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Neurodegeneration With Brain Iron Accumulation (NBIA) Syndromes Presenting With Late-Onset Craniocervical Dystonia: An Illustrative Case Series?.

ABSTRACT: Neurodegeneration with brain iron accumulation (NBIA) mostly has its disease onset in childhood, adolescence, or early adulthood and usually presents with predominant bulbar and axial dystonia along with signs such as spasticity, indicating an involvement of additional neurological systems. Because of their early onset and presentation with a combination of dystonia plus other neurological symptoms, they are usually not considered as differential diagnosis for late-onset isolated (idiopathic) craniocervical dystonia. In this case series, we present 4 genetically proven cases of NBIA (including neuroferritinopathy, pantothenate-kinase-associated neurodegeneration, and aceruloplasminemia) with late disease onset, which resembled isolated adult-onset craniocervical dystonia at disease onset. We also want to highlight the importance of taking NBIA into consideration when dealing with putatively isolated late-onset dystonias and of picking up unusual signs at later stages of the disease.

SUBMITTER: Brugger F

PROVIDER: S-EPMC6353318 | biostudies-literature | 2017 Mar-Apr

REPOSITORIES: biostudies-literature

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Neurodegeneration With Brain Iron Accumulation (NBIA) Syndromes Presenting With Late-Onset Craniocervical Dystonia: An Illustrative Case Series‎.

Brugger Florian F Kägi Georg G Pandolfo Massimo M Mencacci Niccolò E NE Batla Amit A Wiethoff Sarah S Bhatia Kailash P KP

Movement disorders clinical practice 20160718 2

Neurodegeneration with brain iron accumulation (NBIA) mostly has its disease onset in childhood, adolescence, or early adulthood and usually presents with predominant bulbar and axial dystonia along with signs such as spasticity, indicating an involvement of additional neurological systems. Because of their early onset and presentation with a combination of dystonia plus other neurological symptoms, they are usually not considered as differential diagnosis for late-onset isolated (idiopathic) cr ...[more]

PMID: 30838262

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Project description:Neurodegeneration with Brain Iron Accumulation (NBIA) is a heterogeneous group of progressive neurodegenerative diseases characterized by iron deposition in the globus pallidus and the substantia nigra. As of today, 15 distinct monogenetic disease entities have been identified. The four most common forms are pantothenate kinase-associated neurodegeneration (PKAN), phospholipase A2 group VI (PLA2G6)-associated neurodegeneration (PLAN), beta-propeller protein-associated neurodegeneration (BPAN) and mitochondrial membrane protein-associated neurodegeneration (MPAN). Neurodegeneration with Brain Iron Accumulation disorders present with a wide spectrum of clinical symptoms such as movement disorder signs (dystonia, parkinsonism, chorea), pyramidal involvement (e.g., spasticity), speech disorders, cognitive decline, psychomotor retardation, and ocular abnormalities. Treatment remains largely symptomatic but new drugs are in the pipeline. In this review, we discuss the rationale of new compounds, summarize results from clinical trials, provide an overview of important results in cell lines and animal models and discuss the future development of disease-modifying therapies for NBIA disorders. A general mechanistic approach for treatment of NBIA disorders is with iron chelators which bind and remove iron. Few studies investigated the effect of deferiprone in PKAN, including a recent placebo-controlled double-blind multicenter trial, demonstrating radiological improvement with reduction of iron load in the basal ganglia and a trend to slowing of disease progression. Disease-modifying strategies address the specific metabolic pathways of the affected enzyme. Such tailor-made approaches include provision of an alternative substrate (e.g., fosmetpantotenate or 4'-phosphopantetheine for PKAN) in order to bypass the defective enzyme. A recent randomized controlled trial of fosmetpantotenate, however, did not show any significant benefit of the drug as compared to placebo, leading to early termination of the trials' extension phase. 4'-phosphopantetheine showed promising results in animal models and a clinical study in patients is currently underway. Another approach is the activation of other enzyme isoforms using small molecules (e.g., PZ-2891 in PKAN). There are also compounds which counteract downstream cellular effects. For example, deuterated polyunsaturated fatty acids (D-PUFA) may reduce mitochondrial lipid peroxidation in PLAN. In infantile neuroaxonal dystrophy (a subtype of PLAN), desipramine may be repurposed as it blocks ceramide accumulation. Gene replacement therapy is still in a preclinical stage.

Project description:Neurodegeneration with brain iron accumulation encompasses a heterogeneous group of rare neurodegenerative disorders that are characterized by iron accumulation in the brain. Severe generalized dystonia is frequently a prominent symptom and can be very disabling, causing gait impairment, difficulty with speech and swallowing, pain and respiratory distress. Several case reports and one case series have been published concerning therapeutic outcome of pallidal deep brain stimulation in dystonia caused by neurodegeneration with brain iron degeneration, reporting mostly favourable outcomes. However, with case studies, there may be a reporting bias towards favourable outcome. Thus, we undertook this multi-centre retrospective study to gather worldwide experiences with bilateral pallidal deep brain stimulation in patients with neurodegeneration with brain iron accumulation. A total of 16 centres contributed 23 patients with confirmed neurodegeneration with brain iron accumulation and bilateral pallidal deep brain stimulation. Patient details including gender, age at onset, age at operation, genetic status, magnetic resonance imaging status, history and clinical findings were requested. Data on severity of dystonia (Burke Fahn Marsden Dystonia Rating Scale-Motor Scale, Barry Albright Dystonia Scale), disability (Burke Fahn Marsden Dystonia Rating Scale-Disability Scale), quality of life (subjective global rating from 1 to 10 obtained retrospectively from patient and caregiver) as well as data on supportive therapy, concurrent pharmacotherapy, stimulation settings, adverse events and side effects were collected. Data were collected once preoperatively and at 2-6 and 9-15 months postoperatively. The primary outcome measure was change in severity of dystonia. The mean improvement in severity of dystonia was 28.5% at 2-6 months and 25.7% at 9-15 months. At 9-15 months postoperatively, 66.7% of patients showed an improvement of 20% or more in severity of dystonia, and 31.3% showed an improvement of 20% or more in disability. Global quality of life ratings showed a median improvement of 83.3% at 9-15 months. Severity of dystonia preoperatively and disease duration predicted improvement in severity of dystonia at 2-6 months; this failed to reach significance at 9-15 months. The study confirms that dystonia in neurodegeneration with brain iron accumulation improves with bilateral pallidal deep brain stimulation, although this improvement is not as great as the benefit reported in patients with primary generalized dystonias or some other secondary dystonias. The patients with more severe dystonia seem to benefit more. A well-controlled, multi-centre prospective study is necessary to enable evidence-based therapeutic decisions and better predict therapeutic outcomes.

Dataset Information

Neurodegeneration With Brain Iron Accumulation (NBIA) Syndromes Presenting With Late-Onset Craniocervical Dystonia: An Illustrative Case Series?.

Publications

Neurodegeneration With Brain Iron Accumulation (NBIA) Syndromes Presenting With Late-Onset Craniocervical Dystonia: An Illustrative Case Series‎.

Similar Datasets

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