Pantothenate Kinase-associated Neurodegeneration Cases Research Articles

A Case of Pantothenate Kinase-Associated Neurodegeneration (PKAN) in a Patient with One Known Pathologic Variant and One Variant of Unknown Significance (P11-4.006)

<h3>Objective:</h3> Raise interest in the possibility of an unidentified PANK2 gene mutation in the pathogenesis of PKAN <h3>Background:</h3> Pantothenate kinase-associated neurodegeneration (PKAN), previously known as Hallervorden-Spatz Disease, is a neurodegenerative disorder associated with brain iron deposition. PKAN follows an autosomal recessive inheritance pattern and presents in childhood (classical) or around the second decade of life (atypical). Individuals with PKAN typically present with dysarthria, dystonia, speech difficulties, and extrapyramidal symptoms. PKAN has a characteristic “eye of the tiger” sign on MRI with hypointensity of the globus pallidus surrounded by an area of hyperintensity. Pantothenate kinase 2 (PANK2) gene sequencing changes have been identified as markers of PKAN. <h3>Case Description:</h3> The patient discussed is a 27-year-old woman who presented in 2013 for abnormal posturing and cramping of her hands and feet since she was four. Based on the patient’s physical exam, it was believed she was suffering from young-onset Parkinson’s disease or dystonia. However, a trial of Levodopa resulted in no improvement, genetic testing for dystonia was negative, and her brain MRI was read as normal. Due to worsening symptoms, her MRI was reassessed, and the subtle “eye of the tiger” sign was recognized. Further genetic testing showed she was a carrier for two heterozygous PANK2 mutations, one known pathologic variant and one unknown. The patient elected to join a clinical trial as her symptoms progressed. Nine years since presenting, she has completed two clinical trials and is currently on Deferiprone (an iron chelator), Artane, and Baclofen for symptom management. <h3>Design/Methods:</h3> NA <h3>Results:</h3> NA <h3>Conclusions:</h3> This report discusses a patient with PKAN who has one PANK2 mutation of known significance and one unknown variant. Considering PKAN is an autosomal recessive disease, this report suggests a novel PANK2 pathogenic variant. This study also demonstrates how the diagnosis of PKAN can be easily missed due to subtle MRI changes. <b>Disclosure:</b> Dr. Cevallos has nothing to disclose. Miss Rubin has nothing to disclose. Miss Rhinehart has nothing to disclose. Dr. Houghton has nothing to disclose.

Long-Term Outcomes of Deep Brain Stimulation in Pantothenate Kinase-Associated Neurodegeneration-Related Dystonia.

ObjectiveTo investigate the long-term clinical outcomes of pallidal deep brain stimulation (GPi-DBS) in patients with pantothenate kinase-associated neurodegeneration (PKAN).MethodsWe reviewed the records of patients with genetically confirmed PKAN who received bilateral GPi-DBS for refractory dystonia and were clinically followed up for at least 2 years postoperatively at two centers in Korea. Pre- and postoperative Burke–Fahn–Marsden Dystonia Rating Scale motor subscale (BFMDRS-M) scores, disability subscale (BFMDRS-D) scores, and qualitative clinical information were prospectively collected. Descriptive analysis was performed for BFMDRS-M scores, BFMDRS-D scores, and the orofacial, axial, and limb subscores of the BFMDRS-M at 6–12, 24–36, and 60–72 months postoperatively.ResultsFive classic-type, four atypical-type, and one unknown-type PKAN cases were identified. The mean preoperative BFMDRS-M score was 92.1 for the classic type and 38.5 for the atypical or unknown type, with a mean BFMDRS follow-up of 50.7 months and a clinical follow-up of 69.0 months. The mean improvements in BFMDRS-M score were 11.3%, 41.3%, and 30.5% at 6–12, 24–36, and 60–72 months, respectively. In four patients with full regular evaluations until 60–72 months, improvements in the orofacial, axial, and limb subscores persisted, but the disability scores worsened from 24–36 months post-operation compared to the baseline, mainly owing to the aggravation of eating and feeding disabilities.ConclusionThe benefits of GPi-DBS on dystonia may persist for more than 5 years in PKAN. The effects on patients’ subjective disability may have a shorter duration despite improvements in dystonia owing to the complex manifestations of PKAN.

Neurodegeneration with brain iron accumulation: Characterization of clinical, radiological, and genetic features of pediatric patients from Southern India

BackgroundNeurodegeneration with brain iron accumulation (NBIA) is a group of rare inherited neurodegenerative disorders. Ten types of NBIA are known. Studies reporting various NBIA subtypes together are few. This study was aimed at describing clinical features, neuroimaging findings, and genetic mutations of different NBIA group disorders. MethodsClinical, radiological, and genetic data of patients diagnosed with NBIA in a tertiary care centre in Southern India from 2014 to 2020 was retrospectively collected and analysed. ResultsIn our cohort of 27 cases, PLA2G6-associated neurodegeneration (PLAN) was most common (n = 13) followed by Pantothenate kinase-associated neurodegeneration (PKAN) (n = 9). We had 2 cases each of Mitochondrial membrane-associated neurodegeneration (MPAN) and Beta-propeller protein- associated neurodegeneration (BPAN) and 1 case of Kufor-Rakeb Syndrome (KRS). Walking difficulty was the presenting complaint in all PKAN cases, whereas the presentation in PLAN was that of development regression with onset at a mean age of 2 years. Overall, 50% patients of them presented with development regression and one-third had epilepsy. Presence of pyramidal signs was most common examination feature (89%) followed by one or more eye findings (81%) and movement disorders (50%). Neuroimaging was abnormal in 24/27 cases and cerebellar atrophy was the commonest finding (52%) followed by globus pallidus hypointensities (44%). ConclusionsOne should have a high index of clinical suspicion for the diagnosis of NBIA in children presenting with neuroregression and vision abnormalities in presence of pyramidal signs or movement disorders. Neuroimaging and ophthalmological evaluation provide important clues to diagnosis in NBIA syndromes.

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

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. 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, 5years after the onset, before surgery, 6months and 14-36months after the surgery. Improvement of 20% was accepted as significant. Overall, dystonia significantly improved after GPi-DBS at 6 and 14-36months 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. Three out of our five patients experienced beneficial effects of the GPi-DBS, in up to 36months 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.

PP12.5 – 2798: DBS-implanted PKAN cases: Two clinical observations

Introduction Pantothenate kinase-associated neurodegeneration (PKAN) is caused by the mutation of the pantothenate kinase 2 (PANK2) gene. Medical therapy such as anti-cholinergic agents, benzodiazepines, barbiturates, and baclofen is commonly used for dystonia, but without much effect. We here discuss deep brain stimulation as a promising surgical method for the treatment of dystonia. Purpose We aim to present the responses to deep brain stimulation (DBS) treatment in two patients with PKAN. Method Two PKAN cases (a 10-year-old girl and an 18-year-old boy) were included in this study. They had typical clinical and neuroimaging findings, as well as positive PANK2 mutation. Bilateral DBS electrodes were placed into the internal globus pallidus region of both the patients. Burke-Fahn-Marsden scale were used for clinical evaluation. Results The female patient, who had developed status dystonicus throughout the extremities and her trunk, was refractory to benzodiazepine and curare infusion, but recovered on the tenth day following DBS operation. After one month, the mother was able to easily provide care for her. The child remained stable and did not have any episodes of status dystonicus during the 27-month follow-up. The male patient had had feeding and swallowing problems accompanied by aspiration due to severe oromandibular dystonia, as well as bilateral arm and neck dystonia prominent on the left side. Following the DBS operation, he started to swallow without any difficulty. He was stable during the 12-month follow-up period. Conclusion DBS may increase the quality of life of drug-resistant dystonic patients and may prevent them from being hospitalized in intensive care units. Large case series are needed to thoroughly evaluate the effect of DBS on PKAN patients. Burke-Fahn-Marsden can be used to evaluate the patients, however other scales can be added for the clinical details.

Novel homozygous PANK2 mutation causing atypical pantothenate kinase-associated neurodegeneration (PKAN) in a Cypriot family

Pantothenate kinase-associated neurodegeneration (PKAN) is the commonest, recessively inherited form of neurodegeneration with brain iron accumulation (NBIA) resulting from mutations in the pantothenate kinase 2 (PANK2) gene on chromosome 20. PKAN is usually rapidly progressive, presenting in the vast majority in the first decade of life (classic form). A rarer, later onset and slowly progressive (atypical) PKAN form also exists. We present two siblings of Cypriot descent, a 27-year-old man and his clinically asymptomatic younger sister, both of whom were found to be homozygous for a novel c.695A>G (p.Asp232Gly) missense mutation in exon 2 of the PANK2 gene. The index patient presented with a 5-year history of slowly progressive gait disturbance, dysarthria, mild axial rigidity and bradykinesia. His brain MRI scan revealed the characteristic “eye-of-the-tiger” sign. Atypical genetically confirmed PKAN cases are sparsely reported and should be considered in the differential diagnosis of patients presenting with a progressive extrapyramidal syndrome particularly if the radiographic findings are suggestive of iron accumulation. Effective treatment strategies for PKAN are not currently available and symptomatic therapy is often unsatisfactory. However, early diagnosis including the presymptomatic stage is important for genetic counseling and will be crucial for testing novel therapeutics in the future.

Neurodegeneration with Brain Iron Accumulation in an Eleven-Year-Old Jamaican Male

We present a case of an eleven-year-old boy presenting with progressive extrapyramidal signs and dementia. His imaging findings demonstrated the classic eye-of-the-tiger sign on T2W magnetic resonance imaging. He was diagnosed with pantothenate kinase-associated neurodegeneration (PKAN). This is a rare autosomal recessive inborn error of coenzyme A metabolism, caused by mutations in PANK2. This is the first reported case of PKAN from the Caribbean.

A case of PKAN treated with botulinum toxin A

A 26-year-old girl had typical clinical presentation of pantothenate kinase associated neurodegeneration (PKAN) and autosomal recessive transmission was evaluated. She had marked contractions of the lower facial muscles and severe contraction of calf muscles, with both feet in a crooked position, more evident on the left side. Since infancy, she walked abnormally and was unstable when standing, due to rapidly progressive hypertonia of lower limbs. She could walk only with double support and using a rigid ankle–foot orthesis in both legs to correct for internal foot rotation. Walking barefoot was impossible. Hyperactivity of the medial calf muscles (tibialis posterior and medial gastrocnemius) was evident upon inspection and EMG recording. In order to reduce the abnormal foot posture and prevent falls, we injected both legs with botulinum toxin A: 200 Dysport ® U in the motor points of the tibialis posterior muscle and 200 Dysport ® U in the medial part of gastrocnemius muscle. She continued to follow a thorough daily rehabilitation to improve balance and postural stability. We observed a gradual reduction of hypertonus and correction of internal foot rotation. The patient gradually achieved stability while standing and could walk independently without orthesis. Her social life improved markedly.

T2* and FSE MRI distinguishes four subtypes of neurodegeneration with brain iron accumulation

Neurodegeneration with brain iron accumulation (NBIA) defines a group of genetic disorders characterized by brain iron deposition and associated with neuronal death. The known causes of NBIA include pantothenate kinase-associated neurodegeneration (PKAN), neuroferritinopathy, infantile neuroaxonal dystrophy (INAD), and aceruloplasminemia. To define the radiologic features of each NBIA subtype. Brain MRIs from patients with molecularly confirmed PKAN (26 cases), neuroferritinopathy (21 cases), INAD (four cases), and aceruloplasminemia (10 cases) were analyzed blindly to delineate patterns of iron deposition and neurodegeneration. In most cases of PKAN, abnormalities were restricted to globus pallidus and substantia nigra, with 100% having an eye of the tiger sign. In a minority of PKAN cases there was hypointensity of the dentate nuclei (1/5 on T2* sequences, 2/26 on fast spin echo [FSE]). In INAD, globus pallidus and substantia nigra were involved on T2* and FSE scans, with dentate involvement only seen on T2*. By contrast, neuroferritinopathy had consistent involvement of the dentate nuclei, globus pallidus, and putamen, with confluent areas of hyperintensity due to probable cavitation, involving the pallida and putamen in 52%, and a subset having lesions in caudate nuclei and thalami. More uniform involvement of all basal ganglia and the thalami was typical in aceruloplasminemia, but without cavitation. In the majority of cases, different subtypes of neurodegeneration associated with brain iron accumulation can be reliably distinguished with T2* and T2 fast spin echo brain MRI, leading to accurate clinical and subsequent molecular diagnosis.

Partial deficit of pantothenate kinase 2 catalytic activity in a case of tremor-predominant neurodegeneration with brain iron accumulation

We describe an atypical case of pantothenate kinase-associated neurodegeneration (PKAN) in which slowly progressive arm tremor was the predominant symptom beginning at the age of 25, with late-onset dystonia and dysarthria developing at the age of 50. Compound heterozygous mutations resulting in missense amino acid substitutions G521R and I529V were identified in the pantothenate kinase (PANK2) gene. We demonstrate that while the G521R mutation results in an unstable and inactive protein, the previously unreported I529V substitution has no apparent effect on the stability or catalytic activity of PanK2. The phenotype that results from this combination of mutations suggests that atypical presentations of PKAN may arise from partial deficits in PanK2 catalytic activity.