Original ArticlesAn MRI and MRS Study of Pelizaeus-Merzbacher Disease
Introduction
Pelizaeus-Merzbacher disease (PMD) is a rare X-linked disorder in which the pathogenesis involves dysmyelination rather than demyelination of the central nervous system (CNS) 1, 2. In most patients with the classical form of PMD the development of symptoms is almost complete early in life: they manifest hypotonicity and spontaneous nystagmus with onset in the initial months after birth. Spasticity appears in late infancy. Mental retardation, athetosis, and motor ataxia are recognized by early childhood. However, the subsequent clinical course is most commonly stable or slowly progressive. The proteolipid protein (PLP) gene is the sole candidate gene for PMD. It encodes PLP and DM20, the major structural myelin proteins of the CNS that presumably contribute to early oligodendrocyte development and maintain the intraperiod line of compact myelin 3, 4. The various point mutations have been reported since the 1980s, and duplication has recently been revealed 5, 6.
There have been many case reports concerning the characteristics of magnetic resonance imaging (MRI) of classical PMD in the past decade 7, 8, 9, 10, 11, 12, 13, 14. However, the findings have not been entirely identical in all cases. The abnormal patterns seemed to be divisible into three subtypes, according to the distribution of the white matter lesions: type I, diffuse alteration in the hemispheres and corticospinal tracts 7, 8; type II, diffuse alteration in the hemispheres with intact corticospinal tracts 9, 10, 11, 12; and type III, patchy changes in the hemispheres [13]. In this report, because all four patients with classical PMD previously reported on by us were recently determined to have a PLP gene duplication 6, 15, we present their MRI findings with follow-up evaluation and proton magnetic resonance spectroscopy (1H-MRS). Which differences in the clinical or genetic factors are related to ones in the MRI subtypes is also discussed.
Section snippets
Methods
The detailed clinical features of our four patients with sporadic classical PMD, between 10 and 17 years of age, were previously reported elsewhere [15]. All the patients had manifested spontaneous pendular nystagmus and hypotonia since the initial months after birth. Developmental milestones were variously delayed because of mental retardation, spastic contractures of the lower limbs, ataxia, and athetotic movements of the upper extremities. Their neurologic status was almost stable for more
Results
In all patients the white matter of the cerebral and cerebellar hemispheres exhibited diffuse iso-intensity compared with the cortex in T1-weighted images, except for the mildly high intensity of the internal capsules and the optic radiations. T2-weighted images revealed diffusely high intensity not only in the hemispheric white matter but also throughout the corticospinal tracts. Axial images at the pontine level thus showed a couple of circular high-intense lesions in the pontine nuclei (Fig.
Discussion
Compared with the connatal form of PMD attributed to the complete or subtotal absence of myelination in the CNS, classical PMD is neuropathologically characterized by the patchy absence of myelin with persistent myelinated islands, especially in the hemispheres of the cerebrum and cerebellum. This finding has been traditionally described as the “tigroid pattern of myelin defects” 2, 16. However, patchy lesions demonstrating such a tigroid pattern are a minority on MRI [13]. In most cases of
References (22)
- et al.
Magnetic resonance imaging and computed tomography in Pelizaeus-Merzbacher disease
Magnet Reson Imag
(1990) - et al.
Magnetic resonance imaging in Pelizaeus-Merzbacher disease
Pediatr Neurol
(1988) Neurophysiological study in Pelizaeus-Merzbacher disease
Brain Dev
(1995)- et al.
DNA deletion associated with hereditary neuropathy with liability to pressure palsies
Cell
(1993) Über eine eigentümliche Form spastischer Lähmung mit Zerebralerscheinungen auf hereditärer Grundlage (multiple Sklerose)
Arch Psychiatr Nervenkr
(1885)Eine eigenartige familiäre Erkrankungsform (Aplasia axialis extracorticalis)
Zges Neurol Psychiatr
(1910)- et al.
Genetics of Pelizaeus-Merzbacher disease
Dev Neurosci
(1993) - et al.
The proteolipid protein gene
Neuropathol Appl Neurobiol
(1995) - et al.
Proteolipid protein gene dosage effect in Pelizaeus-Merzbacher disease
Nat Genet
(1994) - et al.
A duplicated PLP gene causing Pelizaeus-Merzbacher disease detected by comparitive multiplex PCR
Am J Hum Genet
(1996)
The reflection of histology in MR imaging of Pelizaeus-Merzbacher disease
Am J Neuroradiol
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