Correspondence

AGC1 Deficiency and Cerebral Hypomyelination

N Engl J Med 2009; 361:1997-1998November 12, 2009

Article

To the Editor:

Wibom et al. (July 30 issue)1 suggest that impaired function of mitochondrial aspartate–glutamate carrier isoform 1 (AGC1) leads to hypomyelination. However, the results of magnetic resonance imaging (MRI) suggest differently. In true hypomyelination, the supratentorial white matter is hyperintense on T₂-weighted MRI, and in young children cerebral atrophy is mild or absent (Figure 1Figure 1MRI of the Brain in Two Children with Different Disorders.).2 Early-onset, severe atrophy points to primary cortical degeneration.1 The clinical features of the patient, including epilepsy and severe retardation, also suggest a cortical disease rather than a leukoencephalopathy. The reduced peak of N-acetyl aspartate found on spectroscopy indicates neuronal degeneration; this peak is considered to be normal or high in hypomyelination.3 Given the severe cerebral atrophy and less homogeneous hyperintensity of the white matter seen on T₂-weighted imaging, the MRI in this patient resembles that of patients with other early-onset neurodegenerative disorders, such as infantile neuronal ceroid lipofuscinosis (Figure 1), in which impaired formation of myelin results from neuronal dysfunction and is not related to a defect in myelin or myelin metabolism. AGC1 deficiency should be considered a disorder of the gray matter, not a primary hypomyelinating disease.

Nicole I. Wolf, M.D., Ph.D.
Marjo S. van der Knaap, M.D., Ph.D.
VU University Medical Center, Amsterdam, the Netherlands
n.wolf@vumc.nl

3 References

1. 1

   Wibom R, Lasorsa FM, Tohonen V, et al. AGC1 deficiency associated with global cerebral hypomyelination. N Engl J Med 2009;361:489-495[Erratum, N Engl J Med 2009;361:731.]
   Full Text | Web of Science | Medline

2. 2

   Schiffmann R, van der Knaap MS. Invited article: an MRI-based approach to the diagnosis of white matter disorders. Neurology 2009;72:750-759
   CrossRef | Web of Science | Medline

3. 3

   Hanefeld FA, Brockmann K, Pouwels PJ, Wilken B, Frahm J, Dechent P. Quantitative proton MRS of Pelizaeus-Merzbacher disease: evidence of dys- and hypomyelination. Neurology 2005;65:701-706
   CrossRef | Web of Science | Medline

Author/Editor Response

We agree that the primary defect is located in the gray matter, a view supported by the expression of AGC1 in neurons and its absence in glial cells1,2; we made no claims to the contrary. Neuronal dysfunction is known to result in both reduced formation of N-acetyl aspartate and secondary hypomyelination, but the underlying mechanisms have been incompletely understood. The phenotype that we described, together with data from a previous report on a mouse model,3 suggests a mechanism through which an abnormal neuronal metabolism could result in disrupted cross-talk between neurons and oligodendrocytes, which in turn results in defective myelination. AGC1 deficiency is also likely to have adverse effects on neuronal function, although in our imaging data this was not as apparent as the lack of normal myelin development.

Thomas Kucinski, M.D., Ph.D.
Karolinska Institutet, Stockholm, Sweden

Ferdinando Palmieri, M.D.
University of Bari, Bari, Italy

Anna Wedell, M.D., Ph.D.
Karolinska Institutet, Stockholm, Sweden
anna.wedell@ki.se

3 References

1. 1

   Ramos M, del Arco A, Pardo B, et al. Developmental changes in the Ca2+-regulated mitochondrial aspartate-glutamate carrier aralar1 in brain and prominent expression in the spinal cord. Brain Res Dev Brain Res 2003;143:33-46
   CrossRef | Medline

2. 2

   del Arco A, Morcillo J, Martinez-Morales JR, et al. Expression of the aspartate/glutamate mitochondrial carriers aralar1 and citrin during development and in adult rat tissues. Eur J Biochem 2002;269:3313-3320
   CrossRef | Medline

3. 3

   Jalil MA, Begum L, Contreras L, et al. Reduced N-acetylaspartate levels in mice lacking aralar, a brain- and muscle-type mitochondrial aspartate-glutamate carrier. J Biol Chem 2005;280:31333-31339
   CrossRef | Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

   Prasanth S. Ariyannur, John R. Moffett, Pachiappan Manickam, Nagarajan Pattabiraman, Peethambaran Arun, Atsumi Nitta, Toshitaka Nabeshima, Chikkathur N. Madhavarao, Aryan M.A. Namboodiri. (2010) Methamphetamine-induced neuronal protein NAT8L is the NAA biosynthetic enzyme: Implications for specialized acetyl coenzyme A metabolism in the CNS. Brain Research 1335, 1-13
   CrossRef