Van Der Knaap disease; A case having a defined mutation and novel mutation

Abstract

Context: Van der Knaap Syndrome (MLC1) is a slowly progressive neurodegenerative diseasecharacterized by macrocephaly, megalencephaly, ataxia, spasticity, motor retardation, moderatemental retardation, diffuse cerebral white matter, subcortical cysts (MEGALENCEPHALICLEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 1,OMIM 604004). The prevalence is reportedapproximately 1/1,000,000. MLC1 is a autosomal recessive disorder due to mutations in the MLC1gene at 22q13.33 locus localization. In this study, aimed to diagnose a girl who is guided by ataxicwalking and pathologic cranial MR findings of a family with first degree cousin marriage and to givegenetic counseling to the family. Methods: Affected girls and their parents were included in the study. The cranial MR and examination findings of the index case were evaluated and MLC1 gene have been analyzed by a next generation sequencing methods. Results: Parent 7 years old , ataxic walking, spasticity, slowing of motor movements and intrinsic tremor, cranial MR showed a pathologic signal increase in cerebral white matter compatible with neurometabolic disease. Macrocephaly in infantile period. The amino acid and acylcarnitine profiles were evaluated as normal with the tandem mass spectrometry. MLC1 gene sequence analysis including all coding exons and exon-intron boundiries was done and MLC1 gene NM_015166.3: IVS2+1G>T (c.177+1G>T) homozygous mutation was detected. This mutation was previously described and have been reported (HGMD No: CS035660). In the familial segregation this mutation was detected heterozygous in parents. In addition, previously undeA (c.1059+6T>A) heterozygous mutation was detected in the parent. In silico analysis with Mutation Taster, Polyphen2, SIFT was predict this variant as a disease causing mutation. Prenatal, preimplantation genetic diagnosis for new pregnancies was recommended especially for those who are married to relatives. Since MLC1 is a rare form of megaencephalic leukoencephalopathy, it is presented to emphasize that parents with macrocephaly, ataxic gait and diffuse white matter involvement should be kept in mind.