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Disease Profile

Mitochondrial Membrane Protein-Associated Neurodegeneration

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

1-9 / 1 000 000

US Estimated

Europe Estimated

Age of onset

Childhood

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ICD-10

G23.0

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease.

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype.

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder.

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

MPAN; NBIA due to C19orf12 mutation; NBIA4;

Categories

Congenital and Genetic Diseases; Eye diseases; Nervous System Diseases

Summary

The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.
orphanet

Orpha Number: 289560

Definition
A rare neurodegenerative disorder characterized by iron accumulation in specific regions of the brain, usually the basal ganglia, and associated with slowly progressive pyramidal (spasticity) and extrapyramidal (dystonia) signs, motor axonal neuropathy, optic atrophy, cognitive decline, and neuropsychiatric abnormalities.

Epidemiology
Mitochondrial membrane protein-associated neurodegeneration (MPAN) is an extremely rare disease with an estimated worldwide prevalence of about 1/1,000,000. MPAN accounts for approximately 6-10% of cases neurodegeneration with brain iron accumulation (NBIA) cases, with less than 80 cases reported to date.

Clinical description
MPAN usually manifests during childhood (mean age: 10 years), but cases during adolescence or adulthood have been reported too. It presents with gait difficulty, dysarthria and bilateral optic atrophy. Early upper motor neuron signs (pyramidal signs, e.g. spasticity) are constant findings and are later followed by signs of lower motor neuron dysfunction (deep tendon reflex loss, muscular weakness and atrophy). Progressive dystonia, parkinsonism, cognitive decline, and neuropsychiatric symptoms are present in more than half of the patients. Weight loss and bowel and/or bladder dysfunction are common.

Etiology
MPAN is caused by mutations in the chromosome 19 open reading frame 12 gene (C19orf12 ; 19q13.11). A founder mutation (c.204_214del11 (p.Gly69ArgfsX10)) has been described in Eastern Europe. The function of C19orf12 remains uncertain, but it may be involved in mitochondrial function, lipid homeostasis and coenzyme A metabolism.

Diagnostic methods
Diagnosis is based on neuroimaging that shows evidence of iron deposits mainly in the globus pallidus and substantia nigra, often with unique T2-hyperintense streaking between the hypointense internal globus pallidus and external globus pallidus. Ophthalmologic examinations and evoked visual potentials are important to identify optic atrophy. Neuropathologic examination shows axonal spheroids, Lewy bodies and hyperphosphorylated tau-containing inclusions. Mutation analysis of the C19orf12 gene confirms the diagnosis.

Differential diagnosis
Differential diagnosis includes other NBIAs, more particularly fatty acid hydroxylase-associated neurodegeneration and PLA2G6-associated neurodegeneration. Spasticity, more prominent than dystonia, optic atrophy, motor neuropathy, and a slowly progressive course with cognitive decline help to differentiate MPAN from the other NBIAs.

Antenatal diagnosis
Prenatal diagnosis may be available for families in which disease-causing mutations have been identified in a previous affected sib.

Genetic counseling
MPAN is an autosomal recessive disorder. It is more common in consanguineous families or families of the same origin (i.e. both parents from the same small town). Parents of a patient with MPAN are obligate carriers. The risk of having an affected child in further pregnancies is of 25%.

Management and treatment
There is currently no curative treatment. Management strategies focus on the medical and surgical palliation of symptoms. Follow-up by a multidisciplinary team formed by neurologists, geneticists, ophthalmologists, physiotherapists, occupational therapists, speech and language therapists, orthopedic surgeons, and neurosurgeons is essential.

Prognosis
The progression of MPAN is usually slow and may lead to loss of independent ambulation due to spasticity, dystonia and parkinsonism; limited communication due to dysarthria and cognitive decline; and severe dementia. Life expectancy is variable. Premature death may occur due to secondary complications such as aspiration pneumonia.

Visit the Orphanet disease page for more resources.

Symptoms

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Babinski sign
0003487
Behavioral abnormality
Behavioral changes
Behavioral disorders
Behavioral disturbances
Behavioral problems
Behavioral/psychiatric abnormalities
Behavioural/Psychiatric abnormality
Psychiatric disorders
Psychiatric disturbances

[ more ]

0000708
Dysarthria
Difficulty articulating speech
0001260
Hand tremor
Tremor of hand
Tremor of hands
tremors in hands

[ more ]

0002378
Mental deterioration
Cognitive decline
Cognitive decline, progressive
Intellectual deterioration
Progressive cognitive decline

[ more ]

0001268
Muscle weakness
Muscular weakness
0001324
Postural instability
Balance impairment
0002172
Rigidity
Muscle rigidity
0002063
30%-79% of people have these symptoms
Abnormal globus pallidus morphology
0002453
Abnormal substantia nigra morphology
0045007
Bowel incontinence
Loss of bowel control
0002607
Bradykinesia
Slow movements
Slowness of movements

[ more ]

0002067
Dysphagia
Poor swallowing
Swallowing difficulties
Swallowing difficulty

[ more ]

0002015
Dystonia
0001332
Frequent falls
0002359
Hyperactive deep tendon reflexes
0006801
Motor axonal neuropathy
0007002
Optic atrophy
0000648
Parkinsonism
0001300
Spastic paraparesis
0002313
Urinary incontinence
Loss of bladder control
0000020
5%-29% of people have these symptoms
Abnormal saccadic eye movements
0000570
Cerebellar atrophy
Degeneration of cerebellum
0001272
Global developmental delay
0001263
Shuffling gait
Shuffled walk
0002362
1%-4% of people have these symptoms
Respiratory insufficiency
Respiratory impairment
0002093
Percent of people who have these symptoms is not available through HPO
Abnormal lower motor neuron morphology
0002366
Ataxia
0001251
Autosomal dominant inheritance
0000006
Autosomal recessive inheritance
0000007
Delayed speech and language development
Deficiency of speech development
Delayed language development
Delayed speech
Delayed speech acquisition
Delayed speech development
Impaired speech and language development
Impaired speech development
Language delay
Language delayed
Language development deficit
Late-onset speech development
Poor language development
Speech and language delay
Speech and language difficulties
Speech delay

[ more ]

0000750
Dementia
Dementia, progressive
Progressive dementia

[ more ]

0000726
Depressivity
Depression
0000716
Distal amyotrophy
Distal muscle wasting
0003693
Distal muscle weakness
Weakness of outermost muscles
0002460
Elevated serum creatine kinase
Elevated blood creatine phosphokinase
Elevated circulating creatine phosphokinase
Elevated creatine kinase
Elevated serum CPK
Elevated serum creatine phosphokinase
High serum creatine kinase
Increased CPK
Increased creatine kinase
Increased creatine phosphokinase
Increased serum CK
Increased serum creatine kinase
Increased serum creatine phosphokinase

[ more ]

0003236
Emotional lability
Emotional instability
0000712
Gait disturbance
Abnormal gait
Abnormal walk
Impaired gait

[ more ]

0001288
Hyperreflexia
Increased reflexes
0001347
Hyporeflexia
Decreased reflex response
Decreased reflexes

[ more ]

0001265
Impulsivity
Impulsive
0100710
Lewy bodies
0100315
Neurodegeneration
Ongoing loss of nerve cells
0002180
Oromandibular dystonia
0012048
Pes cavus
High-arched foot
0001761
Progressive
Worsens with time
0003676
Progressive visual loss
Progressive loss of vision
Progressive vision loss
Progressive visual impairment
Slowly progressive visual loss
Vision loss, progressive
Visual loss, progressive

[ more ]

0000529
Scapular winging
Winged shoulder blade
0003691
Spasticity
Involuntary muscle stiffness, contraction, or spasm
0001257
Tremor
0001337

Learn more

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

In-Depth Information

  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
  • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.