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GTR Home > Tests > NBIA Panel

Overview

Test name

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NBIA Panel

Purpose of the test

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This is a clinical test intended for Help: Risk Assessment, Diagnosis, Mutation Confirmation, Screening, Pre-symptomatic, Monitoring

Condition

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How to order

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All samples should be shipped via overnight delivery at room temperature. No weekend or holiday deliveries. Label each specimen with the patient’s name, date of birth and date sample collected. Send specimens with complete requisition and consent form, otherwise, specimen processing may be delayed.
Order URL Help: http://dnatesting.uchicago.edu/submitting-sample

Specimen source

Cell culture
Buccal swab
Fibroblasts
Saliva
Fetal blood
Peripheral (whole) blood
Cord blood

Methodology

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Molecular Genetics
DDeletion/duplication analysis
Next-Generation (NGS)/Massively parallel sequencing (MPS)
CSequence analysis of the entire coding region
Next-Generation (NGS)/Massively parallel sequencing (MPS)

Summary of what is tested

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Clinical utility

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Establish or confirm diagnosis

Citations
  • Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. - PubMed ID: 11438811
  • A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. - PubMed ID: 11479594
  • Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome. - PubMed ID: 12510040
  • Neuroferritinopathy: a neurodegenerative disorder associated with L-ferritin mutation. - PubMed ID: 15737889
  • Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. - PubMed ID: 16964263
  • Clinical features and natural history of neuroferritinopathy caused by the FTL1 460InsA mutation. - PubMed ID: 17142829
  • Mutations in C2orf37, encoding a nucleolar protein, cause hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome. - PubMed ID: 19026396
  • Absence of an orphan mitochondrial protein, c19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation. - PubMed ID: 21981780
  • Analysis of ATP13A2 in large neurodegeneration with brain iron accumulation (NBIA) and dystonia-parkinsonism cohorts. - PubMed ID: 22743658
  • New NBIA subtype: genetic, clinical, pathologic, and radiographic features of MPAN. - PubMed ID: 23269600
  • De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. - PubMed ID: 23435086

Clinical validity

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Mutations in ATP13A2 are associated with Kufor-Rakeb syndrome, which is characterized by juvenile-onset parkinsonism, dementia, supranuclear gaze palsy, pyramidal signs, visual hallucinations and oculogyric dystonic spasms. Some affected individuals have been described with evidence of brain iron accumulation in the caudate and putamen, however this not observed in all patients. ATP13A2 encodes for an ATPase that transports inorganic cations and other substrates across cell membranes, and is most strongly expressed in the brain. MPAN is caused by mutations in the C19orf12 gene, and is associated with motor neuronopathy, spasticity, dystonia, optic atrophy and neuropsychiatric abnormalities. Most patients also have cognitive decline. Onset of symptoms is typically in childhood or early adulthood, and the disorder is slowly progressive. Iron accumulation occurs in all patients and exhibits a distinctive pattern involving the globus pallidus and substantia nigra. C19orf12 encodes a protein that localizes to the mitochondria and is expressed most prominently in the brain, blood cells and adipocytes. Mutations in CP cause Aceruloplasminemia, which is associated with retinal degeneration, diabetes and neurological disease. Neurological manifestations can include facial and neck dystonia, blepharospasm, grimacing, tremors, chorea, gait ataxia and dysarthria. Age of onset ranges from early to late adulthood. Iron accumulation typically occurs in the striatum, thalamus and dentate nucleus of the brain, as well as visceral organs. Affected individuals also have low serum copper and iron, and high serum ferritin. CP encodes for the precursor to ceruloplasmin, which transports copper and also plays an important role in iron mobilization. Woodhouse-Sakati syndrome is associated with mutations in DCAF17, and is characterized by hypogonadism, partial alopecia, diabetes, intellectual disability, deafness and a progressive extrapyramidal disorder. Brain iron accumulation occurs in the globus pallidus, substantia nigra and other regions of the basal ganglia, and white matter disease is also frequently observed. DCAF17 encodes a nucleolar protein of unknown function. FAHN is caused by mutation in the FA2H gene, and is associated with spasticity, ataxia and dystonia. Age of onset is typically in childhood, and affected individuals typically develop optic atrophy and oculomotor abnormalities during the early stages of disease, and progressive intellectual impairment and seizures in the later stages. Iron accumulation occurs in the globus pallidus and substantia nigra. Progressive white matter changes and cerebellar and brain stem atrophy are also observed. FA2H encodes for fatty acid 2-hydroxylase, which alpha-hydroxylates fatty acids, which are then incorporated into several diverse lipid species. Mutations in FTL cause neuroferritinopathy, which is characterized by extrapyramidal features similar to Huntington disease or parkinsonism. The average age of onset is 39 years. Additional symptoms can include tremor, cerebellar ataxia, and cognitive decline. Affected individuals typically have low serum ferritin levels, and brain MRI findings consistent with excess iron storage and cystic changes involving the globus pallidus and the putamen. FTL encodes for a subunit of ferritin, and mutations in FTL cause abnormally shaped ferritin molecules and aggregation of ferritin and associated iron molecules in the brain. PKAN (previously known as Hallervorden-Spatz syndrome) is caused by mutations in PANK2. There is wide phenotypic variability, including classic PKAN and atypical PKAN. Classic PKAN is associated with early onset (3-4 years of age), rapid progression, impaired gait, restricted visual fields, dystonia, dysarthria, spasticity, retinopathy, and possible cognitive impairment. Atypical PKAN has a mean age of onset of 13-14, slow progression, speech difficulties, neurobehavioral changes, Parkinson-like syndrome, spasticity, hyperreflexia and possible cognitive impairment. Most individuals with PANK2 mutations show brain iron accumulation, which is specific to the globus pallidus and substantia nigra and appears as the “eye of the tiger” sign. PANK2 is a key regulatory enzyme in several metabolic pathways of Coenzyme A biosynthesis. PLAN is caused by mutations in PLA2G6 and is associated with a continuum of three phenotypes: classic infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (atypical NAD), and PLA2G6-associated dystonia-parkinsonism. Patients with INAD and atypical NAD both have hypointensity of the globus pallidus on T2-weighted MRI, indicating iron accumulation. INAD patients also have cerebellar gliosis, white matter abnormalities and a thin, vertically oriented corpus callosum. Patients with PLA2G6-associated dystonia-parkinsonism may show iron accumulation in the globus pallidus, substantia nigra and/or striatum, however this is often not evident until late in the disease course. PLA2G6 encodes for an enzyme that plays an important role in cell membrane homeostasis and phospholipid metabolism, and PLA2G6 mutations gene may result in phospholipase A2 dysfunction critical in brain iron regulation and normal axonal pathology. Mutations in WDR45 cause BPAN, which is associated with global developmental delay in childhood and sudden onset of progressive dystonia-parkinsonism and dementia in adolescence or adulthood. Brain iron accumulation occurs in the globus pallidus and substantia nigra. WDR45 encodes for a protein which has an important role in autophagy, and mutations in the WDR45 gene leads to an accumulation of aberrant early autophagic structures.

Citations
  • Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. - PubMed ID: 11438811
  • A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. - PubMed ID: 11479594
  • Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome. - PubMed ID: 12510040
  • Neuroferritinopathy: a neurodegenerative disorder associated with L-ferritin mutation. - PubMed ID: 15737889
  • Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. - PubMed ID: 16964263
  • Clinical features and natural history of neuroferritinopathy caused by the FTL1 460InsA mutation. - PubMed ID: 17142829
  • Mutations in C2orf37, encoding a nucleolar protein, cause hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome. - PubMed ID: 19026396
  • Absence of an orphan mitochondrial protein, c19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation. - PubMed ID: 21981780
  • Analysis of ATP13A2 in large neurodegeneration with brain iron accumulation (NBIA) and dystonia-parkinsonism cohorts. - PubMed ID: 22743658
  • New NBIA subtype: genetic, clinical, pathologic, and radiographic features of MPAN. - PubMed ID: 23269600
  • De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. - PubMed ID: 23435086
  • Neurodegeneration with Brain Iron Accumulation Disorders Overview - PubMed ID: 23447832
  • Gregory A. PLA2G6-Associated Neurodegeneration.: GeneReviews [Internet]. Seattle, WA: University of Washington, Seattle., 2008, Jun 18 [Updated 2012 Apr 19].
  • Miyajima H. Aceruloplasminemia.: GeneReviews [Internet]. Seattle, WA: University of Washington, Seattle., 2003, Aug 12 [Updated 2013, Apr 18].
  • https://0-www-ncbi-nlm-nih-gov.brum.beds.ac.uk/books/NBK121988

Test services

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  • Clinical Testing/Confirmation of Mutations Identified Previously
  • Confirmation of research findings
  • Custom mutation-specific/Carrier testing
  • Custom Prenatal Testing

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