An Approach to Diagnosing Adult Onset Leukodystrophies
The term leukodystrophy refers to a group of conditions that are inherited and involve the progressive destruction or loss of previously acquired myelin. The most commonly reported of these disorders have a metabolic origin and are associated with abnormalities on specialist biochemical testing. Recently, a number of conditions caused by genes coding for proteins not directly involved in metabolic pathways and for which the diagnosis relies directly on gene analysis have also been described. In clinical practice, distinguishing 'classical' inherited leukodystrophies from other causes of white matter disease, including vascular and inflammatory disorders, may not always be straightforward.
Although individually rare, with no single condition having a prevalence of >1 in 20 000, the reported prevalence of adult onset leukodystrophies is rising. This is likely to be related to the increased use of brain MRI and new genetic insights. Collectively their incidence may rival that of multiple sclerosis (MS). Nonetheless, the rarity of each condition and the wide differential means that diagnosis can be challenging and most clinicians will lack experience in the area. Currently, a significant proportion of individuals may remain without a precise diagnosis despite intensive investigations.
Much has been written in the paediatric literature about leukodystrophies, but the adult neurologist, with a new case, is often left with an extensive and detailed table of rare disorders to consider, without an obvious diagnostic pathway to follow. In addition, leukodystrophies that classically present in infancy or childhood may have a very different or attenuated clinical presentation in adulthood, making diagnostic features less familiar. In this review, taking a clinical case as a starting point, we address:
Table 1 summarises the most frequent of the inherited leukodystrophies that have been reported to present in adulthood (age of onset of >16 years). This list is not exhaustive and almost certainly underestimates the true numbers—with more widespread access to genetic testing it is likely that the list of potential diagnoses and actual prevalences will continue to increase.
Abstract and Introduction
Introduction
The term leukodystrophy refers to a group of conditions that are inherited and involve the progressive destruction or loss of previously acquired myelin. The most commonly reported of these disorders have a metabolic origin and are associated with abnormalities on specialist biochemical testing. Recently, a number of conditions caused by genes coding for proteins not directly involved in metabolic pathways and for which the diagnosis relies directly on gene analysis have also been described. In clinical practice, distinguishing 'classical' inherited leukodystrophies from other causes of white matter disease, including vascular and inflammatory disorders, may not always be straightforward.
Although individually rare, with no single condition having a prevalence of >1 in 20 000, the reported prevalence of adult onset leukodystrophies is rising. This is likely to be related to the increased use of brain MRI and new genetic insights. Collectively their incidence may rival that of multiple sclerosis (MS). Nonetheless, the rarity of each condition and the wide differential means that diagnosis can be challenging and most clinicians will lack experience in the area. Currently, a significant proportion of individuals may remain without a precise diagnosis despite intensive investigations.
Much has been written in the paediatric literature about leukodystrophies, but the adult neurologist, with a new case, is often left with an extensive and detailed table of rare disorders to consider, without an obvious diagnostic pathway to follow. In addition, leukodystrophies that classically present in infancy or childhood may have a very different or attenuated clinical presentation in adulthood, making diagnostic features less familiar. In this review, taking a clinical case as a starting point, we address:
the most commonly presenting leukodystrophies in adults
their clinical presentations
MRI patterns for specific leukodystrophies
how to investigate leukodystrophies in an adult
current and future treatment possibilities.
Table 1 summarises the most frequent of the inherited leukodystrophies that have been reported to present in adulthood (age of onset of >16 years). This list is not exhaustive and almost certainly underestimates the true numbers—with more widespread access to genetic testing it is likely that the list of potential diagnoses and actual prevalences will continue to increase.
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