A common mutation and a novel mutation in Japanese patients with van der Knaap disease

Abstract

Van der Knaap disease, or megalencephalic leukoencephalopathy with subcortical cysts (MLC), is an autosomal recessive disorder clinically characterized by macrocephaly, ataxia, spasticity, and mental decline. Magnetic resonance imaging (MRI) shows swollen brain with diffuse white-matter abnormalities and subcortical cysts, particularly in the anterior-temporal region. Recently, the MLC1 gene was identified as the gene responsible for this disorder, and mutations in this gene were described in several patients. We studied three Japanese patients with van der Knaap disease at the molecular genetic level. Two of them were homozygous for a previously-described mutation, S93L, and one was a compound heterozygote for S93L and a novel mutation, 452-468del+g, which leads to frameshift with a premature termination codon. Combining our data with previous reports allowed us to estimate the molecular genetic basis of this disorder in seven Japanese patients. In summary, S93L was observed in six of seven (85.7%) patients at least in one allele, and ten of 14 (71.4%) alleles had this mutation. Therefore, S93L appears to be fairly frequent in Japanese patients with van der Knaap disease, and analysis for this mutation in DNA isolated from leukocytes would provide for an easy and precise diagnosis of this disorder in Japanese patients.

Identification of novel MLC1 mutations in Chinese patients with megalencephalic leukoencephalopathy with subcortical cysts (MLC)

“…10 In this study of Chinese patients, a spectrum of MLC1 mutations different from that in earlier reports was found. The above commonly reported mutations were not identified in any of our patients, except for p.S93L, which was found in one allele in one patient.…”

“…Another known missense mutation, p.S93L, has been reported fairly frequently in Japanese individuals. 10 Altogether, the 10 novel and reported MLC1 mutations found in the present study seemed to be functionally important because they may affect amino acids conserved among rat, mouse and human proteins, and amino-acid positions of the 10 mutations were distributed over a wide range from the N-to the C-terminus of the MLC1 protein.…”

A Japanese Adult Case of Megalencephalic Leukoencephalopathy with Subcortical Cysts with a Good Long-term Prognosis

“…To the best of our knowledge, this case is the oldest patient with genetically confirmed MLC in Japan. Saijo et al (4) reported a 41-year-old patient with MLC who was already wheelchair-dependent at the age of 11, indicating the possibility that appropriate care leads to a better prognosis, as proposed by previous researchers (3,4). Although MLC is a rare neurological disorder, undiagnosed cases may exist.…”

“…Little information regarding the average life span in MLC is available, because this disease was defined only recently (1). Some reported patients have died in their teens or twenties, but several adult cases of MLC have been reported (3,4,8,14,15). The patient described in the present case was over 50 years old at the time of diagnosis.…”

“…After obtaining written informed consent from the patient's brother, sequencing of MLC1 cDNA from peripheral leukocytes was performed, as previously reported (3,4). This examination revealed the presence of a 393C>T mutation, resulting in a missense mutation of S93L.…”