How to detect late-onset inborn errors of metabolism in patients with movement disorders – A modern diagnostic approach

Abstract

We propose a modern approach to assist clinicians to recognize and diagnose inborn errors of metabolism (IEMs) in adolescents and adults that present with a movement disorder. IEMs presenting in adults are still largely unexplored. These disorders receive little attention in neurological training and daily practice, and are considered complicated by many neurologists. Adult-onset presentations of IEMs differ from childhood-onset phenotypes, which may lead to considerable diagnostic delay. The identification of adult-onset phenotypes at the earliest stage of the disease is important, since early treatment may prevent or lessen further brain damage. Our approach is based on a systematic review of all papers that concerned movement disorders due to an IEM in patients of 16 years or older. Detailed clinical phenotyping is the diagnostic cornerstone of the approach. An underlying IEM should be suspected in particular in patients with more than one movement disorder, or in patients with additional neurological, psychiatric, or systemic manifestations. As IEMs are all genetic disorders, we recommend next-generation sequencing (NGS) as the first diagnostic approach to confirm an IEM. Biochemical tests remain the first choice in acute-onset or treatable IEMs that require rapid diagnosis, or to confirm the metabolic diagnosis after NGS results. With the use of careful and systematic clinical phenotyping combined with novel diagnostic approaches such as NGS, the diagnostic yield of late-onset IEMs will increase, in particular in patients with mild or unusual phenotypes.

Eye movement disorders in inborn errors of metabolism: A quantitative analysis of 37 patients

“…This is the case for movement disorders, where the exact type of movement disorder often does not guide into the direction of a specific IEM. 6,14 As movement disorders and eye movement disorders may share an anatomical substrate, for example, cerebellar dysfunction, 15 the variety of eye movement disorders in the same IEM could be expected. However, no clear association was found when eye movement abnormalities were assessed in relation to a specific movement disorder, which may be partially related to the combined movement disorder phenotypes in most of the patients.…”

“…VSGP is a very characteristic sign of progressive supranuclear palsy, and progressive ophthalmoplegia can be found in other energy metabolism disorders as well 12 . However, a systematic approach that involves next‐generation sequencing after exclusion of more common acquired or neurodegenerative disorders will lead to the diagnosis of both metabolic and non‐metabolic disorders 4–6 …”

“…However, as earlier described in the literature, many other symptoms are heterogeneous in IEMs as well. This is the case for movement disorders, where the exact type of movement disorder often does not guide into the direction of a specific IEM 6,14 . As movement disorders and eye movement disorders may share an anatomical substrate, for example, cerebellar dysfunction, 15 the variety of eye movement disorders in the same IEM could be expected.…”

“…In the late-onset forms, movement disorders, psychiatric symptoms, and cognitive deficits are often the presenting symptoms. [4][5][6] Interestingly, abnormal eye movements appear to be a frequent symptom as well, but are frequently missed as physicians do not always look for them, and patients may only complain about nonspecific symptoms, such as vertigo, imbalance, and frequent falling. 7,8 Recognition of eye movement disorders in patients is important because they may serve as an additional clue in the diagnosis of an IEM.…”

Visualization of Nutrient-Related Clinical Practice Guidelines in Childhood

“…The use of CPGs in algorithmic form is very common for the appropriate assessment and care for many pathological conditions, both in adulthood and in childhood. Especially in childhood, many CPGs are presented in the format of an algorithm, either for the diagnosis of a variety of disorders, such as inborn anomalies of metabolism 61 , or the management of several conditions, such as constipation 62 . However, to the best of our knowledge, although CPGs for nutrient intake and nutrient-related chronic metabolic conditions are well established in the literature, this work is the first one that summarizes and presents them in algorithmic form, in order to further increase their adoption in everyday clinical practice.…”