Mitochondrial membrane protein-associated neurodegeneration

Short description: Genetic neurodegenerative disease with brain iron accumulation

Mitochondrial membrane protein-associated neurodegeneration

Other names| Neurodegeneration with brain iron accumulation 4
Specialty| Neurology
Symptoms| Dystonia, parkinsonism, dementia
Types| Recessive, dominant
Causes| C19orf12 mutation
Frequency| 1/1,000,000

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a genetic neurodegenerative disease that causes dystonia, parkinsonism, and iron accumulation in the brain.[1][2] It is caused by mutations to the gene C19orf12, which has unknown function. This was originally discovered as an autosomal recessive disorder, caused by individuals having two mutations to the gene C19orf12, but autosomal dominant disease caused by a single mutation in the same gene has also been rarely described.[1] Due to the common features of neurodegeneration, brain iron accumulation, and movement disorder it is classified as a neurodegeneration with brain iron accumulation (NBIA) disorder and another name for the condition is neurodegeneration with brain iron accumulation 4 (NBIA4).[1][2]

## Contents

* 1 Signs and symptoms
* 2 Genetics
* 3 Diagnosis
* 3.1 Neuropathology
* 4 Management
* 5 Prognosis
* 6 Epidemiology
* 7 History
* 8 References
* 9 External links

## Signs and symptoms

Symptoms typically begin in childhood and worsen over time. Typical initial features include difficulty walking and dystonia, with later progression to difficulty moving called parkinsonism. Associated problems can include optic nerve atrophy. As movement difficulties worsen, it can cause difficulty swallowing (dysphagia), difficulty speaking (dysarthria), and dementia.[1][2][3]

## Genetics

MPAN is caused by variants to a single gene, C19orf12, the function of which is not currently known.[1][4] The more common form is caused by an individual having two dysfunctional copies of C19orf12 which are typically inherited from unaffected parents carrying one mutated copy and one normal copy (carrier status). This is called autosomal recessive inheritance. More rarely described are individuals with a single dysfunctional copy of C19orf12 causing disease, considered to be an autosomal dominant form of the disease that can either be inherited or arise from a de novo mutation.[1][2]

The protein C19orf12 is not well understood, it is expressed in most cells and is thought to localize to mitochondria and the endoplasmic reticulum.[5]

## Diagnosis

MPAN might be suspected with typical presentation and findings on MRI (Magnetic Resonance Imaging), these include evidence of iron deposition in the brain, particularly in the basal ganglia (globus pallidus and substantia nigra).[1][3] The diagnosis is confirmed by genetic testing identifying harmful variant(s) in C19orf12.[1]

### Neuropathology

Pathological findings in brains of people with MPAN include iron deposition and scarring in the globus pallidus, loss of neurons in the substantia nigra, and widespread Lewy bodies and spherical bodies from degenerating neurons.[1][3][6]

## Management

There are no current treatments or clinical trials for MPAN, so medical treatment focusses on relief of symptoms such as spasticity and dystonia using medications (such as gabapentin, trihexyphenidyl or baclofen), or surgery.[1][3][6]

## Prognosis

MPAN typically progresses more slowly than other NBIA disorders, and people usually survive into adulthood. As it progresses, people have more difficulty with cognition, speaking, swallowing, movement difficulties, and neuropsychiatric problems.[1]

## Epidemiology

Prevalence data regarding this disorder remains incomplete, however it is estimated that less than 1 in 1,000,000 have the disease worldwide. It is more common in Turkish people, due to a founder mutation.[1]

## History

MPAN was first described in 2011 in 24 Polish patients with mutations in C19orf12,[7] later confirmed in a further 23 people.[8][4]

## References

1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 "Mitochondrial Membrane Protein-Associated Neurodegeneration". GeneReviews [Internet]. 2014. PMID 24575447. https://www.ncbi.nlm.nih.gov/books/NBK185329.
2. ↑ 2.0 2.1 2.2 2.3 "Mitochondrial membrane protein-associated neurodegeneration: MedlinePlus Genetics" (in en). https://medlineplus.gov/genetics/condition/mitochondrial-membrane-protein-associated-neurodegeneration/.
3. ↑ 3.0 3.1 3.2 3.3 Hogarth, P (January 2015). "Neurodegeneration with Brain Iron Accumulation: Diagnosis and Management" (in English). Journal of Movement Disorders 8 (1): 1–13. doi:10.14802/jmd.14034. PMID 25614780.
4. ↑ 4.0 4.1 Online Mendelian Inheritance in Man (OMIM) NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 4 -614298
5. ↑ Online Mendelian Inheritance in Man (OMIM) CHROMOSOME 19 OPEN READING FRAME 12 -614297
6. ↑ 6.0 6.1 Spaull, R; Soo, A; Hogarth; Hayflick, S; Kurian, M (November 2021). "Towards Precision Therapies for Inherited Disorders of Neurodegeneration with Brain Iron Accumulation" (in en). Tremor and Other Hyperkinetic Movements 11 (1): 51. doi:10.5334/tohm.661. ISSN 2160-8288. PMID 34909266.
7. ↑ Hartig, Monika B.; Iuso, Arcangela; Haack, Tobias; Kmiec, Tomasz; Jurkiewicz, Elzbieta; Heim, Katharina; Roeber, Sigrun; Tarabin, Victoria et al. (October 2011). "Absence of an Orphan Mitochondrial Protein, C19orf12, Causes a Distinct Clinical Subtype of Neurodegeneration with Brain Iron Accumulation" (in en). The American Journal of Human Genetics 89 (4): 543–550. doi:10.1016/j.ajhg.2011.09.007. PMID 21981780.
8. ↑ Hogarth, P.; Gregory, A.; Kruer, M. C.; Sanford, L.; Wagoner, W.; Natowicz, M. R.; Egel, R. T.; Subramony, S. H. et al. (15 January 2013). "New NBIA subtype: Genetic, clinical, pathologic, and radiographic features of MPAN" (in en). Neurology 80 (3): 268–275. doi:10.1212/WNL.0b013e31827e07be. ISSN 0028-3878. PMID 23269600.

## External links

Classification|

* ICD-10: G23.0
* OMIM: 614298
* DiseasesDB: 35161

|

External resources|

* GeneReviews: Mitochondrial Membrane Protein-Associated Neurodegeneration
* Orphanet: 289560

* v
* t
* e

Diseases of the nervous system, primarily CNS (G04–G47, 323–349)

Inflammation|

| Brain|

* Encephalitis
* Viral encephalitis
* Herpesviral encephalitis
* Limbic encephalitis
* Encephalitis lethargica
* Cavernous sinus thrombosis
* Brain abscess
* Amoebic

|

Spinal cord|

* Myelitis: Poliomyelitis
* Demyelinating disease
* Transverse myelitis
* Tropical spastic paraparesis
* Epidural abscess

Both/either|

* Encephalomyelitis
* Acute disseminated
* Myalgic
* Meningoencephalitis

Brain/
encephalopathy|

| Degenerative|

| Extrapyramidal and
movement disorders|

* Basal ganglia disease
* Parkinsonism
* PD
* Postencephalitic
* NMS
* PKAN
* Tauopathy
* PSP
* Striatonigral degeneration
* Hemiballismus
* HD
* OA

* Dyskinesia
* Dystonia
* Status dystonicus
* Spasmodic torticollis
* Meige's
* Blepharospasm
* Athetosis
* Chorea
* Choreoathetosis
* Myoclonus
* Myoclonic epilepsy
* Akathisia

* Tremor
* Essential tremor
* Intention tremor
* Restless legs
* Stiff-person

|

Dementia|

* Tauopathy
* Alzheimer's
* Early-onset
* Primary progressive aphasia
* Frontotemporal dementia/Frontotemporal lobar degeneration
* Pick's
* Dementia with Lewy bodies
* Posterior cortical atrophy

* Vascular dementia

Mitochondrial disease|

* Leigh syndrome

Demyelinating|

* autoimmune
* Multiple sclerosis
* Neuromyelitis optica
* Schilder's disease
* hereditary
* Adrenoleukodystrophy
* Alexander
* Canavan
* Krabbe
* ML
* PMD
* VWM
* MFC
* CAMFAK syndrome
* Central pontine myelinolysis
* Marchiafava–Bignami disease
* Alpers' disease

Episodic/
paroxysmal|

| Seizure/epilepsy|

* Focal
* Generalised
* Status epilepticus
* Myoclonic epilepsy

|

Headache|

* Migraine
* Familial hemiplegic
* Cluster
* Tension

Cerebrovascular|

* TIA
* Amaurosis fugax
* Transient global amnesia
* Acute aphasia

* Stroke
* MCA
* ACA
* PCA
* Foville's
* Millard–Gubler
* Lateral medullary
* Medial medullary
* Weber's
* Lacunar stroke

Sleep disorders|

* Insomnia
* Hypersomnia
* Sleep apnea
* Obstructive
* Congenital central hypoventilation syndrome
* Narcolepsy
* Cataplexy
* Kleine–Levin
* Circadian rhythm sleep disorder
* Advanced sleep phase disorder
* Delayed sleep phase disorder
* Non-24-hour sleep–wake disorder
* Jet lag

CSF|

* Intracranial hypertension
* Hydrocephalus/NPH
* Choroid plexus papilloma
* Idiopathic intracranial hypertension
* Cerebral edema
* Intracranial hypotension

Other|

* Brain herniation
* Reye's
* Hepatic encephalopathy
* Toxic encephalopathy
* Hashimoto's encephalopathy

Spinal cord/
myelopathy|

* Syringomyelia
* Syringobulbia
* Morvan's syndrome
* Vascular myelopathy
* Foix–Alajouanine syndrome
* Spinal cord compression

Both/either|

| Degenerative|

| SA|

* Friedreich's ataxia
* Ataxia–telangiectasia

|

MND|

* UMN only:
* Primary lateral sclerosis
* Pseudobulbar palsy
* Hereditary spastic paraplegia

* LMN only:
* Distal hereditary motor neuronopathies
* Spinal muscular atrophies
* SMA
* SMAX1
* SMAX2
* DSMA1
* Congenital DSMA
* SMA-PCH
* SMA-LED
* SMA-PME
* Progressive muscular atrophy
* Progressive bulbar palsy
* Fazio–Londe
* Infantile progressive bulbar palsy

* both:
* Amyotrophic lateral sclerosis

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