AIMP1/p43 Mutation and PMLD

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To the Editor: In the December 2010 issue of the American Journal of Human Genetics, Feinstein et al. reported that AIMP1/p43 (MIM 603605) homozygous mutation causes Pelizaeus-Merzbacher-like disease (PMLD [MIM 608804]).¹ The term PMLD indicates the autosomal-recessive variant of Pelizaeus-Merzbacher disease (PMD [MIM 312080]) that is the X-linked prototype of hypomyelinating disorders. The clinical phenotype of PMLD is similar to the characteristic clinical picture of PMD and is characterized by nystagmus, impaired motor development, spasticity, and ataxia.^2,3 Seizures are exceedingly unusual. Mild peripheral neuropathy may occur in some patients.² The course tends to be slowly progressive. PMLD is caused by mutations in GJC2/GJA12 (MIM 608803).² Brain magnetic resonance imaging (MRI) studies show diffuse cerebral hypomyelination similar to the typical MRI pattern of PMD. The presence of high T2 signal intensity of the pons has been reported as suggestive of PMLD.⁴ The clinical and neuroradiological features of the patients reported by Feinstein et al.¹ seem consistent with a cortical disease rather than a primary white matter disorder. Severe failure to thrive with a concordant reduced head circumference, a rapid neurological deterioration progressing over the first months of life, and abnormal epileptiform EEG pattern suggest a cortical disease more than PMLD. On brain MRI of young children with true hypomyelination, brain atrophy is mild or absent, whereas early-onset generalized atrophy, as shown in Figures 2D–2F of the paper, points to a primary cortical degeneration. Furthermore, the reduced peak of N-acetyl aspartate found on MR spectroscopy indicates neuronal degeneration, whereas this peak is considered to be normal or high in hypomyelination.⁵ In addition, the MRI criterion for a diagnosis of hypomyelination is an unchanged pattern of deficient myelination on two successive MRI scans at least 6 months apart.⁶ Thus, hypomyelination cannot be diagnosed on the basis of the single MR exam of the 14-month-old girl (Figures 2D–2F of the paper), despite a similar MRI at later ages in other members of the family that might be indicative of hypomyelination.

Finally, the major role of AIMP1 in neurons¹ further supports the hypothesis that these patients may suffer from an early-onset neurodegenerative disorder causing impaired myelin formation due to neuronal dysfunction, and not from a primary defect in myelin formation/metabolism, as in PMLD.

Because hypomyelinating disorders still represent the single largest category among undiagnosed leukoencephalopathies,⁴ the phenotype of possible novel genetic diseases should be correctly defined to avoid unnecessary molecular screening in PMLD patients.

As final remark, in Figure 2 of the paper,¹ panel B is not a FLAIR sequence and panel D is not a T1-weighted image (it is likely that these two images have been incorrectly labeled).

Web Resources

The URL for data presented herein is as follows:

• Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/