The leukodystrophies are a heterogeneous group of inherited disorders with broad clinical manifestations and variable pathologic mechanisms. Improved diagnostic methods have allowed identification of the underlying cause of these diseases, facilitating identification of their pathologic mechanisms. Clinicians are now able to prioritize treatment strategies and advance research in therapies for specific disorders. Although only a few of these disorders have well-established treatments or therapies, a number are on the verge of clinical trials. As investigators are able to shift care from symptomatic management of disorders to targeted therapeutics, the unmet therapeutic needs could be reduced for these patients.
Key points
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Although leukodystrophies remain incurable, they are uniformly treatable disorders.
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Next-generation sequencing technologies have enhanced the ability to detect the underlying cause of disease and have permitted identification of pathologic mechanisms in many disorders.
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Several pilot and phase I, II, or III clinical trials are currently in progress for patients with leukodystrophy covering various disorders.
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Awareness and early recognition of the signs and symptoms of patients with leukodystrophy is of utmost importance for the small number with existing therapies.
The leukodystrophies are a heterogeneous group of inherited disorders with broad clinical manifestations and variable pathologic mechanisms. Although these disorders are individually rare, an incidence of 1 in 7000 suggests that these disorders are collectively more common than was once thought. In many cases, patients with leukodystrophy remain in the diagnostic category of unsolved disorders, despite significant improvements in diagnostic approaches. Even more important, only a few of these disorders have well-established treatments or therapies readily available to the leukodystrophy population. With this in mind, this article provides an update on the emerging treatments available to patients with leukodystrophy and the prospect for future therapies based on new molecular understanding of these conditions in the context of next-generation sequencing.
The leukodystrophies: clinical background
Although a comprehensive and disease-specific overview of clinical features of the leukodystrophies is beyond the scope of this article, important neurologic and extraneurologic features are described ( Table 1 ). The early clinical course for patients with leukodystrophy is most commonly marked by motor symptoms, manifesting as delayed development of motor skills, a plateau in development, or regression in motor skills. Although patients typically present with acute or subacute onset of neurologic symptoms, a few of these disorders have such a slowly progressive course that they seem more like static encephalopathy until their course is considered over a long span of time. Although marked spasticity and pyramidal motor symptoms are prominent features, leukodystrophies are often associated with rigidity, dystonia, ataxia, and bulbar symptoms.
