ABSTRACT
BACKGROUND: In order to identify biomarkers useful for the diagnosis of genetic white matter disorders we compared the metabolic profile of patients with leukodystrophies with a hypomyelinating or a non-hypomyelinating MRI pattern. METHODS: We used a non-a priori method of in vitro ¹H-NMR spectroscopy on CSF samples of 74 patients with leukodystrophies. RESULTS: We found an elevation of CSF N-acetylaspartylglutamate (NAAG) in patients with Pelizaeus-Merzbacher disease (PMD)-PLP1 gene, Pelizaeus-Merzbacher-like disease-GJC2 gene and Canavan disease-ASPA gene. In the PMD group, NAAG was significantly elevated in the CSF of all patients with PLP1 duplication (19/19) but was strictly normal in 6 out of 7 patients with PLP1 point mutations. Additionally, we previously reported increased CSF NAAG in patients with SLC17A5 mutations. CONCLUSIONS: Elevated CSF NAAG is a biomarker that suggests specific molecular diagnostic abnormalities in patients with white matter diseases. Our findings also point to unique pathological functions of the overexpressed PLP in PMD patients with duplication of this gene.
Subject(s)
Biomarkers/cerebrospinal fluid , Canavan Disease/cerebrospinal fluid , Dipeptides/cerebrospinal fluid , Pelizaeus-Merzbacher Disease/cerebrospinal fluid , Adolescent , Adult , Canavan Disease/diagnosis , Canavan Disease/genetics , Child , Child, Preschool , Dipeptides/chemistry , Female , Gene Duplication , Humans , Magnetic Resonance Spectroscopy/methods , Male , Molecular Structure , Myelin Proteolipid Protein/genetics , Organic Anion Transporters/genetics , Pelizaeus-Merzbacher Disease/diagnosis , Pelizaeus-Merzbacher Disease/genetics , Point Mutation , Sensitivity and Specificity , Symporters/geneticsABSTRACT
Autosomal recessive Pelizaeus-Merzbacher-like disease 1 (PMLD1) is a hypomyelinating disorder of the central nervous system (CNS) with virtually identical phenotype to Pelizaeus-Merzbacher disease (PMD). PMLD1 is caused by mutations in GJA12 gene, PMD is due to mutations in PLP1 gene. Elevated levels of N-acetylaspartylglutamate (NAAG), the most abundant peptide neuromodulator in the human brain, have been recently reported in cerebral spinal fluid (CSF) of patients with PMD. Using capillary electrophoresis, we analyzed for the first time, the CSF from a girl with PMLD1 and detected high concentrations of NAAG. This finding confirms the hypothesis that NAAG may be involved in myelination-related processes and can be considered as a useful diagnostic marker not only for patients with the PLP1 related disorder, but also in those with Pelizaeus-Merzbacher like hypomyelinating disease due to other defined genetic causes, such as PMLD1.
Subject(s)
Connexins/genetics , Dipeptides/cerebrospinal fluid , Mutation , Pelizaeus-Merzbacher Disease/diagnosis , Child, Preschool , Electrophoresis/methods , Female , Genes, Recessive , Hereditary Central Nervous System Demyelinating Diseases/cerebrospinal fluid , Hereditary Central Nervous System Demyelinating Diseases/diagnosis , Hereditary Central Nervous System Demyelinating Diseases/genetics , Humans , Pelizaeus-Merzbacher Disease/cerebrospinal fluid , Pelizaeus-Merzbacher Disease/geneticsSubject(s)
Dipeptides/cerebrospinal fluid , Membrane Proteins/genetics , Myelin Proteolipid Protein/genetics , Pelizaeus-Merzbacher Disease/cerebrospinal fluid , Pelizaeus-Merzbacher Disease/genetics , Child , Child, Preschool , Humans , Infant , Mutation , Pelizaeus-Merzbacher Disease/physiopathologyABSTRACT
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. METHOD: 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.
