Olfactory status in neurodegeneration with brain iron accumulation disorders.

BACKGROUND: Olfactory dysfunction has been suggested as a diagnostic and discriminative biomarker in some neurodegenerative disorders. However, there are few studies regarding the olfactory status in rare diseases including neurodegeneration with brain iron accumulation (NBIA) disorders. METHODS: Genetically-confirmed NBIA patients were enrolled. Neurological and cognitive examinations were conducted according to the Pantothenate Kinase-Associated Neurodegeneration-Disease Rating Scale (PKAN-DRS) and the Mini-Mental State Examination (MMSE) questionnaire, respectively. Olfaction was assessed in three domains of odor threshold (OT), odor discrimination (OD), odor identification (OI), and total sum (TDI) score by the Sniffin' Sticks test. The olfactory scores were compared to a control group and a normative data set. RESULTS: Thirty-seven patients, including 22 PKAN, 6 Kufor Rakeb syndrome, 4 Mitochondrial membrane Protein-Associated Neurodegeneration (MPAN), 5 cases of other 4 subtypes, and 37 controls were enrolled. The mean PKAN-DRS score was 51.83±24.93. Sixteen patients (55.2%) had normal cognition based on MMSE. NBIA patients had significantly lower olfactory scores compared to the controls in TDI and all three subtests, and 60% of them were hyposmic according to the normative data. Including only the cognitively-normal patients, still, OI and TDI scores were significantly lower compared to the controls. The phospholipase A2-Associated Neurodegeneration (PLAN) and MPAN patients had a significantly lower OI score compared to the cognitively-matched PKAN patients. CONCLUSION: Olfactory impairment as a common finding in various subtypes of NBIA disorder can potentially be considered a discriminative biomarker. Better OI in PKAN compared to PLAN and MPAN patients may be related to the different underlying pathologies.

Neuronal Ablation of CoA Synthase Causes Motor Deficits, Iron Dyshomeostasis, and Mitochondrial Dysfunctions in a CoPAN Mouse Model.

COASY protein-associated neurodegeneration (CoPAN) is a rare but devastating genetic autosomal recessive disorder of inborn error of CoA metabolism, which shares with pantothenate kinase-associated neurodegeneration (PKAN) similar features, such as dystonia, parkinsonian traits, cognitive impairment, axonal neuropathy, and brain iron accumulation. These two disorders are part of the big group of neurodegenerations with brain iron accumulation (NBIA) for which no effective treatment is available at the moment. To date, the lack of a mammalian model, fully recapitulating the human disorder, has prevented the elucidation of pathogenesis and the development of therapeutic approaches. To gain new insights into the mechanisms linking CoA metabolism, iron dyshomeostasis, and neurodegeneration, we generated and characterized the first CoPAN disease mammalian model. Since CoA is a crucial metabolite, constitutive ablation of the Coasy gene is incompatible with life. On the contrary, a conditional neuronal-specific Coasy knock-out mouse model consistently developed a severe early onset neurological phenotype characterized by sensorimotor defects and dystonia-like movements, leading to premature death. For the first time, we highlighted defective brain iron homeostasis, elevation of iron, calcium, and magnesium, together with mitochondrial dysfunction. Surprisingly, total brain CoA levels were unchanged, and no signs of neurodegeneration were present.

Clinical course of patients with pantothenate kinase-associated neurodegeneration (PKAN) before and after DBS surgery.

INTRODUCTION: Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive disorder with a progressive clinical course. In addition to symptomatic therapy, DBS has been increasingly recognized as a potential therapeutic strategy, especially in severe cases. Therefore, we wanted to report our experience regarding benefits of DBS in five PKAN cases in 3-year follow-up study. METHODS: Five genetically confirmed PKAN patients from Serbia underwent GPi-DBS. To assess clinical outcome, we reviewed medical charts and applied: Schwab and England Activities of Daily Living Scale (S&E), EQ-5D questionnaire for quality of life, Patient Global Impression of Improvement (GPI-I), Functional Independence Measure (FIM), Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS), Barry Albright Dystonia Scale (BAD). Patients were evaluated in five visits: at the disease onset, 5 years after the onset, before surgery, 6 months and 14-36 months after the surgery. Improvement of 20% was accepted as significant. RESULTS: Overall, dystonia significantly improved after GPi-DBS at 6 and 14-36 months postoperatively, when assessed by the BFMDRS and BAD. However, two patients failed to improve considerably. Four patients reported improvement on GPI-I, while one remained unchanged. Three patients reported significant improvement, when assessed with S&E and FIM. EQ-5D showed the most prominent improvement in the domains of mobility and pain/discomfort. CONCLUSION: Three out of our five patients experienced beneficial effects of the GPi-DBS, in up to 36 months follow-up. Two patients who had not reached significant improvement had longer disease duration; therefore, it might be reasonable to recommend GPi-DBS as soon as dystonia became disabling.

Acanthocytosis and the c.680 A>G Mutation in the PANK2 Gene: A Study Enrolling a Cohort of PKAN Patients from the Dominican Republic.

Pantothenate Kinase-Associated Neurodegeneration (PKAN) is a form of Neurodegeneration with Brain Iron Accumulation (NBIA) associated with mutations in the pantothenate kinase 2 gene (PANK2). Pantothenate kinases catalyze the rate-limiting step of coenzyme A synthesis and Pank2 is the only pantothenate kinase isoform in humans that is localized to mitochondria. Acanthocytosis, the occurrence of spiculated erythrocytes, is observed in about 10% of the PKAN patients. Therefore PKAN is also classified together with other rare neurodegenerative diseases like Chorea Acanthocytosis (ChAc) and McLeod syndrome (MLS) into the Neuroacanthocytosis (NA) syndromes. It has not been investigated yet whether acanthocytosis in PKAN is associated with a specific subset of Pank2 mutations. In this study, we analyzed acanthocytosis of a cohort of 25 PKAN patients from the Dominican Republic that are homozygous for the c.680 A>G mutation in the PANK2 gene as compared to control donors that are heterozygous or wild-type with respect to this mutation. 3D modeling of this mutation indicated that the replacement of a tyrosine by a cysteine at position 227 in Pank2 disrupts a polar interaction within the A domain of the enzyme. Mean acanthocyte count was elevated in the cohort of patients, however, acanthocytosis varied among the patients with nearly half of them showing high (>20%) or elevated acanthocytosis and the rest showing mild (6-10%) or no (<6%) acanthocytosis. Heterozygous control donors revealed a tendency to mild acanthocytosis. Based on the insight that Pank2 is a normal constituent of red blood cells and de novo biosynthesis of coenzyme A is likely to take place in the erythrocyte cytosol we propose a hypothetical model that accounts for the variability in the occurrence of acanthocytic cells in PKAN.

Intrathecal morphine therapy in the management of status dystonicus in neurodegeneration brain iron accumulation type 1.

Neurodegeneration with brain iron accumulation type 1 (NBIA-1) is a rare disorder characterized by progressive extrapyramidal dysfunction and dementia. NBIA-1 encompasses typical iron brain accumulation, mostly in the globus pallidus with secondary dementia, spasticity, rigidity, dystonia, and choreoathetosis. Treatment remains mostly symptomatic and is challenging. We present the case of a 14-year-old boy diagnosed with NBIA-1, presenting intractable progressive generalized dystonia leading to unresponsive status dystonicus (SD). The patient received a SynchroMed II (model 8637) programmable system pump (Medtronic®, Inc.) implant with an Ascenda intrathecal catheter for intrathecal morphine therapy (IMT). The initial dose of morphine was 1.0 mg/day. Overall, we observed no complications with IMT treatment and important improvement of the patient's motor function with stabilization of his incapacitating dystonia and his quality of life. On the Global Dystonia Severity Rating Scale, he presented 52% improvement, 30% improvement on the Unified Dystonia Rating Scale, and 38% improvement on the Fahn-Marsden Rating Scale after 10 months, when the dose was 1.7 mg/day. IMT should be considered as a potential palliative treatment in the management of intractable dystonia and SD secondary to NBIA-1.

Idiopathic basal ganglia calcifications: an atypical presentation of PKAN.

BACKGROUND: We report a patient with pantothenate kinase-associated neurodegeneration presenting as idiopathic basal ganglia calcifications, previously known as Fahr's disease. METHODS: A teenage girl presented with slowly progressive dystonia. Her brain magnetic resonance imaging scan revealed T1 and T2 hypointensities in both globus pallidi, and no eye-of-the-tiger sign. Computed tomography showed dense globus pallidi calcifications. Metabolic evaluation was negative. The patient was diagnosed with idiopathic basal ganglia calcifications, a poorly understood syndrome of unknown cause. Whole exome sequencing was performed. RESULTS: The patient was found to have two mutations in the pantothenate kinase 2 (PANK2) gene that have been previously associated with pantothenate kinase-associated neurodegeneration: a paternally inherited p.G521R and maternally inherited p.T528M. No deleterious changes were identified in genes associated with idiopathic basal ganglia calcifications or dystonia. CONCLUSIONS: Pantothenate kinase-associated neurodegeneration should be considered in patients with idiopathic basal ganglia calcifications, especially when findings are confined to the globus pallidus.

[Anesthesia considerations for deep-brain stimulation in a patient with type-2 pantothenate kinase deficiency (Hallervorden-Spatz disease)]. / Consideraciones anestésicas en una paciente con déficit de pantotenato cinasa tipo 2 (enfermedad de Hallervorden-Spatz) para estimulación cerebral profunda.

Neurodegeneration associated with pantothenate kinase deficiency is an autosomal recessive condition caused by mutations in the pantothenate kinase 2 gene (PANK2). Clinical characteristics include progressive motor impairment and dementia. Medical treatment is limited and the dystonia tends to be refractory, making stereotactic surgery with placement of deep-brain electrodes an option that is being adopted with greater frequency in these patients. We report the case of a 32-year-old woman with severe dystonia associated with PANK2 protein deficiency. The patient was scheduled for stereotactic bilateral placement of electrodes in the medial globus pallidus, guided by computed tomography and under general anesthesia, to treat the debilitating dystonia and generalized stiffness associated with her condition. Anesthesia was maintained with propofol, rocuronium and remifentanil in perfusion during the intervention, which was uneventful. After the procedure, the patient was transferred to the intensive care unit and sedation was provided with remifentanil to allow slow, gradual emergence from anesthesia. The patient was discharged from hospital after placement of the implanted pulse generator, and subsequent follow-up showed improvement of the dystonia.

Pallidal deep brain stimulation for longstanding severe generalized dystonia in Hallervorden-Spatz syndrome. Case report.

Generalized dystonia is one of the most disabling movement disorders. Ablative stereotactic surgery such as pallidotomy has been performed for medically refractory dystonia. Recently, deep brain stimulation (DBS) has appeared as an alternative to ablative procedures. Nevertheless, there have been few published reports detailing improvement in dystonia with DBS. This 36-year-old man with Hallervorden-Spatz syndrome suffered from intractable primary generalized dystonia for 28 years. He was completely dependent for activities of daily living and wheelchair bound because of continuous severe dystonic movements in the face, tongue, neck, trunk, and upper and lower extremities while at rest. The Burke-Fahn-Marsden (BFM) Dystonia Rating Scale score was 112 (maximum 120 points). Bilateral DBS of the globus pallidus internus was performed and resulted in marked improvement in motor functioning and dystonic symptoms with a significant reduction in disability. The BFM score improved to 22.5 points (80% improvement) at 3 months postsurgery and the patient's dystonia was still well suppressed 1 year after surgery. Bilateral pallidal stimulation is an effective and safe treatment for intractable generalized dystonia in Hallervorden-Spatz syndrome, even if the disability is severe and longstanding.

Stereotactic pallidotomy in a child with Hallervorden-Spatz disease. Case report.

The authors present a case of Hallervorden-Spatz disease (HSD) in a 10-year-old boy treated with stereotactic pallidotomy for control of severe dystonia. Hallervorden-Spatz disease is a rare type of neuraxonal dystrophy that can be familial or sporadic. This is the first case of HSD reported in the literature in which a pallidotomy was performed. The patient had progressively worsening dystonias and spasms that prevented useful function of his entire right side and eventually threatened his respiratory ability. Pre- and postoperative magnetic resonance images are presented along with electrophysiological recordings made in the globus pallidus at the time of surgery. Functional improvement in the use of the patient's limbs and relief from the painful dystonia were observed. Stereotactic pallidotomy should be considered as a potential treatment in the management of HSD.

Clinical features of neuroleptic malignant syndrome in basal ganglia disease. Spontaneous presentation in a patient with Hallervorden-Spatz disease in the absence of neuroleptic drugs.

Hallervorden-Spatz disease is a rare autosomal recessive disorder in which dopaminergic deficiency in the substantia nigra and its nigrostriatal projection has been identified. It is characterised by a slow but progressive course culminating in death. This case report describes a 13-year-old male, with a clinical diagnosis of Hallervorden-Spatz disease, who developed recurrent episodes of an acute illness, the features of which closely resembled those of the neuroleptic malignant syndrome. However, in this patient there had been no exposure to neuroleptic medication. The clinical events in this case suggest that dopaminergic hypoactivity, which is characteristic of Hallervorden-Spatz disease, can trigger episodes of neuroleptic malignant syndrome.