Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a genetic neurodegenerative disease that causes

dystonia Dystonia is a neurological hyperkinetic movement disorder in which sustained or repetitive muscle contractions result in twisting and repetitive movements or abnormal fixed postures. The movements may resemble a tremor. Dystonia is often inten ...

parkinsonism Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia (slowed movements), rigidity, and postural instability. These are the four motor symptoms found in Parkinson's disease (PD), after which it is named, dementia with Lewy bo ...

, and iron accumulation in the brain. 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. Due to the common features of

neurodegeneration A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...

, brain iron accumulation, and movement disorder it is classified as a

neurodegeneration with brain iron accumulation Neurodegeneration with brain iron accumulation is a heterogenous group of inherited neurodegenerative diseases, still under research, in which iron accumulates in the basal ganglia, either resulting in progressive dystonia, Parkinsonism, spastici ...

(NBIA) disorder and another name for the condition is neurodegeneration with brain iron accumulation 4 (NBIA4).

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 Dysphagia is difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, in some contexts it is classified as a disease#Terminology, condition in its own right. It may be a sensation that suggests difficulty in the passag ...

), difficulty speaking (

dysarthria Dysarthria is a speech sound disorder resulting from neurological injury of the motor component of the motor–speech system and is characterized by poor articulation of phonemes. In other words, it is a condition in which problems effectively ...

), and

dementia Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...

Genetics

MPAN is caused by variants to a single gene, ''C19orf12'', the function of which is not currently known. 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 In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

inheritance. More rarely described are individuals with a single dysfunctional copy of ''C19orf12'' causing disease, considered to be an

autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

form of the disease that can either be inherited or arise from a

de novo mutation A de novo mutation is any mutation/alteration in the genome of any organism (humans, animals, plant, microbes, etc.) that wasn't present or transmitted by their parents. This type of mutation (like any other) occurs spontaneously during the process ...

. The protein C19orf12 is not well understood, it is expressed in most cells and is thought to localize to

mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...

and the

endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...

Diagnosis

MPAN might be suspected with typical presentation and findings on

MRI Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves ...

(Magnetic Resonance Imaging), these include evidence of iron deposition in the brain, particularly in the

basal ganglia The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an extern ...

(

globus pallidus The globus pallidus (GP), also known as paleostriatum or dorsal pallidum, is a subcortical structure of the brain. It consists of two adjacent segments, one external, known in rodents simply as the globus pallidus, and one internal, known in rod ...

and

substantia nigra The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. ''Substantia nigra'' is Latin for "black substance", reflecting the fact that parts of the substantia nigra app ...

). The diagnosis is confirmed by genetic testing identifying harmful variant(s) in ''C19orf12''.

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 Lewy bodies are the inclusion bodies – abnormal aggregations of protein – that develop inside nerve cells affected by Parkinson's disease (PD), the Lewy body dementias ( Parkinson's disease dementia and dementia with Lewy bodies (DLB)), and ...

and spherical bodies from degenerating neurons.

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 Gabapentin, sold under the brand name Neurontin among others, is an anticonvulsant medication primarily used to treat partial seizures and neuropathic pain. It is a first-line medication for the treatment of neuropathic pain caused by diabet ...

trihexyphenidyl Trihexyphenidyl (THP, benzhexol, trihex, marketed as Artane and others) is an antispasmodic drug used to treat stiffness, tremors, spasms, and poor muscle control. It is an agent of the antimuscarinic class and is often used in management of Pa ...

baclofen Baclofen, sold under the brand name Lioresal among others, is a medication used to treat muscle spasticity such as from a spinal cord injury or multiple sclerosis. It may also be used for hiccups and muscle spasms near the end of life. It is ta ...

), or surgery.

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.

Epidemiology

Prevalence In epidemiology, prevalence is the proportion of a particular population found to be affected by a medical condition (typically a disease or a risk factor such as smoking or seatbelt use) at a specific time. It is derived by comparing the number o ...

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 Founder or Founders may refer to: Places *Founders Park, a stadium in South Carolina, formerly known as Carolina Stadium * Founders Park, a waterside park in Islamorada, Florida Arts, entertainment, and media * Founders (''Star Trek''), the ali ...

History

MPAN was first described in 2011 in 24 Polish patients with mutations in ''C19orf12'', later confirmed in a further 23 people.

References

External links

Syndromes affecting the nervous system Extrapyramidal and movement disorders