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.

Incidence of PKAN determined by bioinformatic and population-based analysis of ~140,000 humans.

Panthothenate kinase-associated neurodegeneration (PKAN, OMIM 234200), is an inborn is an autosomal recessive inborn error of metabolism caused by pathogenic variants in PANK2. PANK2 encodes the enzyme pantothenate kinase 2 (EC 2.7.1.33), an essential regulatory enzyme in CoA biosynthesis. Clinical presentation includes dystonia, rigidity, bradykinesia, dysarthria, pigmentary retinopathy and dementia with variable age of onset ranging from childhood to adulthood. In order to provide an accurate incidence estimate of PKAN, we conducted a systematic review of the literature and databases for pathogenic mutations and constructed a bioinformatic profile for pathogenic missense variants in PANK2. We then studied the gnomAD cohort of ~140,000 unrelated adults from global populations to determine the allele frequency of the variants in PANK2 reported pathogenic for PKAN and for those additional variants identified in gnomAD that met bioinformatics criteria for being potentially pathogenic. Incidence was estimated based on three different models using the allele frequencies of pathogenic PKAN variants with or without those bioinformatically determined to be potentially pathogenic. Disease incidence calculations showed PKAN incidence ranging from 1:396,006 in Europeans, 1:1,526,982 in Africans, 1:480,826 in Latino, 1:523,551 in East Asians and 1:531,118 in South Asians. These results indicate PKAN is expected to occur in approximately 2 of every 1 million live births globally outside of Africa, and has a much lower incidence 1 in 1.5 million live births in the African population.

On the complexity of clinical and molecular bases of neurodegeneration with brain iron accumulation.

Neurodegeneration with brain iron accumulation (NBIA) is a group of inherited heterogeneous neurodegenerative rare disorders. These patients present with dystonia, spasticity, parkinsonism and neuropsychiatric disturbances, along with brain magnetic resonance imaging (MRI) evidence of iron accumulation. In sum, they are devastating disorders and to date, there is no specific treatment. Ten NBIA genes are accepted: PANK2, PLA2G6, C19orf12, COASY, FA2H, ATP13A2, WDR45, FTL, CP, and DCAF17; and nonetheless, a relevant percentage of patients remain without genetic diagnosis, suggesting that other novel NBIA genes remain to be discovered. Overlapping complex clinical pictures render an accurate differential diagnosis difficult. Little is known about the pathophysiology of NBIAs. The reported NBIA genes take part in a variety of pathways: CoA synthesis, lipid and iron metabolism, autophagy, and membrane remodeling. The next-generation sequencing revolution has achieved relevant advances in genetics of Mendelian diseases and provide new genes for NBIAs, which are investigated according to 2 main strategies: genes involved in disorders with similar phenotype and genes that play a role in a pathway of interest. To achieve an effective therapy for NBIA patients, a better understanding of the biological process underlying disease is crucial, moving toward a new age of precision medicine.

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.

First successful trial of preimplantation genetic diagnosis for pantothenate kinase-associated neurodegeneration.

PURPOSE: We aim to present a case of a healthy infant born after intracytoplasmic sperm injection-in vitro fertilization (ICSI-IVF) with a preimplantation genetic diagnosis (PGD) for pantothenate kinase-associated neurodegeneration (PKAN) due to PANK2 mutation. METHODS: ICSI-IVF was performed on a Thai couple, 34-year-old female and 33-year-old male, with a family history of PKAN in their first child. Following fertilization, each of the embryos were biopsied in the cleavage stage and subsequently processed for whole-genome amplification. Genetic status of the embryos was diagnosed by linkage analysis and direct mutation testing using primer extension-based mini-sequencing. Comprehensive chromosomal aneuploidy screening was performed using a next-generation sequencing-based strategy. RESULTS: Only a single cycle of ICSI-IVF was processed. There were seven embryos from this couple-two were likely affected, three were likely carriers, one was likely unaffected, and one failed in target genome amplification. Aneuploidy screening was performed before making a decision on embryo transfer, and only one unaffected embryo passed the screening. That embryo was transferred in a frozen thawed cycle, and the pregnancy was successful. The diagnosis was confirmed by amniocentesis, which presented with a result consistent with PGD. At 38 weeks of gestational age, a healthy male baby was born. Postnatal genetic confirmation was also consistent with PGD and the prenatal results. At the age of 24 months, the baby presented with normal growth and development lacking any neurological symptoms. CONCLUSIONS: We report the first successful trial of PGD for PKAN in a developing country using linkage analysis and mini-sequencing in cleavage stage embryos.

Atypical pantothenate kinase-associated neurodegeneration: Clinical description of two brothers and a review of the literature.

Two clinical forms of pantothenate kinase-associated neurodegeneration (PKAN) have been described: typical PKAN and atypical PKAN. Atypical PKAN has later onset and a slower course of disease. This report describes two siblings with the atypical form of PKAN, combining dystonia, irritability and a dysmorphia syndrome. In addition, a review of the literature was carried out for all published cases of atypical PKAN to gather descriptions of its various clinical presentations, age of onset and MRI findings, and to highlight the different treatments used for PKAN patients.

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.

CLINICAL EFFECT OF A MUTATION (p.Glu322Asp, c.966 G>T) IN PANK2 GENE IN A FAMILY WITH ATYPICAL PANTOTHENATE KINASE-ASSOCIATED NEURODEGENERATION.

Pantothenate-kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive disorder caused by mutations in the pantothenate kinase 2 (PANK2) gene. Many different mutations in the PANK2 gene have been detected in association with PKAN. A 20 year old female patient who had been suffering from progressive gait disorder for 1 year was found to have the 'eye-of-the-tiger sign' from the brain magnetic resonance imaging (MRI). The same brain imaging findings were shown in the father and brother of the patient, whose parents arranged a consanguineous marriage. We found c.966 G>T (p.Glu322Asp) mutation in the PANK2 gene mutation analysis in the individuals from the brain imaging findings. Although individuals in this family who had a homozygous mutation in PANK2 gene analyses had the 'eye-of-the-tiger' sign and atypical disease, they were noted to have differing clinical findings.

[«A most strange instance of illness in several siblings¼--first description of a rare neurological disease in 1830?]. / «Et høist mærkeligt Sygdomstilfælde hos flere Sødskende¼--en norsk førstegangsbeskrivelse fra 1830?

Was district medical officer Jensen the first doctor to describe patients with Pantothenate Kinase-Associated Neurodegeneration (PKAN) in Volda in 1830? A case series of four siblings with the same disease written by district medical officer Peter Jensen (1799-1832) in Aalesund in 1830, was published in the Norwegian medical journal Eyr in 1832. The children, who were healthy almost up to school age, developed dystonic involuntary movements and deformities in all extremities, lost their ability to speak and were emaciated before they died at around the age of nine years. Further information about the family and a fifth affected child has been found in the parish records. The clinical picture is consistent with Pantothenate Kinase-Associated Neurodegeneration (PKAN), a rare condition with basal ganglia iron deposition, described in 1922 by the German neuropathologists Julius Hallervorden (1882-1965) and Hugo Spatz (1888-1969). The disease was formerly called Hallervorden-Spatz syndrome, but because of the medical activities undertaken by these two researchers before and during the Second World War, this eponym is no longer recommended.

Clinical, imaging, and molecular findings in a sample of Mexican families with pantothenate kinase-associated neurodegeneration.

Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive disorder characterized by iron accumulation in the brain, because of mutations in the PANK2 gene. Phenotypic and genotypic characteristics of 11 patients from five Mexican families with PKAN disease are reported. Sequencing of PANK2 confirmed the diagnosis. The 11 patients had dysarthria associated with dystonia and Parkinsonism in six. Brain magnetic resonance imaging (MRI) showed the 'eye-of-the-tiger' sign in all patients. Three different mutations were identified, a novel one (p.A469P) and two (p.G219V and p.N404I) very rare. Homozygous sibs for the p.G219V mutation had a severe disease progression with early death. Dystonia predominated in the p.A469P/p.N404I compound heterozygous patients. Homozygous for p.N404I showed Parkinsonism, tics and personality and speech disorders. Early and late disease onset and variable expression was present in carriers of the different identified mutations. The 'eye-of-the-tiger' is an excellent neuroimaging hallmark to predict PANK2 mutations. We detected a 'cluster' of patients harboring the p.N404I mutation, strongly suggesting a founder effect for this mutation. This is the first familial clinical-genetic PKAN disease study accomplished in Mexico.

Case of Hallervorden-Spatz Syndrome: A Tale of Twin Sisters.

Hallervorden-Spatz syndrome, now known as pantothenate kinase-associated neurodegeneration (PKAN), is a rare autosomal recessive disorder that is characterized by cerebral iron deposition and leads to progressive extrapyramidal dysfunction and dementia. Most commonly seen in the first two decades of a person's life, it is a differential for patients presenting with atypical progressive extrapyramidal disorder and cognitive impairment. It is characterized by progressive degeneration of the basal ganglia, globus pallidus, and the reticular part of the substantia nigra due to iron accumulation. The characteristic MRI brain pattern of the disease shows the eye-of-the-tiger sign. We report cases of early onset PKAN in two sisters of the same family, in which diagnosis was based on clinical features, lab parameters, and MRI imaging findings. This report aims to differentiate PKAN from other static and progressive neurological illnesses.

Phenotypes and genotypes of patients with pantothenate kinase-associated neurodegeneration in Asian and Caucasian populations: 2 cases and literature review.

OBJECTIVES: Pantothenate kinase-associated neurodegeneration (PKAN) is a rare disease caused by pantothenate kinase 2 (PANK2, OMIM 606157) mutations. This study is aimed to investigate clinical presentations, pathologies, and genetics in patients with PKAN. METHODS: Two patients with PKAN were reported. We reviewed the literature to include additional 19 patients with PKAN in Eastern Asia. These patients were divided into classic and atypical groups by the age of onset. We compared the data on PKAN patients of Asian and Caucasian populations. RESULTS: We found iron deposits in the globus pallidus in our Patient 1 and a heterozygous truncating mutation (c.1408insT) in Patient 2. Literature review shows that generalized dystonia and bulbar signs are more common in classic PKAN patients, whereas segmental dystonia and tremors are more specific to atypical ones. Asian patients have less complex presentations--lower prevalence of pyramidal signs, mental impairment, and parkinsonism--than Caucasians. D378G in exon 3 is the most frequent mutation (28%) in Asians. CONCLUSIONS: Our study demonstrates that the distribution of dystonia is the major distinction between subgroups of PKAN. Caucasian patients have more complex presentations than Asians. Exon 3 and 4 are hot spots for screening PANK2 mutations in Asian patients.

[Hemochromatosis: one form of iron-overload diseases]. / Haemochromatosis -- mint a vastúlterheléssel járó betegségek egyik formája.

Iron-overload diseases are typically insidious, causing progressive and irreversible organ injury before clinical symptoms develop. Some iron-overload diseases as HFE-associated hemochromatosis and beta-thalassemia are quite common, whereas others are very rare. Early diagnosis is important since iron toxicity can be attenuated or prevented. Significant progress of our knowledge on iron metabolism developed in the past years. We learned a lot about HFE gene mutations, function of ferroportin and hepcidin, the hypoferremia hormone produced by the liver. However, many questions are still open. Special forms of localized iron overload are the Hallervorden-Spatz syndrome and pantothenate kinase gene mutation associated neurodegeneration causing progressive extrapyramidal movement disorders. Neonatal hemochromatosis is a severe systemic iron-overload disorder due to gestational alloimmune liver disease caused by transplacental maternal IgG directed against the fetal liver. This review article gives an overview on iron metabolism and iron-overload disease. Pathomechanism, diagnosis and treatment of hereditary hemochromatosis are discussed.

The first Vietnamese patient who presented late onset of pantothenate kinase-associated neurodegeneration diagnosed by whole exome sequencing: A case report.

RATIONALE: Pantothenate kinase-associated neurodegeneration (PKAN), also called Hallervorden-Spatz syndrome, is a rare autosomal recessive disease associated with brain iron accumulation and characterized by progressive dystonia, dementia, and dysarthria symptoms. PKAN, caused by a defective pantothenate kinase 2 (PANK2) gene, is the most common neurodegeneration with a brain iron accumulation (NBIA) group. The "eye of the tiger" sign in the magnetic resonance imaging demonstrated a bilateral hyperintense signal in the basal ganglia region on T2-weighted images, which is a characteristic feature of the diagnosis. PKAN is classified into 2 main types. The early-onset type (classic type) with rapid progression is characterized by symptoms of gait impairment and dystonia leading to loss of ambulation in early childhood. In the later-onset type (atypical type), slow progression usually takes place in the second decade of life with symptoms of neurodegeneration, dystonia, dysarthria, rigidity, choreoathetosis, and motor impairment. Until now, PKAN patients have only been reported in a few countries in Asia such as China, Korea, India, Iran, Taiwan, and Thailand. PATIENT CONCERNS: Here we report the first case of PKAN in Vietnam. The patient had a late onset but the disease progresses rapidly with symptoms of dyskinesia, dysphagia, and difficulty speaking. DIAGNOSES: Pantothenate kinase-associated neurodegeneration. INTERVENTIONS: Whole exome sequencing was performed to identify heterozygous mutations in the PANK2 gene (NM_153638.4) (c.856C>T, p.Arg286Cys and c.1351C>T, p.Arg451Ter) that has been confirmed as the cause of the disease. OUTCOMES: In this study, the first Vietnamese patient with late-onset PKAN was diagnosed by the whole exome sequencing method. LESSONS: The patient's case marks an important milestone for the first case in Vietnam. The results of the study will provide a scientific basis for clinicians in the diagnosis and genetic counseling of patients.

Concurrent PANK2 and OCA2 variants in a patient with retinal dystrophy, hypopigmented irides and neurodegeneration.

PURPOSE: To report a case of concurrent pantothenate kinase-associated neurodegeneration (PKAN) and oculocutaneous albinism (OCA) with dual PANK2 and OCA2 variants in a Chinese patient who presented with early-onset reduced vision, nyctalopia, and neurological symptoms. MATERIALS AND METHODS: Based on the ocular phenotype and provisional diagnosis of rod-cone dystrophy, genetic testing was pursued. Peripheral blood DNA extraction was carried out with the next-generation sequencing technique, which involved a population-specific medical exome virtual panel. Pre- and post-test counseling were carried out by clinical geneticists. RESULT: Homozygous missense variants in PANK2 {NM_153638.3}:c.655 G>A (p.(Gly219Ser)) and OCA2{NM_025160.6}:c.1327 G>A(p.(Val443Ile)) were identified. The molecular diagnoses of pantothenate kinase associated neurodegeneration (OMIM#234200) and albinism, oculocutaneous, type II (OMIM#203200) were supported by clinical findings. CONCLUSION: Two rare autosomal recessive diseases, pantothenate kinase-associated neurodegeneration (PKAN) and oculocutaneous albinism (OCA) were detected in our patient. Ocular and systemic manifestations, as well as neuroimaging findings were compatible with the diseases identified. Genetic analysis is imperative in making an accurate molecular diagnosis in these rare conditions to allow timely counseling, disease prognostication and management.

Pantothenate - kinase associated neurodegeneration.

Neurodegeneration with brain iron accumulation is a group of disorders, the commonest of which is PKAN (Pantothenate kinase associated neurodegeneration). We present here, a case of 18 year old boy with progressive dementia, pyramidal and extrapyramidal involvement, dysarthria, seizures and myoclonus. The patient was diagnosed as PKAN (formerly Hallervorden Spatz disease) after "eye of tiger" appearance on neuro-imaging.