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Severe hypomyelination associated with increased levels of N-acetylaspartylglutamate in CSF

From the Department of Pediatric Neurology (Drs. Wolf and Rating), University Children’s Hospital Heidelberg, Department of Neuroradiology (Dr. Harting), University Hospital Heidelberg, and Department of Human Genetics (Dr. Zschocke), University of Heidelberg, Germany; and Departments of Pediatric Neurology (Dr. Willemsen) and Human Genetics (Dr. Sistermans) and Laboratory of Pediatrics and Neurology (Dr. Wevers, U.F. Engelke), University Medical Center Nijmegen, and Departments of Pediatric Neurology (Dr. van der Knaap) and Clinical Physics and Informatics (Dr. Pouwels), Free University Medical Center, Amsterdam, the Netherlands.

Address correspondence and reprint requests to Dr. R.A. Wevers, Laboratory of Pediatrics and Neurology, University Medical Center Nijmegen, PO Box 9101, 6500 HB Nijmegen, the Netherlands; e-mail: r.wevers{at}cukz.umcn.nl

Background: Two unrelated girls had early onset of nystagmus and epilepsy, absent psychomotor development, and almost complete absence of myelin on cerebral MRI. The clinical features and MR images of both patients resembled the connatal form of Pelizaeus-Merzbacher disease (PMD), which is an X-linked recessive disorder caused by duplications or mutations of the proteolipid protein gene (PLP).

Objective: To define a unique neurometabolic disorder with failure of myelination.

Methods and Results: ¹H-NMR of CSF in both girls was performed repeatedly, and both showed highly elevated concentrations of N-acetylaspartylglutamate (NAAG). The coding sequence of the gene coding for glutamate carboxypeptidase II, which converts NAAG to N-acetylaspartate (NAA) and glutamate, was entirely sequenced but revealed no mutations. Even though both patients are girls, the authors sequenced the PLP gene and found no abnormality.

Conclusions: NAAG is an abundant peptide neurotransmitter whose exact role is unclear. NAAG is implicated in two cases of unresolved severe CNS disorder. Its elevated concentration in CSF may be the biochemical hallmark for a novel neurometabolic disorder. The cause of its accumulation is still unclear.

Received May 13, 2003. Accepted in final form January 16, 2004.

See also pages 1464, 1509, 1598, and 1601

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