The syndromes of neurodegeneration with brain iron accumulation (NBIA) encompass a group of invalidating and progressive rare diseases that share the abnormal accumulation of iron in the basal ganglia. The onset of NBIA disorders ranges from infancy to adulthood. Main clinical signs are related to extrapyramidal features (dystonia, parkinsonism and choreoathetosis), and neuropsychiatric abnormalities. Ten NBIA forms are widely accepted to be caused by mutations in the genes PANK2, PLA2G6, WDR45, C19ORF12, FA2H, ATP13A2, COASY, FTL1, CP, and DCAF17. Nonetheless, many patients remain without a conclusive genetic diagnosis, which shows that there must be additional as yet undiscovered NBIA genes. In line with this, isolated cases of known monogenic disorders, and also, new genetic diseases, which present with abnormal brain iron phenotypes compatible with NBIA, have been described. Several pathways are involved in NBIA syndromes: iron and lipid metabolism, mitochondrial dynamics, and autophagy. However, many neurodegenerative conditions share features such as mitochondrial dysfunction and oxidative stress, given the bioenergetics requirements of neurons. This review aims to describe the existing link between the classical ten NBIA forms by examining their connection with mitochondrial impairment as well as oxidative stress and neuroinflammation.
The NR4A2/NURR1 gene (MIM*601828) has recently been associated with autosomal-dominant early-onset dystonia-parkinsonism with intellectual disability. 1 NR4A2 codifies for a nuclear transcription factor and is expressed mainly in the substantia nigra, ventral tegmental area, and limbic areas. 2 To date, 14 different alterations in NR4A2 have been described associated with various clinical phenotypes, mainly with neurodevelopment disorders (table e-1, links.lww.com/NXG/ A371). We describe here an interesting case suffering a persistent dystonia-parkinsonism syndrome (DPS) with motor tics, which expands the clinical phenotype of NR4A2-associated DPS. This is a 30-year-old man with no family history of neurologic disease who was born after a normal pregnancy and childbirth. He started walking with support at 13 months, but his gait was clumsy, resulting in numerous falls during childhood. At 2 years old, the patient presented attention deficit. He began to speak at 3 years of age but with impaired fluency, vocabulary, and articulation. The patient required special education to learn basic writing and arithmetic skills. At the age of 7 years, his intelligence quotient was 77. At 16 years old, he presented trichotillomania, and he began to experience motor tics characterized by an urge to move his right shoulder upward, an urge that was relieved after performing the movement. He was satisfactorily treated with atomoxetine. He also noticed an abnormal backward-cervical deviation. This clinical situation remained stable for 10 years, although motor tics tended to improve with age.At 28 years old, the patient complained of slowness, walking difficulties, and a worsening abnormal craniocervical posture. He presented marked jaw-opening dystonia and parkinsonian features, with rigidity and a progressive reduction in the amplitude and frequency of repetitive movements in the left hemibody. The gait difficulties manifested with dragging steps, mainly in the left hemibody (Video 1). The patient also presented nonmotor symptoms such as gastrointestinal and sleep-related symptoms, with the mobility and communication domains affecting his quality of life the most (figures e-1 and e-2, links.lww.com/NXG/A371).The results of supplementary and neuroimaging tests were normal (figure 1, table e-2, links. lww.com/NXG/A371), whereas 123 FP-CIT-single photon emission CT revealed reduced bilateral (predominantly right sided) uptake in both striatum (figure e-1).A genetic analysis using a custom gene panel of 498 genes involved in movement disorders (MovDisord-498) 3 revealed no causative mutations (appendix e-1, links.lww.com/NXG/ A371). The proband and healthy parents (trio) then underwent whole exome sequencing
Our clinical series comprises 124 patients with movement disorders (MDs) and/or ataxia with cerebellar atrophy (CA), many of them showing signs of neurodegeneration with brain iron accumulation (NBIA). Ten NBIA genes are accepted, although isolated cases compatible with abnormal brain iron deposits are known. The patients were evaluated using standardised clinical assessments of ataxia and MDs. First, NBIA genes were analysed by Sanger sequencing and 59 patients achieved a diagnosis, including the detection of the founder mutation PANK2 p.T528M in Romani people. Then, we used a custom panel MovDisord and/or exome sequencing; 29 cases were solved with a great genetic heterogeneity (34 different mutations in 23 genes). Three patients presented brain iron deposits with Fe-sensitive MRI sequences and mutations in FBXO7, GLB1, and KIF1A, suggesting an NBIA-like phenotype. Eleven patients showed very early-onset ataxia and CA with cortical hyperintensities caused by mutations in ITPR1, KIF1A, SPTBN2, PLA2G6, PMPCA, and PRDX3. The novel variants were investigated by structural modelling, luciferase analysis, transcript/minigenes studies, or immunofluorescence assays. Our findings expand the phenotypes and the genetics of MDs and ataxias with early-onset CA and cortical hyperintensities and highlight that the abnormal brain iron accumulation or early cerebellar gliosis may resembling an NBIA phenotype.
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