Typical and atypical MRI patterns of rare brain disorders: The challenge of low numbers

Rare disorders pose a particular challenge to health professionals all over the world. Because they are rare we do not always know what is typical and what is not, especially for diseases where only a few affected individuals are known, and incidence may vary depending on the population studied. Oikarainen et al. describe brain magnetic resonance imaging (MRI) involvement in genetic disorders with brain white matter abnormalities in a small (less than a million), geographically defined (Northern Finland) population during a period of 30 years (1990–2019).¹ Their aim, as stated in the introduction, was twofold: to determine possible specific MRI patterns in this population and to compare MRI abnormalities in recently delineated disorders with published knowledge.

The most common disease in this cohort of 83 patients was X-linked adrenoleukodystrophy with six patients. It is interesting that X-ALD, considered the most frequent leukodystrophy worldwide, is also the most frequent disease in this isolated population. X-ALD is followed by a disease with relatively high prevalence in Finland, seizures, cortical blindness, and microcephaly syndrome.² Somewhat surprisingly, Salla disease, considered as one of the Finnish diseases, is as frequent (or rare) as Krabbe disease (n = 2). Leukodystrophy with brain stem and spinal cord involvement, and lactate elevation was diagnosed in only one patient, despite a relatively high carrier rate in Finland.^{2, 3}

The title of the paper appropriately reflects the heterogeneity of the diseases studied, by referring to ‘genetic disorders associated with white matter abnormalities’ as the paper includes both white and grey matter disorders.^{4, 5} Regarding hypomyelination, this term is used for lack of deposited myelin both permanent and significant.⁵ Radiological diagnosis is possible only after the age of 2 years, when myelination is normally mostly completed, or with repeated scanning in children younger than 2 years. Hypomyelination refers neither to delayed myelination (common in many neurodevelopmental disorders and non-specific) nor to subtle myelin deficit (e.g. incomplete myelination in the temporoanterior or frontobasal white matter). Differential diagnosis in leukodystrophies is unlike differential diagnosis in grey matter disorders with secondary white matter changes, and differential diagnosis in hypomyelinating leukodystrophies is unlike differential diagnosis of delayed or incomplete myelination. A systematic approach and correct use of terminology helps in disease classification and in achieving the right diagnosis for a patient as fast as possible. This might have therapeutic implications (e.g. in metachromatic leukodystrophy), if not for the patient then for possible affected siblings.⁴

What the study does convey are the immensely difficult circumstances of everyday clinical practice in a small population, with a large number of rare diseases never once encountered, and even the most frequent diagnosis (X-ALD) present in only about a handful of patients during a period of 30 years. This means that many differential diagnoses, although probably considered, are never seen in the clinical practice of many physicians even at academic centres. It also means that studying typical or atypical MRI patterns for a given diagnosis cannot be performed in such a restricted setting. To draw conclusions on what is usual or not for a given disease is impossible with such low patient numbers. To answer this question, multicentre (inter)national collaborations are the only way to properly describe the range of possible brain involvement, from mild to severe cases and in different age groups.