Pelizaeus–Merzbacher disease (PMD) is a rare central nervous system disorder in which coordination, motor abilities, and intellectual function are delayed to variable extents.
The disease is one in a group of genetic disorders collectively known as leukodystrophies that affect growth of the myelin sheath, the fatty covering—which acts as an insulator—on nerve fibers in the CNS. PMD is generally caused by a recessive mutation of the gene on the long arm of the X-chromosome (Xq21-22) that codes for a myelin protein called proteolipid protein 1 or PLP1. The majority of disease-causing mutations result in duplications of the entire PLP1 gene. There are several forms of Pelizaeus-Merzbacher disease including, classic, connatal, transitional, and adult variants. Interestingly, deletions at the PLP1 locus (which are more rare) cause a milder form of PMD than is observed with the typical duplication mutations, which demonstrates the critical importance of gene dosage at this locus for normal CNS function. Some of the remaining cases of PMD are accounted for by mutations in the gap junction A12 (GJA12) gene, and are now called Pelizaeus-Merzbacher-like disease (PMLD). Other cases of apparent PMD do not have mutations in either the PLP1 or GJA12 genes, and are presumed to be caused either by mutations in other genes, or by mutations not detected by sequencing the PLP1 gene exons and neighboring intronic regions of the gene. Among these is a new genetic disorder (discovered in 2003, 2004) which is caused by mutation in the transporter of thyroid hormone, MCT8, also known as SLC16A2, is believed to be account for a significant fraction of the undiagnosed neurological disorders (usually resulting in hypotonic/floppy infants with delayed milestones). This genetic defect was known as Allan-Herndon-Dudley syndrome (since 1944) without knowing its actual cause. Some of the signs for this disorder are as follows: normal to slightly elevated TSH, elevated T3 and reduced T4 (ratio of T3/T4 is about double its normal value). Normal looking at birth and for the first few years, hypotonic (floppy), in particular difficulty to hold the head, possibly difficulty to thrive, possibly with delayed myelination (if so, some cases are reported with an MRI pattern similar to Pelizaeus-Merzbacher disease, known as PMD), possibly with decreased mitochondrial enzyme activities, possibly with fluctuating lactate level. Patients have an alert face, a limited IQ, patients may never talk/walk, 50% need feeding tube, patients have a normal life span. MCT8 can be ruled out with a simple TSH/T4/T3 thyroid test.
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