Megalencephalic leukoencephalopathy with subcortical cysts is a leukodystrophy characterized by early-onset macrocephaly and delayed-onset neurologic deterioration, including cerebellar ataxia, spasticity, epilepsy, and mild cognitive decline (summary by Lopez-Hernandez et al., 2011).
- Genetic Heterogeneity of Megalencephalic ... Megalencephalic leukoencephalopathy with subcortical cysts is a leukodystrophy characterized by early-onset macrocephaly and delayed-onset neurologic deterioration, including cerebellar ataxia, spasticity, epilepsy, and mild cognitive decline (summary by Lopez-Hernandez et al., 2011). - Genetic Heterogeneity of Megalencephalic Leukoencephalopathy with Subcortical Cysts See also MLC2A (613925), which is caused by homozygous or compound heterozygous mutation in the HEPACAM gene (611642), and MLC2B (613926), which is caused by heterozygous mutation in the HEPACAM gene.
Van der Knaap et al. (1995) described a syndrome of cerebral leukoencephalopathy and megalencephaly with infantile onset in 8 children, including 2 sibs. Neurologic findings were initially normal or near normal, despite megalencephaly and magnetic resonance imaging (MRI) ... Van der Knaap et al. (1995) described a syndrome of cerebral leukoencephalopathy and megalencephaly with infantile onset in 8 children, including 2 sibs. Neurologic findings were initially normal or near normal, despite megalencephaly and magnetic resonance imaging (MRI) evidence of severe white matter involvement. Slow progressive ataxia and spasticity developed, while intellectual functioning was preserved for years after onset of the disorder. Epilepsy was present in 6 of the 8 patients, with time of first seizure ranging from 1.5 years to 12 years. All patients were from the Netherlands. Age of presentation varied from 2 months to 10 years in a child who had immigrated. All patients had cysts on MRI. MRI showed cysts in the tips of the temporal lobes and frontoparietal subcortical area. Cerebellar hemispheres were mildly involved and not swollen. Cerebral hemispheric white matter was diffusely abnormal with considerable swelling obliterating the subarachnoid spaces. Central white matter structures, including the corpus callosum, internal capsule, and brainstem, were relatively spared. MRI characteristics also included diffuse abnormality in signal intensity. MRI abnormalities that are characteristic for this disorder are the discrepant severity in comparison to clinical picture, the aspect of white matter abnormalities (diffuse, homogeneous abnormality with swelling), the distribution of the abnormalities (supratentorial, hemispheric white matter involvement with relative sparing of central white matter structures), absence of gray matter involvement, and the presence of cysts with a typical location. MR spectra were relatively mildly abnormal. Screening for inborn errors, especially those that cause either megalencephaly or white matter disease or both, was negative. Van der Knaap et al. (1995) stated that this disease can be defined on the basis of clinical and MRI findings. Four of the patients had parents who were consanguineous, and 2 of the patients had an affected sib. The authors suggested an autosomal recessive mode of inheritance. Van der Knaap et al. (1996) described the results of brain biopsy performed in one of the patients described by van der Knaap et al. (1995). A spongiform leukoencephalopathy without cortical involvement was revealed. Histopathologic findings placed the disease among the vacuolating myelinopathies, although it is distinct from the well-known forms. Possible pathophysiologic mechanisms are splitting of the outermost myelin lamellae at the intraperiod line or a disturbance of compaction of the outermost myelin lamellae at the intraperiod line. Topcu et al. (2000) reported on vacuolating megalencephalic leukoencephalopathy characterized by diffuse swelling of the white matter, large subcortical cysts, and megalencephaly with infantile onset. They pointed to additional cases reported by Goutieres et al. (1996), Singhal et al. (1996), Mejaski-Bosnjak et al. (1997), and Topcu et al. (1998). Family studies in several ethnic groups had suggested autosomal recessive inheritance. Patrono et al. (2003) reported clinical, neuroradiologic, and molecular findings in 18 patients from 15 unrelated families with MLC. Most patients had a delay in reaching autonomous walking and presented with early-onset ataxia. About half of the patients lost the ability to walk by age 11 years, and about half showed learning difficulties in the first years of school. All had macrocephaly, and most had seizures. Lopez-Hernandez et al. (2011) reported a woman with megalencephalic leukoencephalopathy with subcortical cysts-1. She developed macrocephaly within the first few months of life, and thereafter showed slow motor deterioration, epilepsy, and cognitive decline. Brain MRI at age 40 years showed diffuse signal abnormalities in the cerebral white matter, with global atrophy and subcortical cysts in the anterior temporal region. She died at age 57 years following a cranial trauma. Postmortem brain examination showed reduced cerebral white matter with cavitation in the frontal and parietal lobes. Microscopic examination showed preservation of the cerebral cortex, but lack of myelin in the deep white matter with cavitation in the most affected areas. There was a reduction in the number of astrocytes and oligodendrocytes and loss of axons. Many astrocytes lacking myelin contained alpha-beta-crystallin (CRYAB; 123590), a stress protein.
In 7 informative and 6 uninformative families with MLC, Leegwater et al. (2001) identified 12 different mutations in the MLC1 gene (see, e.g., 605908.0001).
In 13 of 18 patients with MLC, Patrono et al. (2003) identified ... In 7 informative and 6 uninformative families with MLC, Leegwater et al. (2001) identified 12 different mutations in the MLC1 gene (see, e.g., 605908.0001). In 13 of 18 patients with MLC, Patrono et al. (2003) identified 11 mutations in the MLC1 gene. There was no apparent genotype/phenotype correlation. Five patients did not show MLC1 mutations, indicating genetic heterogeneity. In a woman with megalencephalic leukoencephalopathy with subcortical cysts-1, Lopez-Hernandez et al. (2011) identified a homozygous mutation in the MLC1 gene (S69L; 605908.0013). Patient brain tissue showed no immunostaining for MLC1, indicating that deficiency of cell surface MLC1 protein expression is the basis for the disorder. In vitro expression of the S69L mutation in HeLa cells showed that the mutant protein was located in intracellular compartments, with reduced surface membrane expression compared to wildtype. The mutant protein also showed reduced stability.