MLC-1-related megalencephalic leukoencephalopathy with subcortical cysts (van der Knaap Disease) – a rare cause of macrocephaly and mild motor developmental delay

Case Report: Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare autosomal recessive disease first described by van der Knaap 1995. It is characterized by infantile macrocephaly, delayed motor development, and early onset of seizures. Cerebral MRI shows diffusely abnormal and swollen cerebral white matter and subcortical cysts, cerebral atrophy occurs over time. In approximately 70% of MLC patients, there are mutations in the MLC1 gene. We report the case of a 4-year-old boy, first child of nonconsanguineous and healthy parents, presenting first in our neuropediatric clinic at the age of 1 year, with progressive macrocephaly. Over the course, the boy showed a normal cognitive development, but slight difficulties in balance. Head circumference rose slowly. At the age of 2½ years, we remarked mild problems in motor development with minor overall hypotonia and problems in balance. Cranial MRI showed an abnormal, swollen white matter, and bitemporal subcortical cysts typical for MLC. Genetic testing showed that the patient is heterozygous for the mutations c.423+1G>A and c.878_679delAC within the gene MLC1 (van der Knaap, Amsterdam). Prenatal diagnostic is possible. In the neurologic examination, at the age of 4 years, the boy has mild motor developmental delay without any signs of deterioration over time. He has no pyramidal signs, no ataxia, and no epilepsy. We demonstrate a case with megalencephalic leukoencephalopathy with subcortical cysts (MLC) as a rare cause of macrocephaly with only slight disturbances of motor development. Confirmation of the etiology is important for supporting the child but also for family planning in consideration of the autosomal recessive inheritance. In children with macrocephaly without syndromal features but signs of developmental delay neuroimaging is warranted because there is a broad spectrum of differential diagnosis.