Severe hypomyelination associated with increased levels of N-acetylaspartylglutamate in CSF.
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
S 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.
Wolf
N I
NI
Department of Pediatric Neurology, University Children's Hospital Heidelberg, Germany.
Willemsen
M A A P
MA
Engelke
U F
UF
van der Knaap
M S
MS
Pouwels
P J W
PJ
Harting
I
I
Zschocke
J
J
Sistermans
E A
EA
Rating
D
D
Wevers
R A
RA
D015415:Biomarkers; D001921:Brain / Q000378:metabolism; D001928:Brain Diseases, Metabolic / Q000134:cerebrospinal fluid / Q000175:diagnosis; D002648:Child; D002675:Child, Preschool; D003711:Demyelinating Diseases / Q000134:cerebrospinal fluid* / Q000235:genetics* / Q000378:metabolism; D003937:Diagnosis, Differential; D004151:Dipeptides / Q000134:cerebrospinal fluid* / Q000378:metabolism; D005260:Female; D005838:Genotype; D043425:Glutamate Carboxypeptidase II / Q000235:genetics; D006801:Humans; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D009154:Mutation / Q000235:genetics; D018991:Myelin Proteolipid Protein / Q000235:genetics*; D020371:Pelizaeus-Merzbacher Disease / Q000134:cerebrospinal fluid / Q000175:diagnosis
D015415:Biomarkers; D004151:Dipeptides; D018991:Myelin Proteolipid Protein; C027172:isospaglumic acid; D043425:Glutamate Carboxypeptidase II