The term leukodystrophy was first introduced by Bielschowsky and Henneberg (1928). In his review of the neuropathology of the leukodystrophies, James Powers et al. (2000) recommended that the term leukodystrophy should be applied only to ‘those progressive diseases of myelin in which a molecular abnormality is responsible for metabolic defects in myelin sheaths or myelin forming cells resulting in confluent destruction, or failed development, of central white matter’. Since the 1990s, remarkable progress has been achieved in the definition of the biochemical defect and the molecular basis of the leukodystrophies (Table 100.1).

In line with this recommendation, this chapter focuses on those genetic disorders in which central nervous system myelin is affected out of proportion to other elements of the nervous system, a judgement which may be somewhat arbitrary and subject to change as knowledge advances. Van der Knaap and Valk (1995) provide an excellent guide to the differential diagnosis of white matter abnormalities demonstrable on MRI and the acquired and genetically determined disorders of myelin that mimic the leukodystrophies. Experience in tertiary referral centres indicates that more than 50% of patients referred for ‘second opinion’ have leukoencephalopathies in which the cause cannot be determined utilizing diagnostic techniques that are currently available. The utilization of new neuroimaging techniques, such as magnetic resonance spectroscopy, combined with gene linkage analysis, has led to important recent advances and makes it likely that additional leukodystrophies will be defined in the near future (Alexander, 1949; Brenner et al., 2001; Verloes et al., 1997; van der Knaap et al., 1995, 1999; Topcu et al., 2000; Leegwater et al., 1999).

X-linked adrenoleukodystrophy

Background and general features

X-linked adrenoleukodystrophy (X-ALD) (Moser, 1997; Moser et al., 2000a,b) was described first in 1923. It was at first thought to be a variant of Schilder's disease ‘encephalitis periaxialis diffusa’ (Schilder, 1924), a disease category which has been analysed retrospectively and shown to be heterogeneous (Poser & van Bogaert, 1956). One of the three patients described by Schilder is now thought to have had X-ALD while the others had subacute sclerosing leukoencephalopathy and multiple sclerosis, respectively.