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Neurodegeneration with brain iron accumulation 4(MPAN)

MedGen UID:
482001
Concept ID:
C3280371
Disease or Syndrome
Synonyms: Mitochondrial Membrane Protein Associated Neurodegeneration; MITOCHONDRIAL PROTEIN-ASSOCIATED NEURODEGENERATION; MPAN; NBIA4
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Mitochondrial membrane protein associated neurodegeneration (709415008); Neurodegeneration with brain iron accumulation 4 (709415008); Mitochondrial protein associated neurodegeneration (709415008)
 
Gene (location): C19orf12 (19q12)
OMIM®: 614298
Orphanet: ORPHA289560

Definition

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is characterized initially by gait changes followed by progressive spastic paresis, progressive dystonia (which may be limited to the hands and feet or more generalized), neuropsychiatric abnormalities (e.g., emotional lability, depression, anxiety, impulsivity, compulsions, hallucinations, perseveration, inattention, and hyperactivity), and cognitive decline. Additional early findings can include dysphagia, dysarthria, optic atrophy, axonal neuropathy, parkinsonism, and bowel/bladder incontinence. Survival is usually well into adulthood. End-stage disease is characterized by severe dementia, spasticity, dystonia, and parkinsonism. [from GTR]

Additional descriptions

From GeneReviews
Mitochondrial membrane protein-associated neurodegeneration (MPAN) is characterized initially by gait changes followed by progressive spastic paresis, progressive dystonia (which may be limited to the hands and feet or more generalized), neuropsychiatric abnormalities (e.g., emotional lability, depression, anxiety, impulsivity, compulsions, hallucinations, perseveration, inattention, and hyperactivity), and cognitive decline. Additional early findings can include dysphagia, dysarthria, optic atrophy, axonal neuropathy, parkinsonism, and bowel/bladder incontinence. Survival is usually well into adulthood. End-stage disease is characterized by severe dementia, spasticity, dystonia, and parkinsonism.  https://www.ncbi.nlm.nih.gov/books/NBK185329
From NCBI curation
Mitochondrial membrane protein-associated neurodegeneration (MPAN) is characterized initially by gait changes followed by progressive spastic paresis, progressive dystonia (which may be limited to the hands and feet or more generalized), neuropsychiatric abnormalities (e.g., emotional lability, depression, anxiety, impulsivity, compulsions, hallucinations, perseveration, inattention, and hyperactivity), and cognitive decline. Additional early findings can include dysphagia, dysarthria, optic atrophy, axonal neuropathy, parkinsonism, and bowel/bladder incontinence. Survival is usually well into adulthood. End-stage disease is characterized by severe dementia, spasticity, dystonia, and parkinsonism.
From OMIM
Neurodegeneration with brain iron accumulation-4 (NBIA4) is an autosomal recessive neurodegenerative disorder characterized by progressive spastic paraplegia, parkinsonism unresponsive to L-DOPA treatment, and psychiatric or behavioral symptoms. Other neurologic features, including optic atrophy, eye movement abnormalities, dystonia, dysphagia, dysarthria, and motor axonal neuropathy, may occur. Brain MRI shows T2-weighted hypointensities in the globus pallidus and substantia nigra. Onset is usually in the first 2 decades, but later onset has been reported (summary by Dogu et al., 2013). There is phenotypic variation: some patients may not have extrapyramidal signs and may have muscle weakness and atrophy as well as cognitive impairment or developmental delay (Deschauer et al., 2012) For a general phenotypic description and a discussion of genetic heterogeneity of NBIA, see NBIA1 (234200).  http://www.omim.org/entry/614298
From GHR
Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a disorder of the nervous system. The condition typically begins in childhood or early adulthood and worsens (progresses) over time.MPAN commonly begins with difficulty walking. As the condition progresses, affected individuals usually develop other movement problems, including muscle stiffness (spasticity) and involuntary muscle cramping (dystonia). Many people with MPAN have a pattern of movement abnormalities known as parkinsonism. These abnormalities include unusually slow movement (bradykinesia), muscle rigidity, involuntary trembling (tremors), and an inability to hold the body upright and balanced (postural instability).Other neurological problems that occur in individuals with MPAN include degeneration of the nerve cells that carry visual information from the eyes to the brain (optic atrophy), which can impair vision; problems with speech (dysarthria); difficulty swallowing (dysphagia); and, in later stages of the condition, an inability to control the bowels or the flow of urine (incontinence). Additionally, affected individuals may experience a loss of intellectual function (dementia) and psychiatric symptoms such as behavioral problems, mood swings, hyperactivity, and depression.MPAN is characterized by an abnormal buildup of iron in certain regions of the brain. Because of these deposits, MPAN is considered part of a group of conditions known as neurodegeneration with brain iron accumulation (NBIA).  https://ghr.nlm.nih.gov/condition/mitochondrial-membrane-protein-associated-neurodegeneration

Clinical features

Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
A disorder characterized by loss of optic nerve fibers. It may be inherited or acquired. Acquired causes include ischemia, optic nerve neuropathy, glaucoma, trauma, radiation, brain tumors, and multiple sclerosis. It leads to vision disturbances.
Progressive visual loss
MedGen UID:
326867
Concept ID:
C1839364
Finding
A reduction of previously attained ability to see.
Scapular winging
MedGen UID:
66822
Concept ID:
C0240953
Finding
Abnormal protrusion of the scapula away from the surface of the back.
Pes cavus
MedGen UID:
675590
Concept ID:
C0728829
Congenital Abnormality
The presence of an unusually high plantar arch. Also called high instep, pes cavus refers to a distinctly hollow form of the sole of the foot when it is bearing weight.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Sign or Symptom
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- oder overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Depression
MedGen UID:
4229
Concept ID:
C0011581
Mental or Behavioral Dysfunction
A condition characterized by pervasive dysphoric mood, loss of interests, and inability to experience pleasure.
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Disorders of speech articulation caused by imperfect coordination of pharynx, larynx, tongue, or face muscles. This may result from CRANIAL NERVE DISEASES; NEUROMUSCULAR DISEASES; CEREBELLAR DISEASES; BASAL GANGLIA DISEASES; BRAIN STEM diseases; or diseases of the corticobulbar tracts (see PYRAMIDAL TRACTS). The cortical language centers are intact in this condition. (From Adams et al., Principles of Neurology, 6th ed, p489)
Impulsivity
MedGen UID:
43850
Concept ID:
C0021125
Individual Behavior
An act performed without delay, reflection, voluntary direction or obvious control in response to a stimulus.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A form of muscle hypertonia associated with upper MOTOR NEURON DISEASE. Resistance to passive stretch of a spastic muscle results in minimal initial resistance (a "free interval") followed by an incremental increase in muscle tone. Tone increases in proportion to the velocity of stretch. Spasticity is usually accompanied by HYPERREFLEXIA and variable degrees of MUSCLE WEAKNESS. (From Adams et al., Principles of Neurology, 6th ed, p54)
Neurodegeneration
MedGen UID:
17999
Concept ID:
C0027746
Cell or Molecular Dysfunction
Loss of functional activity and trophic degeneration of nerve axons and their terminal arborizations following the destruction of their cells of origin or interruption of their continuity with these cells. The pathology is characteristic of neurodegenerative diseases. Often the process of nerve degeneration is studied in research on neuroanatomical localization and correlation of the neurophysiology of neural pathways.
Babinski sign
MedGen UID:
19708
Concept ID:
C0034935
Finding
A reflex characterized by upward movement of the great toe and an outward movement of the rest of the toes, when the sole of the foot is stroked. It is a normal reflex up to the age of two. Its presence beyond that age indicates neurological damage.
Tremor
MedGen UID:
21635
Concept ID:
C0040822
Sign or Symptom
An unintentional, oscillating to-and-fro muscle movement about a joint axis.
Mood swings
MedGen UID:
39319
Concept ID:
C0085633
Mental or Behavioral Dysfunction
A condition of frequent mood changes associated with excessive emotional reactions.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Autonomic nervous system overreaction to stimuli, most commonly after spinal cord injury at a T-5 level and above.
Parkinsonism
MedGen UID:
66079
Concept ID:
C0242422
Disease or Syndrome
A group of disorders which feature impaired motor control characterized by bradykinesia, MUSCLE RIGIDITY; TREMOR; and postural instability. Parkinsonian diseases are generally divided into primary parkinsonism (see PARKINSON DISEASE), secondary parkinsonism (see PARKINSON DISEASE, SECONDARY) and inherited forms. These conditions are associated with dysfunction of dopaminergic or closely related motor integration neuronal pathways in the BASAL GANGLIA.
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.
Dementia
MedGen UID:
99229
Concept ID:
C0497327
Mental or Behavioral Dysfunction
A loss of global cognitive ability of sufficient amount to interfere with normal social or occupational function. Dementia represents a loss of previously present cognitive abilities, generally in adults, and can affect memory, thinking, language, judgment, and behavior.
Gait disturbance
MedGen UID:
107895
Concept ID:
C0575081
Finding
A finding referring to walking difficulties.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Sign or Symptom
Reduction of neurologic reflexes such as the knee-jerk reaction.
Lewy body dementia
MedGen UID:
199874
Concept ID:
C0752347
Disease or Syndrome
Dementia with Lewy bodies (DLB) is a neurodegenerative disorder clinically characterized by dementia and parkinsonism, often with fluctuating cognitive function, visual hallucinations, falls, syncopal episodes, and sensitivity to neuroleptic medication. Pathologically, Lewy bodies are present in a pattern more widespread than usually observed in Parkinson disease (see PD; 168600). Alzheimer disease (AD; 104300)-associated pathology and spongiform changes may also be seen (McKeith et al., 1996; Mizutani, 2000; McKeith et al., 2005).
Cognitive delay
MedGen UID:
351243
Concept ID:
C1864897
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.
Abnormal lower motor neuron morphology
MedGen UID:
356272
Concept ID:
C1865412
Finding
Any structural anomaly of the lower motor neuron.
Oromandibular dystonia
MedGen UID:
473560
Concept ID:
C2242577
Sign or Symptom
A kind of focal dystonia characterized by forceful contractions of the face, jaw, and/or tongue causing difficulty in opening and closing the mouth and often affecting chewing and speech.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A form of muscle hypertonia associated with upper MOTOR NEURON DISEASE. Resistance to passive stretch of a spastic muscle results in minimal initial resistance (a "free interval") followed by an incremental increase in muscle tone. Tone increases in proportion to the velocity of stretch. Spasticity is usually accompanied by HYPERREFLEXIA and variable degrees of MUSCLE WEAKNESS. (From Adams et al., Principles of Neurology, 6th ed, p54)
Scapular winging
MedGen UID:
66822
Concept ID:
C0240953
Finding
Abnormal protrusion of the scapula away from the surface of the back.
Distal amyotrophy
MedGen UID:
338530
Concept ID:
C1848736
Disease or Syndrome
Muscular atrophy affecting muscles in the distal portions of the extremities.
Distal muscle weakness
MedGen UID:
355271
Concept ID:
C1864696
Finding
Reduced strength of the musculature of the distal extremities.
Scapular winging
MedGen UID:
66822
Concept ID:
C0240953
Finding
Abnormal protrusion of the scapula away from the surface of the back.

Recent clinical studies

Etiology

Aoun M, Tiranti V
Int J Biochem Cell Biol 2015 Jun;63:25-31. Epub 2015 Feb 7 doi: 10.1016/j.biocel.2015.01.018. PMID: 25668476
Tschentscher A, Dekomien G, Ross S, Cremer K, Kukuk GM, Epplen JT, Hoffjan S
J Neurol Sci 2015 Feb 15;349(1-2):105-9. Epub 2015 Jan 3 doi: 10.1016/j.jns.2014.12.036. PMID: 25592411
Colombelli C, Aoun M, Tiranti V
J Inherit Metab Dis 2015 Jan;38(1):123-36. Epub 2014 Oct 10 doi: 10.1007/s10545-014-9770-z. PMID: 25300979
Dusi S, Valletta L, Haack TB, Tsuchiya Y, Venco P, Pasqualato S, Goffrini P, Tigano M, Demchenko N, Wieland T, Schwarzmayr T, Strom TM, Invernizzi F, Garavaglia B, Gregory A, Sanford L, Hamada J, Bettencourt C, Houlden H, Chiapparini L, Zorzi G, Kurian MA, Nardocci N, Prokisch H, Hayflick S, Gout I, Tiranti V
Am J Hum Genet 2014 Jan 2;94(1):11-22. Epub 2013 Dec 19 doi: 10.1016/j.ajhg.2013.11.008. PMID: 24360804Free PMC Article
Schneider SA, Bhatia KP
J Neural Transm (Vienna) 2013 Apr;120(4):695-703. Epub 2012 Dec 2 doi: 10.1007/s00702-012-0922-8. PMID: 23212724

Diagnosis

Cossu G, Abbruzzese G, Matta G, Murgia D, Melis M, Ricchi V, Galanello R, Barella S, Origa R, Balocco M, Pelosin E, Marchese R, Ruffinengo U, Forni GL
Parkinsonism Relat Disord 2014 Jun;20(6):651-4. Epub 2014 Mar 12 doi: 10.1016/j.parkreldis.2014.03.002. PMID: 24661465
Zhang P, Gao Z, Jiang Y, Wang J, Zhang F, Wang S, Yang Y, Xiong H, Zhang Y, Bao X, Xiao J, Wu X, Wu Y
Eur J Neurol 2013 Feb;20(2):322-30. Epub 2012 Aug 31 doi: 10.1111/j.1468-1331.2012.03856.x. PMID: 22934738
Dusek P, Schneider SA
Curr Opin Neurol 2012 Aug;25(4):499-506. doi: 10.1097/WCO.0b013e3283550cac. PMID: 22691760
Hartig MB, Iuso A, Haack T, Kmiec T, Jurkiewicz E, Heim K, Roeber S, Tarabin V, Dusi S, Krajewska-Walasek M, Jozwiak S, Hempel M, Winkelmann J, Elstner M, Oexle K, Klopstock T, Mueller-Felber W, Gasser T, Trenkwalder C, Tiranti V, Kretzschmar H, Schmitz G, Strom TM, Meitinger T, Prokisch H
Am J Hum Genet 2011 Oct 7;89(4):543-50. doi: 10.1016/j.ajhg.2011.09.007. PMID: 21981780Free PMC Article
Gregory A, Hayflick SJ
Folia Neuropathol 2005;43(4):286-96. PMID: 16416393Free PMC Article

Therapy

Aguirre P, García-Beltrán O, Tapia V, Muñoz Y, Cassels BK, Núñez MT
ACS Chem Neurosci 2017 Jan 18;8(1):178-185. Epub 2016 Nov 16 doi: 10.1021/acschemneuro.6b00309. PMID: 27806193
Uberti F, Morsanuto V, Bardelli C, Molinari C
Physiol Rep 2016 Jun;4(11) doi: 10.14814/phy2.12769. PMID: 27252250Free PMC Article
Cossu G, Abbruzzese G, Matta G, Murgia D, Melis M, Ricchi V, Galanello R, Barella S, Origa R, Balocco M, Pelosin E, Marchese R, Ruffinengo U, Forni GL
Parkinsonism Relat Disord 2014 Jun;20(6):651-4. Epub 2014 Mar 12 doi: 10.1016/j.parkreldis.2014.03.002. PMID: 24661465
Weinreb O, Mandel S, Youdim MB, Amit T
Free Radic Biol Med 2013 Sep;62:52-64. Epub 2013 Jan 30 doi: 10.1016/j.freeradbiomed.2013.01.017. PMID: 23376471
Dusek P, Schneider SA
Curr Opin Neurol 2012 Aug;25(4):499-506. doi: 10.1097/WCO.0b013e3283550cac. PMID: 22691760

Prognosis

Dezfouli MA, Alavi A, Rohani M, Rezvani M, Nekuie T, Klotzle B, Tonekaboni SH, Shahidi GA, Elahi E
Mov Disord 2013 Feb;28(2):228-32. Epub 2012 Nov 19 doi: 10.1002/mds.25271. PMID: 23166001
Zhang P, Gao Z, Jiang Y, Wang J, Zhang F, Wang S, Yang Y, Xiong H, Zhang Y, Bao X, Xiao J, Wu X, Wu Y
Eur J Neurol 2013 Feb;20(2):322-30. Epub 2012 Aug 31 doi: 10.1111/j.1468-1331.2012.03856.x. PMID: 22934738
Hartig MB, Iuso A, Haack T, Kmiec T, Jurkiewicz E, Heim K, Roeber S, Tarabin V, Dusi S, Krajewska-Walasek M, Jozwiak S, Hempel M, Winkelmann J, Elstner M, Oexle K, Klopstock T, Mueller-Felber W, Gasser T, Trenkwalder C, Tiranti V, Kretzschmar H, Schmitz G, Strom TM, Meitinger T, Prokisch H
Am J Hum Genet 2011 Oct 7;89(4):543-50. doi: 10.1016/j.ajhg.2011.09.007. PMID: 21981780Free PMC Article
Gupta R, Kumar A, Sharma MC, Sarkar C, Goyal V, Bihari M
Indian J Pathol Microbiol 2007 Oct;50(4):792-4. PMID: 18306557
Gregory A, Hayflick SJ
Folia Neuropathol 2005;43(4):286-96. PMID: 16416393Free PMC Article

Clinical prediction guides

Cossu G, Abbruzzese G, Matta G, Murgia D, Melis M, Ricchi V, Galanello R, Barella S, Origa R, Balocco M, Pelosin E, Marchese R, Ruffinengo U, Forni GL
Parkinsonism Relat Disord 2014 Jun;20(6):651-4. Epub 2014 Mar 12 doi: 10.1016/j.parkreldis.2014.03.002. PMID: 24661465
Dusek P, Schneider SA
Curr Opin Neurol 2012 Aug;25(4):499-506. doi: 10.1097/WCO.0b013e3283550cac. PMID: 22691760
Hartig MB, Iuso A, Haack T, Kmiec T, Jurkiewicz E, Heim K, Roeber S, Tarabin V, Dusi S, Krajewska-Walasek M, Jozwiak S, Hempel M, Winkelmann J, Elstner M, Oexle K, Klopstock T, Mueller-Felber W, Gasser T, Trenkwalder C, Tiranti V, Kretzschmar H, Schmitz G, Strom TM, Meitinger T, Prokisch H
Am J Hum Genet 2011 Oct 7;89(4):543-50. doi: 10.1016/j.ajhg.2011.09.007. PMID: 21981780Free PMC Article
Gregory A, Hayflick SJ
Folia Neuropathol 2005;43(4):286-96. PMID: 16416393Free PMC Article
Youdim MB
J Neural Transm Suppl 2003;(65):73-88. PMID: 12946050

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