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.     

Novel compound heterozygous mutations in the PANK2 gene in a Chinese patient with atypical pantothenate kinase-associated neurodegeneration.

We investigated the presence of mutations in the pantothenate kinase (PANK2) gene in a 27-year-old male Chinese patient with atypical pantothenate kinase-associated neurodegeneration (PKAN), formerly Hallervorden-Spatz syndrome. Automated DNA sequence analyses revealed compound heterozygous mutations in the exon 3 and 5. This patient had a 10-year history of PKAN characterized by a slight tremor of the right hand when writing at onset and a slow progressive rigidity of the neck and the right arm and resting tremor in upper extremities. Dysarthria, dysphagia, and dystonic-athetoid movements of the face and right fingers were marked. Magnetic resonance showed the typical "eye-of-the-tiger" sign.     

Coexistence of TDP‐43 and tau pathology in neurodegeneration with brain iron accumulation type 1 (NBIA‐1, formerly Hallervorden‐Spatz syndrome)

We report here an autopsy case of sporadic adult‐onset Hallervorden‐Spatz syndrome, also known as neurodegeneration with brain iron accumulation type 1 (NBIA1), without hereditary burden. A 49‐year‐old woman died after a 27‐year disease course. At the age of 22, she suffered from akinesia, resting tremor, and rigidity. At the age of 28, she was admitted to our hospital because of worsening parkinsonism and dementia. Within several years, she developed akinetic mutism. At the age of 49, she died of bleeding from a tracheostomy. Autopsy revealed a severely atrophic brain weighing 460 g. Histologically, there were iron deposits in the globus pallidus and substantia nigra pars reticulata, and numerous axonal spheroids in the subthalamic nuclei. Neurofibrillary tangles were abundant in the hippocampus, cerebral neocortex, basal ganglia, and brain stem. Neuritic plaques and amyloid deposits were absent. Lewy bodies and Lewy neurites, which are immunolabeled by anti‐α‐synuclein, were absent. We also observed the presence of TDP‐43‐positive neuronal perinuclear cytoplasmic inclusions, with variable frequency in the dentate gyrus granular cells, frontal and temporal cortices, and basal ganglia. TDP‐43‐positive glial cytoplasmic inclusions were also found with variable frequency in the frontal and temporal lobes and basal ganglia. The present case was diagnosed with adult‐onset NBIA‐1 with typical histological findings in the basal ganglia and brainstem. However, in this case, tau and TDP‐43 pathology was exceedingly more abundant than α‐synuclein pathology. This case contributes to the increasing evidence for the heterogeneity of NBIA‐1.     

Intellectual and adaptive behaviour functioning in pantothenate kinase-associated neurodegeneration

Background Pantothenate kinase‐associated neurodegeneration (PKAN), an extremely rare autosomal recessive disorder resulting in iron accumulation in the brain, has a diverse phenotypic expression. Based on limited case studies of one or two patients, intellectual impairment is considered part of PKAN. Investigations of cognitive functioning have utilized specific neuropsychological tests, without attention to general intellectual skills or adaptive behaviour. Methods Sixteen individuals with PKAN completed measures of global intellectual functioning, and participants or care providers completed measures of adaptive behaviour skills and day‐to‐day functional limitations. Clinicians provided global ratings of condition severity. Results Testing with standardized measures documented varied phenotypic expression, with general cognitive skills and adaptive behaviour ranging from high average to well below average. Age of disease onset correlated with measures of intellectual functioning, adaptive functioning and disease severity. Conclusions Findings support previously described clinical impressions of varied cognitive impairment and the association between age of onset and impairment. Further, they add important information regarding the natural history of the disease and suggest assessment strategies for use in treatment trials.     

Neurodegeneration with brain iron accumulation: from genes to pathogenesis

Neurodegeneration with brain iron accumulation comprises a clinically and genetically heterogeneous collection of disorders that share key features. These include progressive neurological disease accompanied by high basal ganglia iron and axonal dystrophy. To date, 2 genetic forms have been associated with mutations in PANK2 and PLA2G6, both of which encode proteins that are critical to membrane integrity. The intersection of pathways perturbed by defects in these 2 genes now enables us to test hypotheses of a common pathogenesis and ask why iron accumulates. The mechanisms implicated may contribute to our understanding of more common neurodegenerative disorders with iron dyshomeostasis, including Parkinson and Alzheimer disease.     

Genetic heterogeneity in patients with pantothenate kinase-associated neurodegeneration and classic magnetic resonance imaging eye-of-the-tiger pattern.

We performed a detailed molecular study in two unrelated families with pantothenate kinase-associated neurodegeneration (PKAN) and the specific magnetic resonance imaging (MRI) eye-of-the-tiger pattern. In the first family with classic PKAN, linkage analysis using polymorphic markers from the PANK2 region ruled out linkage with this locus, and no mutation of the PANK2 gene was found. In the second family with atypical PKAN, we identified a novel homozygous C-to-T transition at nucleotide 1069 of the PANK2 gene, which resulted in an arginine to tryptophane substitution at codon 357. As far as we are aware, this is the first case of classic PKAN with the specific MRI eye-of-the-tiger pattern not carrying a PANK2 mutation. Therefore, the present observation reinforces the notion of the phenotypic and genetic heterogeneity in PKAN.     

Efficacy and safety of deferiprone for the treatment of pantothenate kinase-associated neurodegeneration (PKAN) and neurodegeneration with brain iron accumulation (NBIA): Results from a four years follow-up

ObjectiveTo evaluate the long-term effect of Deferiprone (DFP) in reducing brain iron overload and improving neurological manifestations in patients with NBIA.Methods6 NBIA patients (5 with genetically confirmed PKAN), received DFP solution at 15 mg/kg po bid. They were assessed by UPDRS/III and UDRS scales and blinded video rating, performed at baseline and every six months. All patients underwent brain MRI at baseline and during follow up. Quantitative assessment of brain iron was performed with T2* relaxometry, using a gradient multi-echo T2* sequence.ResultsAfter 48 months of treatment clinical rating scales and blinded video rating indicated a stabilization in motor symptoms in 5/6 Pts. In the same subjects MRI evaluation showed reduced hypointensity in the globus pallidus (GP); quantitative assessment confirmed a significant increment in the T2* value, and hence reduction of the iron content of the GP.ConclusionThe data from our 4-years follow-up study confirm the safety of DFP as a chelator agent for iron accumulation. The clinical stabilization observed in 5/6 of our patients suggests that DFP may be a reasonable therapeutic option for the treatment of the neurological manifestations linked with iron accumulation and neurodegeneration, especially in adult patients at early stage of the disease.(Clinicaltrials.gov identifier: NTC00907283).     

Long-term benefit to pallidal deep brain stimulation in a case of dystonia secondary to pantothenate kinase-associated neurodegeneration.

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive disorder with onset in childhood and rapid progression. There is no causative and insufficient symptomatic drug therapy. Deep brain stimulation (DBS) of the internal pallidum (GPi) has been reported to improve motor function. Most case reports, however, are limited to short observational periods. The impact of DBS on the progression and life expectancy in PKAN is unknown. We present a 5-year outcome and video documentation of bilateral GPi-DBS of an adolescent patient suffering from genetically defined PKAN.     

Adult Hallervorden-Spatz syndrome simulating amyotrophic lateral sclerosis

Hallervorden-Spatz syndrome (HSS) is a neurodegenerative disorder characterized by progressive dementia, dystonia, ataxia, and rigidity. An atypical form of adult-onset HSS was observed in a 36-year-old man presenting with progressive dysarthria. Markedly dysarthric speech and a weak atrophic tongue associated with a neurogenic pattern of motor unit recruitment in bulbar-supplied muscles on electromyography led to an initial impression of bulbar amyotrophic lateral sclerosis (ALS). Lack of expected progression of symptoms, however, prompted reinvestigation. Repeat brain magnetic resonance imaging demonstrated an "eye-of-the-tiger" pattern in the basal ganglia, characteristic of HSS, thus requiring genetic studies. DNA analyses of the pantothenate kinase gene (PANK2) was conducted and revealed two novel, disease-causing exon 3 missense mutations (Cys231Ser and Tyr251Cys). This case broadens the genotypic and phenotypic spectrum of HSS to include a late-onset syndrome resembling bulbar-onset ALS.     

ATP13A2 mutations (PARK9) cause neurodegeneration with brain iron accumulation

Kufor Rakeb disease (KRD, PARK9) is an autosomal recessive extrapyramidal‐pyramidal syndrome with generalized brain atrophy due to ATP13A2 gene mutations. We report clinical details and investigational results focusing on radiological findings of a genetically‐proven KRD case. Clinically, there was early onset levodopa‐responsive dystonia‐parkinsonism with pyramidal signs and eye movement abnormalities. Brain MRI revealed generalized atrophy and putaminal and caudate iron accumulation bilaterally. Our findings add KRD to the group of syndromes of neurodegeneration with brain iron accumulation (NBIA). KRD should be considered in patients with dystonia‐parkinsonism with iron on brain imaging and we suggest classifying as NBIA type 3. © 2010 Movement Disorder Society     

Pantothenate kinase-associated neurodegeneration in Korea: recurrent R440P mutation in PANK2 and outcome of deep brain stimulation

Background and Purpose: The purpose of this study was to evaluate the mutation status of PANK2 among Korean patients with pantothenate kinase‐associated neurodegeneration (PKAN) and to document the outcome of pallidal deep brain stimulation (DBS). Methods: Direct sequencing and deletion/duplication analysis of PANK2 were conducted in 12 patients (11 unrelated) with PKAN, diagnosed on the basis of extrapyramidal dysfunction and the ‘eye‐of‐the‐tiger sign’ on brain magnetic resonance imaging (MRI). Pallidal DBS was conducted in four patients, and the outcomes were measured using the Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS). Results: A PANK2 mutation was identified in both alleles in all patients. The most prevalent mutation was c.1319G>C (p.R440P) in 8/22 mutated alleles (36%). An intragenic deletion ranging from exons 2 to 4 was found in one allele (1/22, 4.5%) using deletion/duplication analysis. The outcome of pallidal DBS was favorable in two patients with atypical PKAN and moderate severity of dystonia. However, two patients with typical PKAN and relatively severe symptoms showed variable responses. Conclusions: The c.1319G>C (p.R440P) mutation appears to be a founder genotype among Korean patients with PKAN. Furthermore, this study provides additional data for the recent international effort to evaluate the efficacy of pallidal DBS in the treatment of patients with PKAN.     

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. © 2007 Movement Disorder Society     

Syndromes of neurodegeneration with brain iron accumulation (NBIA): an update on clinical presentations, histological and genetic underpinnings, and treatment considerations

In recent years, understanding of the syndromes of neurodegeneration with brain iron accumulation (NBIA) has grown considerably. In addition to the core syndromes of pantothenate kinsase-associated neurodegeneration (PKAN, NBIA1) and PLA2G6-associated neurodegeneration (PLAN, NBIA2), several other genetic causes have been identified. The acknowledged clinical spectrum has broadened, age-dependent presentations have been recognized, and we are becoming aware of overlap between the different NBIA disorders as well as with other diseases. Autopsy examination of genetically confirmed cases has demonstrated Lewy bodies and/or tangles in some subforms, bridging the gap to more common neurodegenerative disorders such as Parkinson's disease. NBIA genes map into related pathways, the understanding of which is important as we move toward mechanistic therapies. Our aim in this review is to provide an overview of not only the historical developments, clinical features, investigational findings, and therapeutic results but also the genetic and molecular underpinnings of the NBIA syndromes.     

Regression of symptoms after selective iron chelation therapy in a case of neurodegeneration with brain iron accumulation

We report the results of iron chelating treatment with deferiprone in a 61‐year‐old woman with signs and symptoms of neurodegeneration with brain iron accumulation (NBIA). After 6 months of therapy the patient's gait had improved and a reduction in the incidence of choreic dyskinesias was observed. Her gait returned to normal after an additional 2 months of therapy, at which time there was a further reduction in involuntary movements and a partial resolution of the blepharospasm. © 2008 Movement Disorder Society     

Clinical and imaging characteristics of late onset mitochondrial membrane protein-associated neurodegeneration (MPAN)

ABSTRACT

Young onset dementias present significant diagnostic challenges. We present the case of a 35-year-old Kuwaiti man with social withdrawal, drowsiness, irritability, anxiety, aphasia, memory loss, hypereflexia, and Parkinsonism. Brain MRI showed bilateral symmetric gradient echo hypointensities in the globi pallidi and substantiae nigrae. Left cortical hypometabolism was seen on brain fluorodeoxyglucose positron emission tomography. A cortical brain biopsy revealed a high Lewy body burden. Genetic testing revealed a homozygous p.T11M mutation in the C19orf12 gene consistent with mitochondrial membrane protein-associated neurodegeneration. This is the oldest onset age of MPAN reported.