Mitochondrial Membrane Protein-Associated Neurodegeneration

Alternate names

MPAN; NBIA due to C19orf12 mutation; NBIA4; Neurodegeneration with brain iron accumulation due to C19orf12 mutation; Neurodegeneration with brain iron accumulation type 4; Neurodegeneration with brain iron accumulation 4

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.

Cause

• 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.

Inheritance

Autosomal recessive inheritance, a 25% chance

• 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%.

Signs and symptoms

• 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.

Clinical presentation

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

80%-99% of people have these symptoms

• Babinski sign
• Behavioral abnormality(Behavioral changes)
• Dysarthria(Difficulty articulating speech)
• Hand tremor(Tremor of hand)
• Mental deterioration(Cognitive decline)
• Muscle weakness(Muscular weakness)
• Postural instability(Balance impairment)
• Rigidity(Muscle rigidity)

30%-79% of people have these symptoms

• Abnormal globus pallidus morphology
• Abnormal substantia nigra morphology
• Bowel incontinence(Loss of bowel control)
• Bradykinesia(Slow movements)
• Dysphagia(Poor swallowing)
• Dystonia
• Frequent falls
• Hyperactive deep tendon reflexes
• Motor axonal neuropathy
• [[Optic atrophy ]]
• Parkinsonism
• Spastic paraparesis
• Urinary incontinence(Loss of bladder control)

5%-29% of people have these symptoms

• Abnormal saccadic eye movements
• Cerebellar atrophy(Degeneration of cerebellum)
• Global developmental delay
• Shuffling gait(Shuffled walk)

1%-4% of people have these symptoms

• Respiratory insufficiency(Respiratory impairment)

Diagnosis

• 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.
• Genetic testing of the C19orf12 gene confirms the diagnosis.

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

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.

NIH genetic and rare disease info

• NIH info on Mitochondrial Membrane Protein-Associated Neurodegeneration

Mitochondrial Membrane Protein-Associated Neurodegeneration is a rare disease.

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