To provide a guide to the investigation of patients with adult onset genetic leukoencephalopathy and leukodystrophy, and to describe the frequency and phenotypes of patients referred to an international centre.

Inherited disorders of white matter are individually rare, but comprise a larger group of neurodegenerative diseases with onset from childhood to late adulthood.  Patients may present with a variety of neurological symptoms and signs, including neuropsychiatric and cognitive change, spasticity, movement disorders and ataxia.  Relative rarity and overlapping phenotypes present challenges to definitive diagnosis, which is essential for prognostication, genetic counselling and the development of cohorts for emerging clinical trials.

The Queen Square Adult Leukodystrophy Group (QSALG) is one of the largest referral centres for adults with inherited disorders of white matter.  We follow a structured approach, starting with clinical and radiological phenotyping to classify and genetically define the range of these disorders.  We recommend a process to first exclude acquired causes of leukoencephalopathy, then focused metabolic screening, before specific single gene testing according to phenotype or next generation sequencing.

To date, over 160 patients have been reviewed.  A final diagnosis has been achieved in 95 cases (59%).  The most common diagnoses reached include sporadic and inherited small vessel disease, hereditary diffuse leukoencephalopathy with spheroids (HDLS), multiple sclerosis or other CNS inflammatory syndromes, mitochondrial diseases, leukoencephalopathy caused by AARS2 mutations and adrenoleukodystrophy. The remainder of the cases comprised some 30 individual diagnoses, affecting either 1 or 2 patients only.

Using a structured approach to investigation in a multidisciplinary setting, it is possible to achieve a definitive diagnosis in a majority of adult patients with inherited disorders of white matter.