Mitochondrial Membrane Protein-Associated Neurodegeneration

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.