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Neurodegeneration with brain iron accumulation 9(NBIA9)

MedGen UID:
1845761
Concept ID:
C5882740
Disease or Syndrome
Synonym: NBIA9
 
Gene (location): FTH1 (11q12.3)
 
Monarch Initiative: MONDO:0958012
OMIM®: 620669

Definition

Neurodegeneration with brain iron accumulation-9 (NBIA9) is characterized by global developmental delay apparent from infancy and progressive neurodegeneration of motor and cognitive skills. Affected individuals have delayed walking or inability to walk, spasticity with hyperreflexia, ataxia, dystonia, and poor or absent language. Additional more variable features include dysphagia, failure to thrive, poor growth, microcephaly, hypotonia, impaired vision, and seizures. Brain imaging shows progressive cerebral and cerebellar atrophy, iron accumulation in the basal ganglia, thin corpus callosum, and pontocerebellar hypoplasia. The disorder can be classified as a neuroferritinopathy (see NBIA3, 606159) (Shieh et al., 2023). For a general phenotypic description and a discussion of genetic heterogeneity of NBIA, see NBIA1 (234200). [from OMIM]

Clinical features

From HPO
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
Difficulty in swallowing.
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Athetosis
MedGen UID:
2115
Concept ID:
C0004158
Disease or Syndrome
A slow, continuous, involuntary writhing movement that prevents maintenance of a stable posture. Athetosis involves continuous smooth movements that appear random and are not composed of recognizable sub-movements or movement fragments. In contrast to chorea, in athetosis, the same regions of the body are repeatedly involved. Athetosis may worsen with attempts at movement of posture, but athetosis can also occur at rest.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
Dystonic disorder
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Neurodegeneration
MedGen UID:
17999
Concept ID:
C0027746
Cell or Molecular Dysfunction
Progressive loss of neural cells and tissue.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Dysmetria
MedGen UID:
68583
Concept ID:
C0234162
Finding
A type of ataxia characterized by the inability to carry out movements with the correct range and motion across the plane of more than one joint related to incorrect estimation of the distances required for targeted movements.
Mental deterioration
MedGen UID:
66713
Concept ID:
C0234985
Mental or Behavioral Dysfunction
Loss of previously present mental abilities, generally in adults.
Delayed ability to walk
MedGen UID:
66034
Concept ID:
C0241726
Finding
A failure to achieve the ability to walk at an appropriate developmental stage. Most children learn to walk in a series of stages, and learn to walk short distances independently between 12 and 15 months.
Cerebellar hypoplasia
MedGen UID:
120578
Concept ID:
C0266470
Congenital Abnormality
Cerebellar hypoplasia is a descriptive term implying a cerebellum with a reduced volume, but a normal shape and is stable over time.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue. Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event.
Exaggerated startle response
MedGen UID:
329357
Concept ID:
C1740801
Finding
An exaggerated startle reaction in response to a sudden unexpected visual or acoustic stimulus, or a quick movement near the face.
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Iron accumulation in brain
MedGen UID:
866729
Concept ID:
C4021076
Finding
An abnormal build up of iron (Fe) in brain tissue.
Eye of the tiger anomaly of globus pallidus
MedGen UID:
871224
Concept ID:
C4025705
Finding
The presence, on T2-weighted magnetic resonance imaging, of markedly low signal intensity of the globus pallidus that surrounds a central region of high signal intensity in the anteromedial globus pallidus, producing an eye-of-the-tiger appearance. The sign is thought to represent iron accumulation in the globus pallidus.
Delayed ability to sit
MedGen UID:
1368737
Concept ID:
C4476710
Finding
A failure to achieve the ability to sit at an appropriate developmental stage. Most children sit with support at 6 months of age and sit steadily without support at 9 months of age.
Hot cross bun sign
MedGen UID:
1761463
Concept ID:
C5421689
Sign or Symptom
A cruciform-shaped hyperintensity within the pons found on T2-weighted magnetic resonance imaging (MRI).
Thin corpus callosum
MedGen UID:
1785336
Concept ID:
C5441562
Anatomical Abnormality
An abnormally thin corpus callous, due to atrophy, hypoplasia or agenesis. This term is intended to be used in situations where it is not known if thinning of the corpus callosum (for instance, as visualized by magnetic resonance tomography) is due to abnormal development (e.g. a leukodystrophy) or atrophy following normal development (e.g. neurodegeneration).
Reduced cerebral white matter volume
MedGen UID:
1815057
Concept ID:
C5706151
Finding
An abnormally low volume of the white matter of the brain.
Axial hypotonia
MedGen UID:
342959
Concept ID:
C1853743
Finding
Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Abnormal circulating iron concentration
MedGen UID:
808235
Concept ID:
C0235760
Finding
The concentration of iron in the blood circulation is outside the limits of normal.
Decreased circulating ferritin concentration
MedGen UID:
66021
Concept ID:
C0241012
Finding
Abnormally reduced concentration of ferritin, a ubiquitous intracellular protein that stores iron, in the blood.
Decreased transferrin saturation
MedGen UID:
760149
Concept ID:
C0919785
Finding
A below normal level of saturation of serum transferrin with iron.
Cerebral visual impairment
MedGen UID:
890568
Concept ID:
C4048268
Pathologic Function
A form of loss of vision caused by damage to the visual cortex rather than a defect in the eye.

Recent clinical studies

Etiology

Amini E, Rohani M, Fasano A, Azad Z, Miri S, Habibi SAH, Emamikhah M, Mirshahi R, Joghataei MT, Gholibeigian Z, Ghasemi Falavarjani K
Mov Disord 2024 Feb;39(2):411-423. Epub 2023 Nov 10 doi: 10.1002/mds.29644. PMID: 37947042
Iankova V, Sparber P, Rohani M, Dusek P, Büchner B, Karin I, Schneider SA, Gorriz JM, Kmiec T, Klopstock T
Brain 2024 Apr 4;147(4):1389-1398. doi: 10.1093/brain/awad357. PMID: 37831662
Huat TJ, Camats-Perna J, Newcombe EA, Valmas N, Kitazawa M, Medeiros R
J Mol Biol 2019 Apr 19;431(9):1843-1868. Epub 2019 Jan 18 doi: 10.1016/j.jmb.2019.01.018. PMID: 30664867Free PMC Article
Schneider SA
Curr Neurol Neurosci Rep 2016 Jan;16(1):9. doi: 10.1007/s11910-015-0608-3. PMID: 26739693
Hartig MB, Prokisch H, Meitinger T, Klopstock T
Curr Drug Targets 2012 Aug;13(9):1182-9. doi: 10.2174/138945012802002384. PMID: 22515741

Diagnosis

Iankova V, Sparber P, Rohani M, Dusek P, Büchner B, Karin I, Schneider SA, Gorriz JM, Kmiec T, Klopstock T
Brain 2024 Apr 4;147(4):1389-1398. doi: 10.1093/brain/awad357. PMID: 37831662
Bhardwaj NK, Gowda VK, Saini J, Sardesai AV, Santhoshkumar R, Mahadevan A
Brain Dev 2021 Nov;43(10):1013-1022. Epub 2021 Jul 14 doi: 10.1016/j.braindev.2021.06.010. PMID: 34272103
Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, Fulda S, Gascón S, Hatzios SK, Kagan VE, Noel K, Jiang X, Linkermann A, Murphy ME, Overholtzer M, Oyagi A, Pagnussat GC, Park J, Ran Q, Rosenfeld CS, Salnikow K, Tang D, Torti FM, Torti SV, Toyokuni S, Woerpel KA, Zhang DD
Cell 2017 Oct 5;171(2):273-285. doi: 10.1016/j.cell.2017.09.021. PMID: 28985560Free PMC Article
Schneider SA
Curr Neurol Neurosci Rep 2016 Jan;16(1):9. doi: 10.1007/s11910-015-0608-3. PMID: 26739693
Khan AO, AlDrees A, Elmalik SA, Hassan HH, Michel M, Stevanin G, Azzedine H, Salih MA
Br J Ophthalmol 2014 Jul;98(7):889-93. doi: 10.1136/bjophthalmol-2013-304527. PMID: 24522175

Therapy

Thakur N, Klopstock T, Jackowski S, Kuscer E, Tricta F, Videnovic A, Jinnah HA
Mov Disord 2021 Sep;36(9):2005-2016. Epub 2021 May 18 doi: 10.1002/mds.28642. PMID: 34002881
Klopstock T, Tricta F, Neumayr L, Karin I, Zorzi G, Fradette C, Kmieć T, Büchner B, Steele HE, Horvath R, Chinnery PF, Basu A, Küpper C, Neuhofer C, Kálmán B, Dušek P, Yapici Z, Wilson I, Zhao F, Zibordi F, Nardocci N, Aguilar C, Hayflick SJ, Spino M, Blamire AM, Hogarth P, Vichinsky E
Lancet Neurol 2019 Jul;18(7):631-642. doi: 10.1016/S1474-4422(19)30142-5. PMID: 31202468
Huat TJ, Camats-Perna J, Newcombe EA, Valmas N, Kitazawa M, Medeiros R
J Mol Biol 2019 Apr 19;431(9):1843-1868. Epub 2019 Jan 18 doi: 10.1016/j.jmb.2019.01.018. PMID: 30664867Free PMC Article
Hartig MB, Prokisch H, Meitinger T, Klopstock T
Curr Drug Targets 2012 Aug;13(9):1182-9. doi: 10.2174/138945012802002384. PMID: 22515741
Timmermann L, Pauls KA, Wieland K, Jech R, Kurlemann G, Sharma N, Gill SS, Haenggeli CA, Hayflick SJ, Hogarth P, Leenders KL, Limousin P, Malanga CJ, Moro E, Ostrem JL, Revilla FJ, Santens P, Schnitzler A, Tisch S, Valldeoriola F, Vesper J, Volkmann J, Woitalla D, Peker S
Brain 2010 Mar;133(Pt 3):701-12. Epub 2010 Mar 5 doi: 10.1093/brain/awq022. PMID: 20207700Free PMC Article

Prognosis

Amini E, Rohani M, Lang AE, Azad Z, Habibi SAH, Alavi A, Shahidi G, Emamikhah M, Chitsaz A
Mov Disord Clin Pract 2024 Jan;11(1):53-62. Epub 2023 Dec 1 doi: 10.1002/mdc3.13933. PMID: 38291840Free PMC Article
Iankova V, Sparber P, Rohani M, Dusek P, Büchner B, Karin I, Schneider SA, Gorriz JM, Kmiec T, Klopstock T
Brain 2024 Apr 4;147(4):1389-1398. doi: 10.1093/brain/awad357. PMID: 37831662
Huat TJ, Camats-Perna J, Newcombe EA, Valmas N, Kitazawa M, Medeiros R
J Mol Biol 2019 Apr 19;431(9):1843-1868. Epub 2019 Jan 18 doi: 10.1016/j.jmb.2019.01.018. PMID: 30664867Free PMC Article
Darling A, Aguilera-Albesa S, Tello CA, Serrano M, Tomás M, Camino-León R, Fernández-Ramos J, Jiménez-Escrig A, Poó P, O'Callaghan M, Ortez C, Nascimento A, Fernández Mesaque RC, Madruga M, Arrabal L, Roldan S, Gómez-Martín H, Garrido C, Temudo T, Jou-Muñoz C, Muchart J, Huisman TAGM, Poretti A, Lupo V, Espinós C, Pérez-Dueñas B
Parkinsonism Relat Disord 2019 Apr;61:179-186. Epub 2018 Oct 13 doi: 10.1016/j.parkreldis.2018.10.013. PMID: 30340910
Timmermann L, Pauls KA, Wieland K, Jech R, Kurlemann G, Sharma N, Gill SS, Haenggeli CA, Hayflick SJ, Hogarth P, Leenders KL, Limousin P, Malanga CJ, Moro E, Ostrem JL, Revilla FJ, Santens P, Schnitzler A, Tisch S, Valldeoriola F, Vesper J, Volkmann J, Woitalla D, Peker S
Brain 2010 Mar;133(Pt 3):701-12. Epub 2010 Mar 5 doi: 10.1093/brain/awq022. PMID: 20207700Free PMC Article

Clinical prediction guides

Amini E, Rohani M, Fasano A, Azad Z, Miri S, Habibi SAH, Emamikhah M, Mirshahi R, Joghataei MT, Gholibeigian Z, Ghasemi Falavarjani K
Mov Disord 2024 Feb;39(2):411-423. Epub 2023 Nov 10 doi: 10.1002/mds.29644. PMID: 37947042
Iankova V, Sparber P, Rohani M, Dusek P, Büchner B, Karin I, Schneider SA, Gorriz JM, Kmiec T, Klopstock T
Brain 2024 Apr 4;147(4):1389-1398. doi: 10.1093/brain/awad357. PMID: 37831662
Sait H, Srivastava S, Pandey M, Ravichandran D, Shukla A, Mandal K, Saxena D, Shambhavi A, Majethia P, Rao LP, Sharma S, Phadke SR, Moirangthem A
Neurogenetics 2023 Apr;24(2):113-127. Epub 2023 Feb 15 doi: 10.1007/s10048-023-00712-0. PMID: 36790591
Dangel T, Kmieć T, Januszaniec A, Ważny B
Neurol Sci 2020 Mar;41(3):653-660. Epub 2019 Nov 22 doi: 10.1007/s10072-019-04099-5. PMID: 31758347Free PMC Article
Huat TJ, Camats-Perna J, Newcombe EA, Valmas N, Kitazawa M, Medeiros R
J Mol Biol 2019 Apr 19;431(9):1843-1868. Epub 2019 Jan 18 doi: 10.1016/j.jmb.2019.01.018. PMID: 30664867Free PMC Article

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