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.

Femur Fractures in 5 Individuals With Pantothenate Kinase-associated Neurodegeneration: The Role of Dystonia and Suggested Management.

BACKGROUND: Pantothenate kinase-associated neurodegeneration (PKAN) is a rare, neurodegenerative disorder that manifests with progressive loss of ambulation and refractory dystonia, especially in the early-onset classic form. This leads to osteopenia and stress on long bones, which pose an increased risk of atraumatic femur fractures. The purpose of this study is to describe the unique challenges in managing femur fractures in PKAN and the effect of disease manifestations on surgical outcomes. METHODS: A retrospective case review was conducted on 5 patients (ages 10 to 20 y) with PKAN with a femur fracture requiring surgical intervention. Data regarding initial presentation, surgical treatment, complications, and outcomes were obtained. RESULTS: All patients were non-ambulatory, with 4 of 5 patients sustaining an atraumatic femur fracture in the setting of dystonia episode. One patient had an additional contralateral acetabular fracture. Postoperatively, 4 of the 5 patients sustained orthopaedic complications requiring surgical revision, with 3 of these secondary to dystonia. Overall, 4 required prolonged hospitalization in the setting of refractory dystonia. CONCLUSION: Femur fractures in PKAN present distinct challenges for successful outcomes. A rigid intramedullary rod with proximal and distal interlocking screws is most protective against surgical complications associated with refractory dystonia occurring during the postoperative period. Multidisciplinary planning for postoperative care is essential and may include aggressive sedation and pain management to decrease the risk of subsequent injuries or complications. LEVEL OF EVIDENCE: Level IV.

Neuropsychological functions and psychiatric symptoms in late-onset manifestation of pantothenate kinase-associated neurodegeneration: a clinical case report.

Purpose of the study: Pantothenate Kinase-associated Neurodegeneration (PKAN) is a form of Neurodegeneration with brain iron accumulation (NBIA) due to gene mutations. Classical phenotype showed progressive neurological symptoms associated to a characteristic pattern of basal ganglia iron deposits. The atypical case, with adult-onset manifestation, could have neuropsychiatric symptoms with behavioral deficits. We described an adult-onset case of Pantothenate Kinase-associated Neurodegeneration.Materials and methods: The patient underwent neuropsychological and psychiatric evaluation and Magnetic Resonance Imaging, respectively for cognitive and behavioral assessment and to confirm the characteristic findings of this syndrome.Results: The patient showed atypical phenotype of Pantothenate Kinase-associated Neurodegeneration, characterized by language deficits, dixesecutive, and psychiatric manifestations, such as obsessive ideation, impulsivity, and disinhibition.Conclusions: This description could be helpful to a more correct diagnosis and clinical management.

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.

Deep brain stimulation for pantothenate kinase-associated neurodegeneration: A meta-analysis.

BACKGROUND: Pantothenate kinase-associated neurodegeneration is a rare autosomal-recessive disorder, characterized by progressive neurodegeneration associated with brain iron accumulation. DBS has been trialed to treat related movement disorders, particularly dystonia. The objective of this study was to determine the outcome and safety of DBS for pantothenate kinase-associated neurodegeneration. METHODS: We performed a meta-analysis using independent participant data (n = 99) from 38 articles. Primary outcome was change in movement and disability scores of the Burke-Fahn-Marsden Dystonia Rating Scale 1 year postoperatively. Secondary outcomes were response rate and complications. RESULTS: Patients with classic-type (n = 58) and atypical-type (n = 15) pantothenate kinase-associated neurodegeneration were operated on at a median age of 11 and 31 years, respectively (P < 0.001). GPi was primarily targeted (n = 87). Mean dystonia movement score improved 1 year following GPi-DBS (-26%; 95% confidence interval, -37% to -15%), particularly in atypical versus classic cases (-45% vs -16%; P < 0.001). At least 30% improvement was observed in 34% of classic versus 73% of atypical cases (P = 0.04). Higher preoperative score and atypical type predicted larger improvement. GPi-DBS improved dystonia disability score in atypical (-31%; 95% confidence interval, -49% to -13%) but not classic (-5%; 95% confidence interval, -17% to 8%) cases. Prevalence of surgical infections (6%) and hardware failure (7%) was similar to other dystonia etiologies. Two patients died within 3 months. There was insufficient data to describe outcome > 1 year following GPi-DBS or with other DBS targets. Overall, small sample sizes limited generalizability. CONCLUSIONS: This meta-analysis provides level 4 evidence that GPi-DBS for pantothenate kinase-associated neurodegeneration may improve dystonia movement scores in classic type and atypical type and disability scores in atypical type 1 year postoperatively. © 2019 International Parkinson and Movement Disorder Society.

Clinical rating scale for pantothenate kinase-associated neurodegeneration: A pilot study.

BACKGROUND: Pantothenate kinase-associated neurodegeneration is a progressive neurological disorder occurring in both childhood and adulthood. The objective of this study was to design and pilot-test a disease-specific clinical rating scale for the assessment of patients with pantothenate kinase-associated neurodegeneration. METHODS: In this international cross-sectional study, patients were examined at the referral centers following a standardized protocol. The motor examination was filmed, allowing 3 independent specialists in movement disorders to analyze 28 patients for interrater reliability assessment. The scale included 34 items (maximal score, 135) encompassing 6 subscales for cognition, behavior, disability, parkinsonism, dystonia, and other neurological signs. RESULTS: Forty-seven genetically confirmed patients (30 ± 17 years; range, 6-77 years) were examined with the scale (mean score, 62 ± 21; range, 20-106). Dystonia with prominent cranial involvement and atypical parkinsonian features were present in all patients. Other common signs were cognitive impairment, psychiatric features, and slow and hypometric saccades. Dystonia, parkinsonism, and other neurological features had a moderate to strong correlation with disability. The scale showed good internal consistency for the total scale (Cronbach's α = 0.87). On interrater analysis, weighted kappa values (0.30-0.93) showed substantial or excellent agreement in 85% of the items. The scale also discriminated a subgroup of homozygous c.1583C>T patients with lower scores, supporting construct validity for the scale. CONCLUSIONS: The proposed scale seems to be a reliable and valid instrument for the assessment of pediatric and adult patients with pantothenate kinase-associated neurodegeneration. Additional validation studies with a larger sample size will be required to confirm the present results and to complete the scale validation testing. © 2017 International Parkinson and Movement Disorder Society.

Optic Atrophy in a Patient With Atypical Pantothenate Kinase-Associated Neurodegeneration.

Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive neurodegeneration with brain iron accumulation and characterized by extrapyramidal signs, vision loss, and intellectual decline. PKAN is caused by mutations in the PANK2 gene, which codes for a mitochondrial enzyme that phosphorylates vitamin B5 in the first reaction of the coenzyme A biosynthetic pathway. Visual failure in this disorder is typically due to pigmentary retinopathy. Yet our patient, a 13-year-old girl with PKAN, developed bilateral optic atrophy and the appearance of the retina and electroretinography were normal. Optic atrophy is a rare finding in patients with PKAN. It is important for the clinician to consider PKAN in the differential diagnosis of patients presenting with signs of extrapyramidal dysfunction, cognitive decline, and vision loss because of optic atrophy.

Pallidal neuronal apolipoprotein E in pantothenate kinase-associated neurodegeneration recapitulates ischemic injury to the globus pallidus.

Pantothenate kinase-associated neurodegeneration (PKAN) is a progressive movement disorder that is due to mutations in PANK2. Pathologically, it is a member of a class of diseases known as neurodegeneration with brain iron accumulation (NBIA) and features increased tissue iron and ubiquitinated proteinaceous aggregates in the globus pallidus. We have previously determined that these aggregates represent condensed residue derived from degenerated pallidal neurons. However, the protein content, other than ubiquitin, of these aggregates remains unknown. In the present study, we performed biochemical and immunohistochemical studies to characterize these aggregates and found them to be enriched in apolipoprotein E that is poorly soluble in detergent solutions. However, we did not determine a significant association between APOE genotype and the clinical phenotype of disease in our database of 81 cases. Rather, we frequently identified similar ubiquitin- and apolipoprotein E-enriched lesions in these neurons in non-PKAN patients in the penumbrae of remote infarcts that involve the globus pallidus, and occasionally in other brain sites that contain large γ-aminobutyric acid (GABA)ergic neurons. Our findings, taken together, suggest that tissue or cellular hypoxic/ischemic injury within the globus pallidus may underlie the pathogenesis of 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.

Adult onset Hallervorden-Spatz disease with psychotic symptoms.

Hallervorden-Spatz disease is a rare neurological disorder characterized by pyramidal and extrapyramidal manifestations, dysarthria and dementia. Its onset is usually in childhood and most patients have a fatal outcome in few years. A high percentage of cases are hereditary with a recessive autosomal pattern. In the majority of the patients reported, a mutation of the gene that encodes the pantothenate kinase (PANK2) located in the 20p13-p12.3 chromosome that causes iron storage in the basal ganglia of the brain has been found. Its diagnosis is based on clinical symptoms as well as specific MRI imaging findings. The most common psychiatric features are cognitive impairment as well as depressive symptoms. There are few documented cases with psychotic disorders. We present the case of a patient with late onset Hallervorden-Spatz disease and psychotic symptoms that preceded the development of neurological manifestations. The pathophysiology and the treatment of psychotic symptomatology are presented and discussed. Key words: Psicosis, Hallervorden-Spatz, late onset, Basal ganglia.

Indian-subcontinent NBIA: unusual phenotypes, novel PANK2 mutations, and undetermined genetic forms.

Neurodegeneration with brain iron accumulation (NBIA) is etiologically, clinically, and by imaging a heterogeneous group including NBIA types 1 [pantothenate kinase-associated neurodegeneration (PKAN)] and 2 (PLA2G6-associated neurodegeneration), neuroferritinopathy, and aceruloplasminaemia. Data on genetically defined Indian-subcontinent NBIA cases are limited. We report 6 patients from the Indian-subcontinent with a movement disorder and MRI basal ganglia iron deposition, compatible with diagnosis of an NBIA syndrome. All patients were screened for abnormalities in serum ceruloplasmin and ferritin levels and mutations in NBIA-associated genes [pantothenate kinase 2 (PANK2), PLA2G6 and ferritin light chain (exon 4)]. We present clinical, imaging and genetic data correlating phenotype-genotype relations. Four patients carried PANK2 mutations, two of these were novel. The clinical phenotype was mainly dystonic with generalized dystonia and marked orobulbar features in the 4 adolescent-onset cases. One of the four had a late-onset (age 37) unilateral jerky postural tremor. His mutation, c.1379C>T, appears associated with a milder phenotype. Interestingly, he developed the eye-of-the-tiger sign only 10 years after onset. Two of the six presented with adult-onset levodopa (L-dopa)-responsive asymmetric re-emergent rest tremor, developing L-dopa-induced dyskinesias, and good benefit to deep brain stimulation (in one), thus resembling Parkinson's disease (PD). Both had an eye-of-the-tiger sign on MRI but were negative for known NBIA-associated genes, suggesting the existence of further genetic or sporadic forms of NBIA syndromes. In conclusion, genetically determined NBIA cases from the Indian subcontinent suggest presence of unusual phenotypes of PANK2 and novel mutations. The phenotype of NBIA of unknown cause includes a PD-like presentation.

Cerebral blood flow in dystonia due to pantothenate kinase-associated neurodegeneration.

BACKGROUND AND PURPOSE: The aim of this study was to look for deviations of cerebral perfusion in patients suffering from pantothenate kinase-associated neurodegeneration, where the globus pallidus is affected by severe accumulation of iron. MATERIAL AND METHODS: Under resting conditions, cerebral blood flow was measured by the magnetic resonance imaging technique of arterial spin labelling in cortical areas and basal ganglia in eight pantothenate kinase-associated neurodegeneration patients and 14 healthy age-matched control subjects and correlated to T2* time of these areas and - in patients - to clinical parameters. RESULTS: Despite highly significant differences of T2* time of the globus pallidus (20 vs 39 ms, p < 0.001), perfusion values of this nucleus were nearly identical in both groups (32 ± 3.3 vs 31 ± 4.0 ml/min/100 g) as well as in total brain gray matter (both 62 ± 6.7 resp. ±10.3 ml/min/100 g), putamen (41 ± 5.4 vs 40 ± 6.1 ml/min/100 g), in selected cortical regions, and the cerebellum. Correlations between perfusion and T2* time to clinical data did not reach significance (p > 0.05). CONCLUSION: The absence of any obvious deviations of perfusion in the group of patients during a resting condition does not support the view that (non-functional) vascular pathology is a major pathogenic factor in pantothenate kinase-associated neurodegeneration in the younger age group. The findings underline the value of the arterial spin technique to measure cerebral blood flow in areas of disturbed susceptibility.

Tongue Protrusion Dystonia in Pantothenate Kinase-Associated Neurodegeneration.

BACKGROUND: Tongue protrusion dystonia is an uncommon focal dystonia involving the lingual muscles. Causes of tongue protrusion dystonia include tardive dystonia, posthypoxic dystonia, neuroacanthocytosis, pantothenate kinase-associated neurodegeneration, and Lesch-Nyhan syndrome. METHOD: We summarize three children with pantothenate kinase-associated neurodegeneration and tongue protrusion dystonia. All three patients underwent careful neurological examination, brain magnetic resonance imaging, and genetic testing. RESULTS: Tongue protrusion dystonia was a prominent and disabling symptom in all three patients. Brain magnetic resonance imaging revealed a typical eye of the tiger sign in all patients. Two patients had the same genetic mutation (c.1168 A>T mutation, p.I390F). CONCLUSIONS: Tongue protrusion dystonia may be a clue to the underlying etiology of dystonia, including hereditary forms of dystonia. Among them, pantothenate kinase-associated neurodegeneration is an important cause, especially in children.

Generalised dystonia: clinical diagnosis is possible.

Neurodegeneration with brain iron accumulation type 1 (previously known as Hallervorden-Spatz syndrome) is a rare neurodegenerative disorder characterised by its typical clinical and radiological features. We present a case of an adolescent girl with rapidly progressive dystonia in whom the diagnosis of the above disorder was made prior to radiological investigation. This report has been made to highlight the diagnostic relevance of a good history and clinical examination. This is particularly important in a developing country where diagnostic radiological investigations are expensive.

[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.

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.

Anticholinergic-responsive gait freezing in a patient with pantothenate kinase-associated neurodegeneration.

A 43-year-old male patient suddenly developed freezing of gait (FOG) when making a first step, turning, or passing through a narrow path. Dystonic plantar flexion of his left foot always accompanied with FOG. He could walk without FOG when stepping on visual cues. Brain magnetic resonance imaging study showed typical "eye of the tiger" sign in the globus pallidus. He had heterozygous mutations in the exons 3 and 4 in the PANK2 gene. His FOG dramatically responded to the anticholinergic treatment. We report the first instance of a patient with genetically confirmed pantothenate kinase associated neurodegeneration showing typical FOG that responded to anticholinergic treatment.

Botulinum toxin injection to improve functional independence and to alleviate parenting stress in a child with advanced pantothenate kinase-associated neurodegeneration: A case report and literature review.

RATIONALE: Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive disease. Progressive motor symptoms such as dystonia and spasticity begin in childhood and relentlessly become incapacitating later in life. Treatments including anticholinergics and iron chelation are usually ineffective. Botulinum toxin type A (BoNT-A) is effective for adult patients with dystonia or spasticity. PATIENT CONCERNS: We reported a 10-year-old female patient with advanced PKAN, manifesting as generalized dystonia and spasticity. DIAGNOSIS: The patient was diagnosed with PKAN by a pediatric neurologist. INTERVENTIONS: The patient received BoNT-A injection. OUTCOMES: The effect was obvious at four weeks after the injection, with an improvement of 25% in Barry-Albright Dystonia Scale and 4% in Functional Independence Measure for Children score. Furthermore, there was a 3.8% reduction in Parenting Stress Index Short Form score and 8.3% improvement in Pain and Impact of Disability domain in the score of Cerebral Palsy Quality of Life for Children. LESSONS: BoNT-A injection was effective to improve functional independence and to alleviate stress of caregivers in the patient with advanced PKAN.