Patterns of Brain Injury in Inborn Errors of Metabolism

Many inborn errors of metabolism (IEMs) are associated with irreversible brain injury. For many, it is unclear how metabolite intoxication or substrate depletion accounts for the specific neurologic findings observed. IEM-associated brain injury patterns are characterized by whether the process involves gray matter, white matter, or both, and beyond that, whether subcortical or cortical gray matter nuclei are involved. Despite global insults, IEMs may result in selective injury to deep gray matter nuclei or white matter. This manuscript reviews the neuro-imaging patterns of neural injury in selected disorders of metabolism involving small molecule and macromolecular disorders (ie, Phenylketonuria, urea cycle disorders, and maple syrup urine disease) and discusses the contribution of diet and nutrition to the prevention or exacerbation of injury in selected inborn metabolic disorders. Where known, a review of the roles of individual differences in blood–brain permeability and transport mechanisms in the etiology of these disorders will be discussed.

Introduction

The majority of the inborn errors of metabolism (IEMs) are associated with a potential for injury to the developing central nervous system (CNS), resulting in chronic encephalopathy. The etiologies of neurologic injury have not been fully established in many of these disorders but may share mechanisms of injury such as disrupted astrocyte function, excitotoxic energy, and energy failure. There is a striking anatomical pattern of vulnerability in many of the disorders that cannot be easily understood, given that the entire brain is subjected to the global metabolic insult. Neuro-imaging has emerged as a powerful clinical and research tool to study the brain in a noninvasive manner. Several platforms exist to study neural networks underlying cognitive processes, white matter or myelin microstructure, and cerebral metabolism in vivo, providing tools to evaluate the extent and potential mechanisms of neurological damage.

Selectivity for particular brain regions or even cell types based on morphology or neurotransmitter systems (astrocytes or neurons: glutamatergic and gamma-aminobutyric acid [GABA]-ergic) is poorly understood. The presenting neurologic features reflect gray or white matter involvement. Patients with cortical gray matter involvement may present with seizures, encephalopathy, or dementia, whereas deep gray matter injury may result in extrapyramidal movement disorders (dystonia, chorea, or athetosis). White matter disorders present with pyramidal signs and visual findings (spasticity or hyperreflexia). Involvement of the cerebellum or its connecting tracts may lead to ataxia or dysmetria.

Patterns of brain injury in various IEMs may be explained based on various metabolic pathways. For example, some IEMs lead to brain injury due to a substrate intoxication model of injury. This pattern encompasses aminoacidopathies, organic acidurias, urea cycle disorders (UCDs), sugar intolerances, metal disorders, and porphyrias. Clinical expression can be acute and can present at any stage of life from the neonatal period to adulthood or can be intermittent in a partial form, from infancy to late adulthood. Most of these disorders are treatable but require the emergency removal of the neurotoxin by dietary intervention, extracorporeal procedures such as dialysis, scavenging drugs or vitamins serving as cofactors for enzymes.¹ Another pattern of injury may be due to a substrate-depletion model of injury, such as observed in creatine deficiencies. These disorders affect the cytoplasmic and mitochondrial energetic processes. In addition to creatine deficiencies this group also includes disorders of glycolysis, glycogenosis, gluconeogenesis, hyperinsulinisms, and creatine and pentose phosphate pathways.²

Additionally, anatomical patterns of brain injury may be discerned based on location. Although the entire brain is exposed to the insult, there are typically areas of vulnerability. The insult may be focal or more diffuse having a predilection for neurons and impact the gray matter vs the white matter. Additionally, gray matter injury may be cortical only, involve cortical and deep structures, or alternatively involve only the deep gray structures such as the thalamus and basal ganglia. Small molecule disorders and lysosomal disorders have a predilection for white matter involvement, but the location within the white matter often differs based on the individual disorder and may be restricted to deep centrum semiovale white matter, periventricular white matter, and the U fibers.