Neurodegeneration with Brain Iron Accumulation and a Brief Report of the Disease in Iran

Abstract

Neurodegeneration with brain iron accumulation (NBIA) is a term used for a group of hereditary neurological disorders with abnormal accumulation of iron in basal ganglia. It is clinically and genetically heterogeneous with symptoms such as dystonia, dysarthria, Parkinsonism, intellectual disability, and spasticity. The age at onset and rate of progression are variable among individuals. Current therapies are exclusively symptomatic and unable to hinder the disease progression. Approximately 16 genes have been identified and affiliated to such condition with different functions such as iron metabolism (only two genes: Ferritin Light Chain (FTL) Ceruloplasmin (CP)), lipid metabolism, lysosomal functions, and autophagy process, but some functions have remained unknown so far. Subgroups of NBIA are categorized based on the mutant genes. Although in the last 10 years, the development of whole-exome sequencing (WES) technology has promoted the identification of disease-causing genes, there seem to be some unknown genes and our knowledge about the molecular aspects and pathogenesis of NBIA is not complete yet. There is currently no comprehensive study about the NBIA in Iran; however, one of the latest discovered NBIA genes, GTP-binding protein 2 (GTPBP2), has been identified in an Iranian family, and there are some patients who have genetically remained unknown.

A Mild Form of Neurodegeneration with Brain Iron Accumulation attributed to Coenzyme A Synthase Mutation

“…2 NBIAs are characterized by gait abnormalities and clumsiness in childhood as well as spasticity, dystonia, and gradual cognitive and intellectual disability. 1,3 Diagnosis of these disorders is based on the patient's history and symptoms and evidence of iron deposition on brain MRI, 1,3 with the precise diagnosis verified by genetic study including whole exome sequencing (WES). [4][5][6] COASY protein associated neurodegeneration, or CoPAN, a new subtype of NBIA discovered in recent years, results from mutations in the Coenzyme A synthase gene (COASY).…”

“…CoPAN is a rare form of NBIA caused by an autosomal recessive inherited mutation of the CoA-synthase enzyme located on 17q21, with 5 confirmed mutations documented. 1,3,4,7,8 This bifunctional protein synthesizes CoA from pantothenic acid by catalyzing the last 2 steps of its pathway and is located downstream of pantothenate kinase-associated neurodegeneration 2 Usually a childhood onset at 9 years old 3 Dystonia, spasticity, gait abnormalities, and psychiatric symptoms 3 T2 hypointense signaling in the GP and SN, cerebellar and cortical atrophy, T1 hyperintensity of caudate and putamen 5,6 BPAN WDR45 X-linked dominant 5 Usually childhood onset 3 Seizures, cognitive impairment, and ataxia 3 T2 hypointense signaling in the GP and SN and cerebellar and cerebral atrophy 5,6 FAHN FA2H Autosomal recessive 5 Usually childhood onset at 4 years old 8 Ataxic spastic gait, seizures, dystonia, and cognitive impairment 3…”

“…T2 hypointense signaling of the GP and SN 5,6 CoPAN COASY Autosomal recessive 5 Usually childhood onset at 2.5 years old 8 Gait disturbances and mild cognitive impairment with progressive dysarthria and dystonia 3 T2 hypointense signaling of the GP and SN 5,6 Aceruloplasminemia CP Autosomal recessive 5 Usually mid-to lateadulthood onset at 51 years old 3,8 Ataxia, dystonia, and chorea 3…”

“…T2 hypointense signaling of the GP, dentate, thalamus, and red nucleus 6 Neuroferritinopathy FTL Autosomal dominant 5 Usually adult onset at 40 years old 3 Dystonia, ataxia, areflexia, dysarthria, parkinsonism, and cognitive impairment 3 T2 hypointense signaling of the GP, SN, putamen, caudate, and thalamus 6 Kufor-Rakeb syndrome ATP13A2 Autosomal recessive 5 Usually occurring before 20 years old 3 Parkinsonism, spasticity, and cognitive impairment 3,5 T2 hypointensity of the GP, caudate, and putamen 6 Woodhouse-Sakati syndrome DCAF17 Autosomal recessive 5 Variable onset of juvenile to adulthood 8 Dysarthria and sensorineural hearing loss 3,5 T2 hypointensity in the GP 6 Abbreviations: PKAN; pantothenate kinase-associated neurodegeneration, PLAN; PLA2G6-associated neurodegeneration, MPAN; mitochondrial membrane protein-associated neurodegeneration, BPAN; Beta-propeller Protein Associated Neurodegeneration, FAHN; Fatty acid hydroxylase-associated neurodegeneration, CoPAN, COASY protein associated neurodegeneration; GP, globus pallidus; MRI, magnetic resonance imaging; NBIA, neurodegeneration with brain iron accumulation; SN, substantia nigra;…”

“…1,4,7,8 Previous studies showed that mutations in this gene result in a significant reduction of the COASY protein and subsequent CoA and acetyl-CoA biosynthesis. 3,7 As the pathogenic pathway for CoPAN is similar to that of PKAN, the possible etiologies might also be similar. For PKAN, it is hypothesized that the accumulation of cysteine as the precursor for CoA might be responsible for neurodegeneration through rapid oxidization and the release of free radicals in the presence of iron.…”