Neurometabolic disorders: Five new things

Abstract

Purpose of review: To present emerging issues in neurometabolic disorders, with an emphasis on the diagnostic workup of patients with suspected neurometabolic disorders and some future challenges in the care for these patients.

Recent findings: Next-generation sequencing and next-generation metabolic screening increase the speed and yield of the diagnostic process in neurometabolic disorders. Furthermore, they deepen our insights into the underlying disease mechanisms. Care of adult patients with neurometabolic disorders is an expanding subspecialty, especially in internal medicine and neurology.

Summary: We briefly discuss some novel genetic and biochemical laboratory techniques and changing insights in the molecular basis of disease, and illustrate the importance of MRI pattern recognition in the diagnostic process. Furthermore, we discuss gene therapy that is cautiously entering the field, and pay attention to the new field of (transition of) care for adult patients with inborn errors of metabolism.

Figure 1. Mechanisms of disease

Deficient enzyme activity of 1 of the 3 enzymes involved in dopamine biosynthesis, or lack of their cofactors tetrahydrobiopterin and pyridoxine (depicted with an asterisk), leads to neuronal dopamine shortage and thus compromised dopaminergic neurotransmission. In patients with aromatic amino acid decarboxylase (AADC) deficiency, a novel metabolite (3-O-methyldopa), otherwise not found in healthy persons, can be detected in body fluids. Treatment options can directly target the underlying molecular defect. Examples are drugs that replenish the missing metabolite (l-dopa for tyrosine hydroxylase deficiency), drugs that substitute the missing end product (dopa-agonists for all dopamine biosynthesis defects), vitamin supplementation to augment residual enzyme activity (pyridoxine for AADC deficiency), and gene therapy (for AADC deficiency, see text).

Figure 2. Characteristic and recognizable MRI patterns of some well-known, prototypic neurometabolic disorders and some novel disorders

(A, B) X-linked adrenoleukodystrophy with characteristic dorsal predominance and involvement of the corpus callosum. MRI (age of patient: 10 years) depicts 3 zones of different disease activity: the central, burnt-out zone, the contrast-enhancing inflammatory zone, and the outermost zone of demyelination extending with finger-like T2 hyperintensity beyond the enhancing middle zone. (C, D) Metachromatic leukodystrophy with characteristic involvement of the corpus callosum and a so-called tigroid pattern of radiating stripes of more normal signal within the abnormal white matter (age of patient: 2 years). (E–K) Leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate is characterized by selective involvement of brainstem and spinal cord tracts (age of patient: 10 years): the pyramidal tract over its entire length in corona radiata (K), posterior limb of the internal capsule (J), pons and medulla (F–I), sensory tracts in the dorsal columns (E, F), lemniscus medialis (I), corona radiata (K), the superior (I) and inferior (G, H) cerebellar peduncles, the anterior spinocerebellar tracts at the level of the medulla (lateral, in F), and the intraparenchymal trigeminal nerve (I). (L, M) The eye of the tiger sign in a 15-year-old adolescent with neurodegeneration with brain iron accumulation due to PANK2 gene mutations. MRI shows T2-hyperintense foci within the T2-hypointense pallidum, the former assumedly resulting from tissue destruction, the latter from iron deposition. (N, O) The putaminal eye in 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome. There is a characteristic temporal pattern of basal ganglia changes with initial T2 hyperintensity of the pallidum, followed by T2 hyperintensity and swelling of caudate and putamen when normal signals of the mid-dorsal putamens look like eyes in the putamen (N, O; MRI at age 15 months). Ultimately, atrophy of the basal ganglia as well as cerebellum and cerebral hemispheres occurs. MRI sequences: T2: A, C–K, L–N; fluid-attenuated inversion recovery: O; T1 plus contrast: B.