Defective lipid metabolism in neurodegeneration with brain iron accumulation (NBIA) syndromes: not only a matter of iron

Abstract

Neurodegeneration with brain iron accumulation (NBIA) is a group of devastating and life threatening rare diseases. Adult and early-onset NBIA syndromes are inherited as X-chromosomal, autosomal dominant or recessive traits and several genes have been identified as responsible for these disorders. Among the identified disease genes, only two code for proteins directly involved in iron metabolism while the remaining NBIA genes encode proteins with a wide variety of functions ranging from fatty acid metabolism and autophagy to still unknown activities. It is becoming increasingly evident that many neurodegenerative diseases are associated with metabolic dysfunction that often involves altered lipid metabolism. This is not surprising since neurons have a peculiar and heterogeneous lipid composition critical for the development and correct functioning of the nervous system. This review will focus on specific NBIA forms, namely PKAN, CoPAN, PLAN, FAHN and MPAN, which display an interesting link between neurodegeneration and alteration of phospholipids and sphingolipids metabolism, mitochondrial morphology and membrane remodelling.

Contribution of metals to brain MR signal intensity: review articles

“…Although various factors other than iron content also affect the estimated iron concentration in the brain on MRI, MRI is used to diagnose many kinds of iron-storage diseases, such as neurodegeneration with brain iron accumulation (NBIA) [65][66][67][68], Alzheimer's disease [69,70], Parkinson's disease [71,72], multiple sclerosis [73,74], Friedreich's ataxia [75,76], and Huntington's disease [53,77]. NBIA is a group of neurodegenerative diseases characterized by iron accumulation in the basal ganglia.…”

“…Ten disease-associated genes have been identified so far, but 20 % of NBIA cases remain genetically undefined. Only two of these NBIA genes are associated with iron homeostasis; the others are associated with mitochondria or fatty acid metabolism [66]. All of the NBIA disorders feature iron deposition in the globus pallidus but differ in their other findings.…”

Outline of metabolic diseases in adult neurology

“…2c and d). Although a common feature of NBIA is represented by iron accumulation, the biochemical pathways underlying these genetic defects rather involve lipid metabolism and membrane/organelles (mitochondria) remodeling, corroborating the idea that iron deposition may be only a secondary phenomenon [7]. Brain MRI is also critical to identify metabolic white matter diseases [8].…”

Leukodystrophy or genetic leukoencephalopathy? Nature does not make leaps

“…Moreover, the disease-causing gene CYP27A1 is widely expressed in human tissues, and there are key non-neurological manifestations, including bilateral cataracts, diarrhea, and xanthomas. Unlike CTX, SPG35, also known as dysmyelinating leukodystrophy and spastic paraparesis with or without dystonia or fatty acid hydroxylaseassociated neurodegeneration (FAHN), has been classified as "genetic leukoencephalopathy," despite it is a glycosphyngolipid-related disorder, the disease-causing gene FA2H (Fatty Acid 2-Hydroxylase) is primarily expressed in myelin-forming oligodendrocytes and Schwann cells, WM defects are prominent alterations, and the disease has no extraneurological manifestation [13,14]. Of note, FA2H mutations have been associated with a form of neurodegeneration with brain iron accumulation (NBIA) because brain MRI can show bilateral T2 hypointensities in the globi pallidi consistent with iron deposition [14].…”

“…Unlike CTX, SPG35, also known as dysmyelinating leukodystrophy and spastic paraparesis with or without dystonia or fatty acid hydroxylaseassociated neurodegeneration (FAHN), has been classified as "genetic leukoencephalopathy," despite it is a glycosphyngolipid-related disorder, the disease-causing gene FA2H (Fatty Acid 2-Hydroxylase) is primarily expressed in myelin-forming oligodendrocytes and Schwann cells, WM defects are prominent alterations, and the disease has no extraneurological manifestation [13,14]. Of note, FA2H mutations have been associated with a form of neurodegeneration with brain iron accumulation (NBIA) because brain MRI can show bilateral T2 hypointensities in the globi pallidi consistent with iron deposition [14]. However, no autopsy study is available, there is no evidence of iron deposition in the basal ganglia of a mouse model of FA2H deficiency [15], and T2-weighted hypointensities might be from secondary hemosiderin deposition, like in the dentate nuclei of the subjects with CTX, which is not considered as a form of NBIA [8].…”