Pelizaeus-Merzbacher syndrome occurs in a particular type of demyelinating sudanophilic leukodystrophy and has many subtypes. y In all, sudanophilia is produced when neutral fat stains such as Sudan black react with the neutral fat breakdown products of myelin. Since this breakdown of myelin is the result of a variety of metabolic or acquired insults, sudanophilia provides no useful information about the pathogenic origin of the insult. Most of the early reports were based on the pathological process rather than on the clinical picture, and the common denominator histologically is the presence in the CNS of patches of dysmyelination interspaced with perivascular islands of relatively intact myelin. This pattern produces a striped or tigroid appearance and is the origin of the term tigroid leukoencephalopathy.
Classic Pelizaeus-Merzbacher disease has a strong tendency to be more prominent in males, suggesting but not proving a sex-linked inheritance. Although no chemical abnormality has been identified, there is a proteolipid apoprotein defect in gene Xq22 on the X chromosome. y y y The hallmark of the syndrome is the pathological finding of patchy losses of groups of oligodendrocytes with little sudanophilic demyelination. Axons and neurons are usually well preserved. In some patients there are no myelin sheaths and little evidence of myelin breakdown, raising the question of whether an absence of myelin rather than a breakdown of myelin actually occurs.y Attempts at prenatal diagnosis have been made with DNA analysis of chorionic villi samples, but this technique is not yet well developed. The transitional type of disorder (type 3) occurs sporadically. Lowenberg-Hill disease (type 4) shows autosomal dominant transmission.
Classic Pelizaeus-Merzbacher disease usually begins in the first few months of life, heralded by nystagmus and head tremor. Motor development delay occurs, and eventually ataxia, attention tremor, and choreathetosis develop. Other signs include lower extremity spasticity, dysarthria, optic atrophy, and seizures. Motor and ocular impairments are severe compared with the mild degree of dementia. Deterioration assumes an even slower pace after 5 to 6 years of age. Death is usually delayed until the second decade of life or early adulthood. Although not always present, a very characteristic early clinical finding may be a slow, rotary "cogwheel" nystagmus. As the patient becomes older, the nearly diagnostic ocular motility sign changes to a nonspecific movement disorder of the eyes. Jerk nystagmus is invariable.
Among the variants, in the connatal form the neurological features and the rapidity and extent of progressive nystagmus are more severe, and death usually occurs within months to a few years of life. In transitional or type III disease (Seitelberger's disease), the clinical severity falls somewhere between that of the connatal and classic infantile forms. Invariably there is moderately severe mental retardation, and the average age of death is between 5 and 10 years. Lowenberg-Hill disease, the adult form, has a very slow course. In contrast to all other forms, no ocular features are seen, and episodic psychotic events are characteristic.
Abnormalities of the brain stem auditory-evoked responses and sleep EEG are seen in some patients. y Cranial computed tomographic (CT) scans in long-standing cases have demonstrated cerebellar atrophy and focal areas of demyelination. MRI demonstrates persistent myelin islands and a reversal of the normal gray-white matter signal relationships consistent with dysmyelination. In addition, low- intensity signals from the lentiform nucleus in the thalamus suggests iron deposition, y similar to that seen in Hallervorden-Spatz disease (,Chapter.34. ).
All the leukoencephalopathies, genetic and nongenetic, should be included in the differential diagnosis. There is no specific curative therapy for Pelizaeus-Merzbacher disease, and diligent supportive care is essential for both patients and families. While the search for treatment continues, specific clinical genetic characterization and research into the biochemical basis for the diseases continue.
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