a caudo-rostral manner; the cerebellum and posterior limb of the internal capsule exhibit greater myelination than the white matter of the frontal/temporal regions or centrum semiovale. Yet the hypomyelination in this child's brain was greater than that seen in a normally developing brain. The pattern was therefore felt to be most consistent of a leukodystrophy associated with a megalencephaly.
Megalencephaly denotes a large brain as a result of an expanding parenchyma. The differential for megalencephaly includes familial megalencephaly, Tay Sachs disease, glutaric aciduria, galactosemia, neurocutaneous syndromes such as neurofibromatosis and tuberous sclerosis, and leukodystrophies (Canavan's and Alexander's diseases). A minority of patients with globoid leukodystrophy (Krabbe's) and maple syrup urine disease may exhibit megalencephaly.
The child's family had no history of large head circumferences. The formal ophthalmologic exam did not reveal any cataracts or a cherry red macula. No evidence of skin hyper/hypopigmentations or shagreen patches was uncovered. The child did not have hepatosplenomegaly. As a result, these findings lessened the probability of familial megalencephaly, Tay Sachs disease, galactosemia, or a neurocutaneous process.
Serum amino acids and urine organic acids were also normal. Specifically, no accumulation of very long chain fatty acids suggestive of adrenaleukodystrophy or branched chain amino acids indicative of maple syrup urine disease were found. A diagnosis of glutaric aciduria was excluded since normal amounts of glutaric, 3-hydroxyglutaric, 3-hydroxybutyric, and acetoacetic acids were found in the urine.
In checking for Canavan's disease, one must specifically test for the urine metabolite N-acetylaspartic acid. Since no urine N-acetylaspartic acid was detected, and DNA analysis did not show aspartoacylase mutations, Canavan's disease was excluded. A peripheral neuropathy associated with Krabbe's was ruled out because the nerve conduction study and EMG were normal. Also, no abnormality of leukocyte galactosylceramide ß-galactosidase (Krabbe's) was demonstrated.
Children with the infantile form of Alexander's disease may be born with large heads or develop the megalencephaly within the first few months of life. They are developmentally delayed and exhibit hypertonia, hyperreflexia, and poor suck. Children may also have hydrocephalus. Imaging studies typically show mildly dilated ventricles and abnormal myelination of the frontal and central white matter. The EEG demonstrates bifrontal spikes with high voltage slow activity (similar to that seen in this child's EEG). To date, no enzyme, amino acid abnormality, or gene product has been associated with Alexander's disease. The only study available for definitive diagnosis is a brain biopsy; it invariably shows hypomyelination with subpial and subependymal Rosenthal fibers.
A brain biopsy was performed in order to confirm a presumptive diagnosis of Alexander's disease. While extensive gliosis with hypomyelination was present, no subpial Rosenthal fibers (pathognomonic of Alexander's disease) were found in either light microscopic or EM sections. Moreover, the electron micrographs demonstrated "watery cellular processes". Since Rosenthal fibers were absent, Alexander's disease was not confirmed.
The clinical exam suggested a megalencephaly and the MRI showed a leukodystrophy. Yet when the biopsy did not confirm Alexander's disease, a recently described leukodystrophy with a milder clinical course was considered.
Several recent articles detail a leukodystrophy with similar MRI findings to Canavan's and Alexander's diseases but without the metabolic/enzymatic findings of Canavan's or subpial Rosenthal fibers on brain biopsy seen in Alexander's. At least three separate investigators have noted similarities in their patients, i.e., negative laboratory studies, megalencephaly of unknown etiology with hypomyelination, and milder clinical course than expected given the severity of dysmorphology seen in the brain images. Similarities of our findings to these cases lead us to conclude that the child may have this form of leukodystrophy.
Leukodystrophies with megalencephaly include Canavan's, Alexander's, and a recently described leukodystrophy with a milder clinical course. Both Canavan's and Alexander's diseases are distinguished by early onset and progression to death at an early age. The more recently characterized benign leukodystrophy has less severe disability initially, and a slower progression.
Canavan's disease (van Bogaert-Bertrand) is a spongiform leukoencephalopathy characterized by white matter vacuolization. In the neonatal form of the disease, the child is lethargic with decreased spontaneous motor activity and poor suck (Swaiman, 1994). Hypotonia and Cheyne-Stokes breathing are also present. These children may die within weeks of delivery. Although sporadic new mutations occur, the infantile form is found primarily in children of Jewish or Saudi heritage. Onset is within the first six months of life and distinguished by developmental arrest, psychomotor retardation, hypotonia, seizures, and megalencephaly. Poor head and neck control are the results of both the hypotonia and large head. By 12 months of age, the hypotonia gives way to spasticity and episodic decorticate posturing. Pendular nystagmus precedes blindness and optic atrophy (Lyon et al., 1996). Death often occurs prior to four years of age. The juvenile form exhibits ataxia, tremor, and mental deterioration. Progression involves signs of dysarthria, dementia, and spasticity. No megalencephaly is found in this form of the disease.
Laboratory analysis for Canavan's disease reveals elevated levels of N-acetylaspartate due to an autosomal recessive null mutation of N-acetyl aspartate amino hydrolase (aspartoacylase) (Tsai and Coyle, 1995). A recent animal study suggests that the mutation occurs on chromosome 12 in humans (Donahue et al., 1996). Both neonatal and juvenile forms are thought to have spontaneous mutations.
In his original article, Alexander (1947) described a 15 month old child with enlarging head size from seven months of age, seizures, mild hydrocephalus, and developmental delay. The child came to autopsy following severe dehydration secondary to prolonged vomiting and diarrhea. Histology of the brain revealed elongated rods surrounding blood vessels and subpial region perpendicular to the brain surface (Rosenthal fibers). Hypertrophied fibrillary astrocytes were found throughout the white matter.
Russo et al., (1976) and Borrett and Becker (1985) reviewed the case reports of Alexander's disease and classified them into three categories: infantile, juvenile, and adult. The infantile form is the most severe of the three. Afflicted children may present at birth, but symptoms usually develop over the first six months of life. These include progressive psychomotor retardation, seizures, spasticity, and megalencephaly; death is generally within the first three years of life. The juvenile and adult forms are less affected. Bulbar symptomatology dominates the juvenile form, e.g., dysarthria, vocal cord paralysis, difficulty swallowing, and decreased facial sensation. Onset occurs after infancy, and there is preservation of intellectual level and sensory functioning. In the adult form, the findings are similar to multiple sclerosis.
For all classifications of Alexander's disease, brain biopsy and neuroimaging are the only studies currently available to support a clinical diagnosis. Histology of brain biopsies shows characteristic gliosis, dysmyelination, and subpial Rosenthal fibers. Comparative neuroimaging (Hess et al., 1990) reveals diffuse, confluent high signal intensity in frontal white matter and low attenuation in the centrum semi ovale with preservation of the posterior limb of the internal capsule and subcortical U fibers.
EEG patterns in Alexander's disease appear distinct. Pridmore et al. (1993) describe EEGs of 10 children with Alexander's disease; the tracings show frontal slowing accompanied by focal discharges in the frontal/central areas.
A leukodystrophy with significant white matter findings but a less devastating clinical course has been described by several authors. Gourtieres et al., (1996) described five patients with leukoencephalopathy and megalencephaly. Eight patients with similar characteristics were reported by van der Knapp et al. (1995). Clinical features in common were progressive ataxia, spasticity, but preserved intellectual functioning. Seizures developed as early as 1.5 years of age. One patient, however, was 12 years old when the first clinical seizure occurred. Other findings include abnormal MRI white matter intensity with preservation of normal intensity in the corpus callosum, posterior internal capsule, and portions of the occipital lobe white matter. Cysts developed in the frontal, temporal, or parietal lobes and enlarge with age. Most children achieve developmental milestones, albeit slowly (some had "normal" development). Both Gourtieres et al. (1996) and van der Knapp et al. (1995) stated that their subjects walked between 14-22 months of age. Onset of progressive ataxia was between 3-5 years of age.
No enzymatic or metabolic deficiencies are found in children with this newer form of leukodystrophy. Harbord et al. (1990) noted one child had slightly increased long-chain fatty acids and mildly decreased arylsulfatase A, but neither were at levels consistent with adrenaleukodystropy or metachromatic leukodystrophy, respectively. A brain biopsy of an affected sibling revealed dense gliosis and increased extracellular fluid. No subpial or subependymal Rosenthal fibers were found (Harbord et al., 1990).
The results of electrophysiologic studies are variable. The patients van der Knapp et al. (1995) described had normal visual evoked responses (VER), brainstem auditory evoked responses (BAER), and EMGs. Electroencephalograms (EEG) prior to the onset of clinical seizures were "normal". Once seizures developed, however, increased beta and delta activity with sharp wave and independent spike foci were found.
In the article by van der Knapp et al., at least two of the eight children were products of consanguinous marriages. Harbord et al. (1990) reported similar findings in two siblings from a consanguinous marriage.
In summary, leukodystrophy with megalencephaly and hypomyelination may be ascribed to Canavan's, Alexander's, or a milder form of leukodystrophy, but laboratory differences and clinical course distinguish each. Canavan's disease has increased levels of urine N-acetylaspartate, the result of a genetic mutation involving aspartoacylase. Alexander's disease can only positively be identified by the presence of subpial and subependymal Rosenthal fibers on brain biopsy. The recently described leukodystrophy is distinguished by a milder clinical course, absence of Rosenthal fibers on brain biopsy, and may involve consanguinous parentage.
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