This is a rare autosomal disorder that is based on a mutation in ASAH1. The onset is in the first weeks of life, with a hoarse cry because of fixation of laryngeal cartilage, respiratory distress, and sensitivity of the joints, followed by characteristic periarticular and subcutaneous swellings and progressive arthropathy, leading finally to ankylosis. Usually there is severe psychomotor delay, but a few patients have been neurologically normal. Inanition and recurrent infections lead to death in the first 2 years. The diagnostic abnormality is a deficiency of ceramidase, leading to accumulation of ceramide. There is widespread lipid storage in neurons, granulomas of the skin, and accumulation of periodic acid-Schiff (PAS)-positive macrophages in periarticular and visceral tissues.
These are a heterogeneous group of disorders that have in common a defective myelination of the cerebrum, brainstem, cerebellum, spinal cord, and peripheral nerves. Morphologic peculiarities and genetic features separate a certain group called Pelizaeus-Merzbacher disease; other types have been artificially delineated; as a result, a relatively meaningless terminology has been introduced. The term sudanophilic refers to the tinctorial properties of staining with sudan dye, an indication of breakdown of the fatty component of myelin.
This is predominantly an X-linked disease of infancy, childhood, and adolescence, and includes other closely related pathologic entities with different modes of inheritance. The affected gene encodes proteolipid protein (PLP), one of the two myelin basic proteins. Koeppen and associates have provided evidence of a defective synthesis of this protein. While one group of PLP mutations causes Pelizaeus-Merzbacher disease, another set causes an infantile spastic paraplegia.
The onset of symptoms is most often in the first months of life; other cases begin later in childhood. The first signs are abnormal movements of the eyes (rapid, irregular, often asymmetrical pendular nystagmus), jerk nystagmus on extremes of lateral movements, upbeat nystagmus on upward gaze, and hypometric saccades (Trobe et al). There is spastic weakness of the limbs, optic atrophy (often with unexplained retention of pupillary light reflex), ataxia of limb movement and intention tremor, choreiform or athetotic movements of the arms, and slow psychomotor development with delay in sitting, standing, and walking. Seizures occur occasionally. In later-developing cases, pendular nystagmus, choreoathetosis, corticospinal signs, dysarthria, cerebellar ataxia, and mental deterioration are the major manifestations. There are milder cases of later onset with behavioral peculiarities and loss of tendon reflexes and, rarely, pure spastic paraparesis.
Imaging confirms the extensive and symmetrical white matter involvement. In the most severe cases, Seitelberger has observed an absence of oligodendrocytes and myelinated fibers. It is hypothesized that proteolipids accumulate in the endoplasmic reticulum of the oligodendrocytes, resulting in apoptosis. Patients may survive to the second and third decades. One group of cases resembles the
Cockayne syndrome, with photosensitivity of skin, dwarfism, cerebellar ataxia, corticospinal signs, cataracts, retinitis pigmentosa, and deafness. Pathologically, islands of preserved myelin impart a tigroid pattern of degenerated and intact myelin in the cerebrum. Seitelberger has obtained pathologic verification of this lesion in cases beginning as late as adult years. This disease and Cockayne syndrome are the only leukodystrophies in which nystagmus has been an invariable finding.
Koeppen and Robitaille, in a review of the subject of the pathogenesis of Pelizaeus-Merzbacher disease, summarized the evidence supporting the concept that misfolding of myelin proteins is the essential cause.