Neurodegeneration with iron deposition in the brain

Classification according to ICD-10
G23.0	Hallervorden-Spatz syndrome
ICD-10 online (WHO version 2019)

The neurodegeneration with brain iron accumulation (NBIA, Eng. Neurodegeneration with Brain Iron Accumulation) is a group of neurodegenerative diseases , in particularly in the basal ganglia ( pallidus globe and substantia nigra ) but abnormally in other brain areas can be detected elevated levels of iron . At the same time, various physical and mental impairments occur. Initially, this term was introduced as a synonym for Hallervorden-Spatz syndrome (HSS). Over time, however, it was recognized that a number of causes lead to the accumulation of iron. Therefore, the HSS is only a variant of NBIA and is now equated with pantothenate kinase-associated neurodegeneration (PKAN). However, it can be assumed that among the patients described by Julius Hallervorden and Hugo Spatz , the namesake of this disease, there were also some who are affected by one of the various other variants of NBIA. Since Hallervorden and Spatz benefited from the euthanasia programs in Germany in the 1940s during their research , the new name is preferred.

variants

Overview of the NBIA variants

NBIA variant	gene	Inheritance	MRI diagnosis	Clinical picture
Pantothenate kinase-associated neurodegeneration (PKAN)	PANK2	autosomal recessive	Tiger's eye in the Globus pallidus	Classic form (early onset, faster progression): gait disorder , dystonia , dysarthria , retinitis pigmentosa Atypical form (later onset, slower progression): Overall milder clinical picture, e.g. Sometimes with psychiatric abnormalities
Mitochondrial Membrane Protein Associated Neurodegeneration (MPAN)	C19orf12	autosomal recessive	Iron deposits in the globus pallidus and substantia nigra ; z. T. cerebellar atrophy	Start i. d. Usually in childhood or early adulthood Gait disorder , progressive spastic paraparesis , dystonia , parkinsonism , dysarthria , optic atrophy , cognitive degradation, e.g. Sometimes pronounced psychiatric symptoms, urinary and / or Fecal incontinence
PLA2G6-associated neurodegeneration (PLAN)	PLA2G6	autosomal recessive	cerebellar atrophy , iron deposits in the globus pallidus and substantia nigra (not detectable in all cases)	Classical infantile neuraxonal dystrophy (INAD) (early onset, rapid progression): severe psychomotor regression , initial muscle hypotension with increasing spastic tetraparesis , cerebellar atrophy , optic atrophy Atypical neuraxonal dystrophy (NAD) (later onset, slower progression): psychomotor regression , dystonia , dysarthria , cerebellar atrophy , optic atrophy , psychiatric abnormalities, epilepsy Dystonia - Parkinsonism (late onset, slow progression): Parkinsonism , dystonia , cognitive regression , initially clear response to dopaminergic therapy
Beta Propeller Protein Associated Neurodegeneration (BPAN)	WDR45	X-linked dominant , (mostly de novo )	Iron deposits in the substantia nigra are stronger than in the globus pallidus	Psychomotor regression beginning in childhood , epilepsy In the further course z. T. rapid progression of dystonia and parkinsonism
Acaeruloplasminemia	CP	autosomal recessive	Iron deposits in the brain ( globus pallidus , thalamus , putamen , nucleus caudatus and dentatus ) and in internal organs ( liver )	Iron deposits in the brain as well as in the liver Diabetes mellitus , retinal degeneration, blepharospasm , dystonia of the face and neck, chorea , tremor , dysarthria , ataxia Usually onset in adulthood
COASY protein-associated neurodegeneration (CoPAN)	COASY	autosomal recessive	Iron deposits in the globus pallidus and substantia nigra ; z. T. calcifications in the globus pallidus	Early onset of spasticity - dystonic paraparesis , dystonia , dysarthria , parkinsonism , cognitive impairments Overall slow progression
Fatty acid hydroxylase-associated neurodegeneration (FAHN)	FA2H	autosomal recessive	Iron deposits in the globus pallidus and substantia nigra ; pontocerebellar atrophy, thinning of the corpus callosum	Beginning in the first to second decade of life Ataxia , dystonia , spastic paraplegia or tetraplegia , pos. Pyramidal tract signs , dysarthria , optic atrophy
Kufor-Rakeb Syndrome	ATP13A2	autosomal recessive	Generalized brain atrophy, variable intracerebral iron deposition	Parkinsonism occurring in adolescence , cognitive decline, visual hallucinations , progressive supranuclear palsy , myoclonus , oculogyric crisis
Neuroferritinopathy	FTL	autosomal dominant	Iron deposits in the globus pallidus , putamen , thalamus ; cystic changes in the basal ganglia	Similarities to Huntington's Disease: adult chorea or dystonia , orofacial dystonia , cognitive decline
Woodhouse-Sakati syndrome	DCAF17	autosomal recessive	Elevated iron in the globus pallidus and substantia nigra , leukoencephalopathy	Dystonia , dysarthria , cognitive decline, hypogonadism , diabetes mellitus , hair loss
NBIA7	REPS1	autosomal recessive	cerebellar and cerebral atrophy , thin corpus callosum , iron deposits in the globus pallidus and in the cerebellar style	Hypotension , developmental delay in walking and talking, dysarthria , cerebellar - ataxia , pyramidal syndrome, Dysmetria , spasticity of the lower limbs, loss of ability to walk
NBIA8	CRAT	autosomal recessive	cerebellar atrophy , iron deposits in the basal ganglia , globus pallidus and substantia nigra	Hypotension , developmental delay in motor skills and in speaking, cerebellum - ataxia , restless transition, Dysmetria , loss of walking and writing ability, tremors , hyperreflexia

A number of idiopathic NBIA disorders exist for which little or incomplete information is currently available.

The German patient organization Hoffnungsbaum e. V. together with ACHSE e. V. , the umbrella organization for rare diseases , published a patient-oriented description of NBIA in 2017, which contains a few more details and information.

state of research

These diseases are subject to active medical research. Since PKAN has been known for a long time, this is where the scientific and therapeutic findings are currently the most advanced. In general, every single NBIA variant is a very rare disease . Medical research suffers from a lack of funding. New advances are slow to be made. It is to be expected that additional symptoms and diagnoses will be determined through the evaluation of further progress studies .

Interest groups and self-help groups

• Hope tree e. V.
• NBIA Disorders Association
• NBIA cure
• NBIA Alliance
• EURORDIS
• AXIS e. V.

Individual evidence

1. ↑ Christina Berndt: Experiments from the Nazi era catch up with the Max Planck Society. In: Süddeutsche Zeitung. Süddeutscher Verlag, April 25, 2017, accessed on May 2, 2018 . 
2. ↑ Pamela Dörhöfer: Research without any scruples. In: Frankfurter Rundschau. May 8, 2015, accessed May 2, 2018 . 
3. ↑ Introduction and clinical symptoms. In: NBIA - clinical pictures. Friedrich-Baur-Institut, Klinikum der Universität München, accessed on April 28, 2018 . 
4. ^ Allison Gregory, Susan Hayflick: Neurodegeneration with Brain Iron Accumulation Disorders Overview . In: GeneReviews® . University of Washington, Seattle, Seattle WA 1993, PMID 23447832 ( nih.gov [accessed May 3, 2018]).
5. ^ Penelope Hogarth: Neurodegeneration with Brain Iron Accumulation: Diagnosis and Management . In: Journal of Movement Disorders . tape 8 , no. 1 , January 13, 2015, ISSN  2005-940X , p. 1–13 , doi : 10.14802 / jmd.14034 , PMID 25614780 , PMC 4298713 (free full text) - ( e-jmd.org [accessed May 13, 2018]).
6. ↑ Allison Gregory, Susan J. Hayflick: Pantothenate Kinase-Associated Neurodegeneration . In: GeneReviews® . University of Washington, Seattle, Seattle WA 1993, PMID 20301663, ( nih.gov [accessed May 3, 2018]).
7. ↑ Allison Gregory, Monika Hartig, Holger Prokisch, Tomasz Kmiec, Penelope Hogarth, Susan J. Hayflick: Mitochondrial Membrane Protein-Associated Neurodegeneration . In: Margaret P. Adam, Holly H. Ardinger, Roberta A. Pagon, Stephanie E. Wallace (Eds.): GeneReviews® [Internet] . https://www.ncbi.nlm.nih.gov/books/NBK185329 . University of Washington, February 27, 2014, ISSN  2372-0697 .
8. ↑ Allison Gregory, Manju A. Kurian, Eamonn R. Maher, Penelope Hogarth, Susan J. Hayflick: PLA2G6-Associated Neurodegeneration . In: GeneReviews® . University of Washington, Seattle, Seattle WA 1993, PMID 20301718 ( nih.gov [accessed May 3, 2018]).
9. ^ Allison Gregory, Manju A. Kurian, Tobias Haack, Susan J. Hayflick, Penelope Hogarth: Beta-Propeller Protein-Associated Neurodegeneration . In: GeneReviews® . University of Washington, Seattle, Seattle WA 1993, PMID 28211668 ( nih.gov [accessed May 3, 2018]).
10. ↑ Hiroaki Miyajima: Aceruloplasminemia . In: Noryiuki Shibata (Ed.): Neuropathology . tape 35 , no. 1 . Japanese Society of Neuropathology, August 28, 2014, ISSN  0919-6544 , p. 83-90 , doi : 10.1111 / neup.12149 ( wiley.com [accessed May 3, 2018]).
11. ↑ Christina Evers, Angelika Seitz, Birgit Assmann, Thomas Opladen, Stephanie Karch, Katrin Hinderhofer, Martin Granzow, Nagarajan Paramasivam, Roland Eils, Nicolle Diessl, Claus R. Bartram, Ute Moog: Diagnosis of CoPAN by whole exome sequencing: Waking up a sleeping tiger's eye . In: American Journal of Medical Genetics Part A . tape 173 , no. 7 , May 10, 2017, ISSN  1552-4825 , p. 1878–1886 , doi : 10.1002 / ajmg.a.38252 ( wiley.com [accessed May 3, 2018]).
12. ↑ Michael C. Kruer, Allison Gregory, Susan J. Hayflick: Fatty Acid Hydroxylase-Associated Neurodegeneration . In: GeneReviews® . University of Washington, Seattle, Seattle WA 1993, PMID 21735565 ( nih.gov [accessed May 3, 2018]).
13. ↑ DJ Hampshire, E. Roberts, Y. Crow, J. Bond, A. Mubaidin: Kufor-Rakeb syndrome, pallido-pyramidal degeneration with supranuclear upgaze paresis and dementia, maps to 1p36 . In: Journal of Medical Genetics . tape 38 , no. October 10 , 2001, ISSN  1468-6244 , p. 680-682 , doi : 10.1136 / jmg.38.10.680 , PMID 11584046 , PMC 1734748 (free full text).
14. ↑ Patrick F. Chinnery: Neuroferritinopathy . In: GeneReviews® . University of Washington, Seattle, Seattle WA 1993, PMID 20301320 ( nih.gov [accessed May 3, 2018]).
15. ↑ Saeed A. Bohlega, Fowzan S. Alkuraya: Woodhouse-Sakati Syndrome . In: GeneReviews® . University of Washington, Seattle, Seattle WA 1993, PMID 27489925 ( nih.gov [accessed May 3, 2018]).
16. ↑ ^{a b} Anthony Drecourt, Joël Babdor, Michael Dussiot, Floriane Petit, Nicolas Goudin: Impaired Transferrin Receptor Palmitoylation and Recycling in Neurodegeneration with Brain Iron Accumulation . In: The American Journal of Human Genetics . tape 102 , no. 2 , February 2018, ISSN  0002-9297 , p. 266–277 , doi : 10.1016 / j.ajhg.2018.01.003 , PMID 29395073 ( elsevier.com [accessed May 13, 2018]).
17. ↑ A. Klucken, H. Jaskolka: Neurodegeneration with iron deposition in the brain (PDF) ACHSENetzwerk. Retrieved September 14, 2019.

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