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Mitochondrial Membrane Protein-Associated Neurodegeneration

Synonyms: NBIA4

, MS, CGC, , MD, , PhD, , MD, , MD, and , MD.

Author Information

Initial Posting: .

Summary

Clinical characteristics.

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is characterized initially by gait changes followed by progressive spastic paresis, progressive dystonia (which may be limited to the hands and feet or more generalized), neuropsychiatric abnormalities (e.g., emotional lability, depression, anxiety, impulsivity, compulsions, hallucinations, perseveration, inattention, and hyperactivity), and cognitive decline. Additional early findings can include dysphagia, dysarthria, optic atrophy, axonal neuropathy, parkinsonism, and bowel/bladder incontinence. Survival is usually well into adulthood. End-stage disease is characterized by severe dementia, spasticity, dystonia, and parkinsonism.

Diagnosis/testing.

The diagnosis of MPAN is confirmed in individuals with biallelic pathogenic variants in C19orf12. (Although no non-molecular tests are able to reliably distinguish MPAN from other NBIA disorders, postmortem neuropathologic examination in individuals in whom molecular testing was not performed may help support the diagnosis of MPAN.)

Management.

Treatment of manifestations: Pharmacologic treatment of spasticity, dystonia, and parkinsonism; psychiatric treatment of significant neuropsychiatric symptoms; physical, occupational, speech, and other therapies as indicated. Nutritional supplements and gastric feeding as needed. Management of excessive secretions and aspiration risk with glycopyrrolate, transdermal scopolamine patch, and/or tracheostomy as indicated.

Surveillance: Routine follow up by a neurologist for medication management and interval assessment of ambulation, speech, and swallowing (often done every 3-6 months, but may be annual for patients who are more stable). Monitoring of patients receiving dopaminergic drugs for parkinsonism for adverse neuropsychiatric effects, and monitoring of patients receiving dopamine antagonist agents for psychiatric symptoms for the development or worsening of parkinsonism. Annual ophthalmologic examination is recommended.

Genetic counseling.

MPAN is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified. (Note: Possible autosomal dominant inheritance in one family has been reported.)

Diagnosis

Clinical Diagnosis

While formal guidelines have not yet been developed to aid in the identification of mitochondrial membrane protein-associated neurodegeneration (MPAN), several of the predominant features of the disorder help distinguish it from other forms of neurodegeneration with brain iron accumulation (NBIA).

The diagnosis of MPAN is suspected in individuals with the following:

  • Onset in childhood to early adulthood with slow progression and survival well into adulthood
  • Cognitive decline progressing to severe dementia
  • Prominent neuropsychiatric abnormalities including emotional lability, depression, anxiety, impulsivity, compulsions, hallucinations, perseveration, inattention, and hyperactivity
  • Optic atrophy
  • Dystonia, often of the hands and feet
  • Muscle weakness
  • Early spasticity sometimes followed by flaccid paresis
  • Babinski sign
  • Dysarthria
  • Iron accumulation observed on brain MRI in both the globus pallidus and substantia nigra (Figure 1B). Serial MRI studies show that iron accumulation and brain atrophy progress with the disease course. To date, abnormal brain iron accumulation has been associated with all but two molecularly confirmed cases of MPAN (affected sisters) [Landouré et al 2013] (see Genetically Related Disorders). Since most affected individuals are identified following abnormal brain MRI studies, this strong correlation may reflect ascertainment bias.
Figure 1.

Figure 1.

Imaging in MPAN

The diagnosis of MPAN is further supported by the following findings:

  • Dysphagia
  • Motor axonopathy with a pattern of distal denervation observed on electromyography and nerve conduction studies consistent with the clinical findings of distal to proximal loss of deep tendon reflexes.
  • Parkinsonism (bradykinesia, rigidity, tremor, postural instability, and/or REM sleep behavior disorder)
  • Incontinence of bowel and/or bladder
  • On T2-weighted brain MRI some individuals have hyperintense streaking of the medial medullary lamina between the globus pallidus interna and externa that could be mistaken for an eye-of-the-tiger sign (Figure 1C). Other less frequent MRI abnormalities include generalized cortical atrophy and cerebellar atrophy [Hogarth et al 2013, Schottmann et al 2013] and T1-weighted hyperintensity in the caudate nucleus and putamen [Schulte et al 2013].

The diagnosis of MPAN is confirmed in individuals with biallelic pathogenic variants in C19orf12 (Table 1). (Note: Although no non-molecular tests are able to reliably distinguish MPAN from other NBIA disorders, postmortem neuropathologic examination (see Neuropathology) in individuals in whom molecular testing was not performed may help support the diagnosis of MPAN.)

One molecular genetic testing strategy is sequence analysis of C19orf12, the only gene in which pathogenic variants are known to cause MPAN.

Another molecular genetic testing strategy is use of a multigene panel that includes C19orf12 and other genes of interest (see Differential Diagnosis). Note that the genes included and the methods used in multigene panels vary by laboratory and over time. For more information on multigene panels click here.

Table 1.

Molecular Genetic Testing Used in Mitochondrial Membrane Protein Associated with Neurodegeneration (MPAN)

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by this Method
C19orf12Sequence analysis 295%
1.

See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants.

2.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

Neuropathology. MPAN is characterized by increased iron deposition in the globus pallidus and substantia nigra. Neuronal loss, gliosis, widespread iron deposits, and eosinophilic spheroidal structures in the globus pallidus in MPAN are similar to the neuropathologic changes seen in pantothenate kinase-associated neurodegeneration (PKAN). In MPAN, however, widespread Lewy bodies throughout the neocortex, deep gray matter, and midbrain are more prominent than the findings observed in PLA2G6-associated neurodegeneration (PLAN) and other forms of NBIA [Hartig et al 2011, Hogarth et al 2013].

Peripheral axonal spheroids, previously thought to be limited to PLA2G6-associated neurodegeneration (PLAN), may be detected on skin or nerve biopsies [Kurian et al 2008, Hogarth et al 2013].

Clinical Characteristics

Clinical Description

Onset of mitochondrial membrane protein-associated neurodegeneration (MPAN) typically occurs in childhood (3-16 years) to early adulthood (16-24 years) but has been reported as late as age 30 years. Among sibs the age of onset is similar.

The phenotypic spectrum of MPAN is likely to broaden as more cases are described. Fewer than 100 cases have been described to date.

Unlike in many other forms of neurodegeneration with brain iron accumulation (NBIA), the progression of MPAN is usually slow with survival well into adulthood. However, rare individuals with abrupt adult onset and rapid progression have been reported [Dogu et al 2013, Hogarth et al 2013].

Individuals with MPAN learn to walk and are usually mobile into early adulthood [Hartig et al 2011]. The most common presenting feature is impaired gait. Some present with vision impairment associated with optic atrophy, which is more common in childhood-onset than adult-onset MPAN and is strongly associated with homozygosity for a common deletion c.204_214del11 [Hartig et al 2011, Hogarth et al 2013].

Early gait changes are typically followed by the onset of progressive spastic paresis. The lower limbs are usually affected earlier and more significantly than the upper limbs. Reflexes are initially brisk, and the majority of affected individuals develop extensor plantar responses. Later in the disease course, lower motor neuron signs emerge, with loss of deep tendon reflexes from distal to proximal, variably accompanied by muscle atrophy. In three families, juvenile-onset mixed upper and lower motor neuron dysfunction mimicking amyotrophic lateral sclerosis was the presenting and salient feature [Deschauer et al 2012, Schottmann et al 2013].

Dystonia is also common and progressive. It may be limited to the hands and feet or more generalized. Dysarthria has been reported in most patients, and dysphagia in about half.

Parkinsonism also occurs in about half of individuals reported, with varying combinations of bradykinesia, rigidity, tremor, postural instability, and REM sleep behavior disorder. Parkinsonism is more common in adult-onset MPAN, particularly in those with rapid progression; however, it can develop late in the course of juvenile-onset MPAN.

Progressive cognitive decline is the norm in MPAN, in contrast to the common pantothenate kinase-associated neurodegeneration (PKAN) form of NBIA.

Neuropsychiatric changes are also frequent and varied; they include depression, anxiety, emotional lability, compulsions, hallucinations, perseveration, impulsivity, inattention, and hyperactivity.

While incontinence has been noted late in the course of other forms of NBIA, some individuals with MPAN develop this earlier in disease while they may still be ambulatory with little cognitive decline [Hogarth et al 2013].

The end stages of MPAN are characterized by severe dementia, spasticity, dystonia, and parkinsonism. Affected individuals are no longer ambulatory; communication is limited due to dysarthria and cognitive decline. Weight loss and bowel and/or bladder incontinence are common. Persons with advanced disease may have stereotypic hand or head movements with alterations in consciousness that do not appear to be related to seizures. Death typically occurs secondary to complications such as aspiration pneumonia.

Genotype-Phenotype Correlations

Individuals homozygous for the common deletion c.204_214del11, reported originally in a Polish cohort, have childhood-onset disease with optic atrophy [Hartig et al 2011, Hogarth et al 2013].

The pathogenic variant c.32C>T is associated with later disease onset (mean age of 25 years for persons homozygous for c.32C>T) compared to a mean age of ten years for all published cases [Hartig et al 2013].

Prevalence

MPAN is a newly recognized form of NBIA with a prevalence roughly estimated at less than one in 1,000,000. Fewer than 100 cases with molecular confirmation have been described to date.

As the awareness of MPAN increases and molecular testing is used more frequently, a better estimation may be made.

Differential Diagnosis

See Neurodegeneration with Brain Iron Accumulation (NBIA) Overview. Of note, MPAN appears to be the third most common NBIA, after PKAN and PLAN.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with mitochondrial membrane protein-associated neurodegeneration (MPAN), the following evaluations are recommended:

  • Complete neurologic examination, including evaluation of ambulation, speech, and swallowing
  • Ophthalmologic examination to assess for optic atrophy
  • Assessment by specialists in physical, occupational, and/or speech therapy
  • Brain MRI (T2-weighted at a minimum) if one has not been obtained within the past two years
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

The following are indicated:

  • Pharmacologic treatment of dystonia and spasticity, including consideration of oral baclofen, trihexyphenidyl, intramuscular botulinum toxin, and a trial of intrathecal baclofen if indicated
  • Pharmacologic treatment of parkinsonism (response to levodopa has been variable in this population)
  • Treatment by a psychiatrist for those with significant neuropsychiatric symptoms
  • Physical, occupational, speech, and other therapies as indicated
  • Use of a liquid nutritional supplement to help maintain weight as needed
  • A gastric feeding tube to help minimize weight loss (which becomes more frequent with disease progression) and to reduce the risk of aspiration pneumonia
  • Glycopyrrolate or transdermal scopolamine patch to reduce the volume of secretions in those with excessive drooling or difficulty controlling secretions
  • Tracheostomy as indicated for difficulty managing secretions
  • Over-the-counter fiber supplements and/or stool softeners to treat constipation, which is likely caused by a combination of immobility, diet, and medications

Surveillance

Patients are typically followed most closely by a neurologist for medication management and for interval assessment of ambulation, speech, and swallowing. This is often done every three to six months, but may be annual for patients who are more stable.

Patients receiving dopaminergic drugs (for parkinsonism) are monitored for adverse neuropsychiatric effects; conversely, patients receiving typical or atypical dopamine antagonist agents (for psychiatric features) are monitored for the development or worsening of parkinsonism.

Annual ophthalmologic examination is recommended.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Deep brain stimulation (DBS) has not been specifically studied in MPAN, even in case reports. DBS has become a common treatment for primary dystonia and is being used more frequently to attempt to treat the secondary dystonia in PKAN with some success. It is likely that the use of DBS in MPAN will eventually be reported.

Iron chelation using deferiprone is currently under investigation in PKAN (see ClinicalTrials.gov). A small phase II pilot trial in PKAN showed statistically significant reduction of brain iron by MRI evaluation; however, no change in clinical status was observed [Zorzi et al 2011]. The current double-blind, placebo controlled trial in PKAN may inform whether deferiprone treatment should be considered for MPAN.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is inherited in an autosomal recessive manner.

Note: Possible autosomal dominant inheritance in one family has been reported [Hogarth et al 2013].

Risk to Family Members – Autosomal Recessive Inheritance

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. Unless an individual with MPAN has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for a pathogenic variant in C19orf12.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier (Heterozygote) Detection

Carrier testing for at-risk family members is possible if the pathogenic variants in the family have been identified.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Fibroblast cell line banking should be considered if fibroblast cells of an affected individual are available.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for MPAN are possible.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • NBIA Disorders Association
    2082 Monaco Court
    El Cajon CA 92019-4235
    Phone: 619-588-2315
    Fax: 619-588-4093
    Email: info@NBIAdisorders.org
  • NBIA Disorders Association Research Registry and Treat Iron-Related Childhood-Onset Neurodegeneration (TIRCON) Registry
    CA 92019-4235
    Phone: 619-588-2315
    Fax: 619-588-4093
    Email: pwood@nbiadisorders.org
  • NBIAcure Registry for NBIA and Related Disorders
    Oregon Health & Science University
    Phone: 503-494-4344
    Fax: 503-494-6886
    Email: gregorya@ohsu.edu
  • Treat Iron-Related Childhood Onset Neurodegeneration (TIRCON) Registry
    Germany
    Phone: 49-89-5160-7421
    Fax: 49-89-5160-7402
    Email: tircon@med.uni-muenchen.de

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Mitochondrial Membrane Protein-Associated Neurodegeneration: Genes and Databases

GeneChromosome LocusProteinHGMDClinVar
C19orf1219q12Protein C19orf12C19orf12C19orf12

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Mitochondrial Membrane Protein-Associated Neurodegeneration (View All in OMIM)

614297CHROMOSOME 19 OPEN READING FRAME 12; C19ORF12
614298NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 4; NBIA4

Gene structure. C19orf12 comprises three exons that span less than 17 kb of genomic sequence. In humans there are two transcript variants, the longest being NM_001031726.3. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. A common founder variant, c.204_214del11, has been observed in persons of eastern European descent (mainly Polish) [Hartig et al 2011]. Most families have private pathogenic variants. Pathogenic nonsense, frameshift, and missense variants are distributed throughout the coding region.

Table 2.

C19orf2 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.32C>T 1, 2p.Thr11MetNM_001031726​.3
NP_001026896​.2
c.187G>Cp.Ala63Pro 1
c.204_214del11p.Gly69ArgfsTer10
c.205G>Ap.Gly69Arg

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.
2.

Normal gene product. The two protein isoforms in humans have 141 and 152 amino acids, NP_001242976.1 and NP_001026896.2, respectively. The protein localizes predominantly to the mitochondria [Hartig et al 2011]; little is known about its function.

Abnormal gene product. Association with the mitochondrial membrane and co-regulation with proteins of fatty acid biogenesis and branched chain amino acid degradation expression profiles suggest similarities to other proteins known to be defective in NBIA. Protein C19orf12 is suspected to play a role in lipid homeostasis [Hartig et al 2011].

References

Literature Cited

  • Deschauer M, Gaul C, Behrmann C, Prokisch H, Zierz S, Haack TB. C19orf12 mutations in neurodegeneration with brain iron accumulation mimicking juvenile amyotrophic lateral sclerosis. J Neurol. 2012;259:2434–9. [PubMed: 22584950]
  • Dogu O, Krebs CE, Kaleagasi H, Demirtas Z, Oksuz N, Walker RH, Paisán-Ruiz C. Rapid disease progression in adult-onset mitochondrial membrane protein-associated neurodegeneration. Clin Genet. 2013;84:350–5. [PubMed: 23278385]
  • Hartig M, Prokisch H, Meitinger T, Klopstock T. Mitochondrial membrane protein-associated neurodegeneration (MPAN). Int Rev Neurobiol. 2013;110:73–84. [PubMed: 24209434]
  • Hartig MB, Iuso A, Haack T, Kmiec T, Jurkiewicz E, Heim K, Roeber S, Tarabin V, Dusi S, Krajewska-Walasek M, Jozwiak S, Hempel M, Winkelmann J, Elstner M, Oexle K, Klopstock T, Mueller-Felber W, Gasser T, Trenkwalder C, Tiranti V, Kretzschmar H, Schmitz G, Strom TM, Meitinger T, Prokisch H. Absence of an orphan mitochondrial protein, c19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation. Am J Hum Genet. 2011;89:543–50. [PMC free article: PMC3188837] [PubMed: 21981780]
  • Hogarth P, Gregory A, Kruer MC, Sanford L, Wagoner W, Natowicz MR, Egel RT, Subramony SH, Goldman JG, Berry-Kravis E, Foulds NC, Hammans SR, Desguerre I, Rodriguez D, Wilson C, Diedrich A, Green S, Tran H, Reese L, Woltjer RL, Hayflick SJ. New NBIA subtype: genetic, clinical, pathologic, and radiographic features of MPAN. Neurology. 2013;80:268–75. [PMC free article: PMC3589182] [PubMed: 23269600]
  • Kurian MA, Morgan NV, MacPherson L, Foster K, Peake D, Gupta R, Philip SG, Hendriksz C, Morton JE, Kingston HM, Rosser EM, Wassmer E, Gissen P, Maher ER. Phenotypic spectrum of neurodegeneration associated with mutations in the PLA2G6 gene (PLAN). Neurology. 2008;70:1623–9. [PubMed: 18443314]
  • Landouré G, Zhu PP, Lourenço CM, Johnson JO, Toro C, Bricceno KV, Rinaldi C, Meilleur KG, Sangaré M, Diallo O, Pierson TM, Ishiura H, Tsuji S, Hein N, Fink JK, Stoll M, Nicholson G, Gonzalez MA, Speziani F, Dürr A, Stevanin G, Biesecker LG. Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12. Hum Mutat. 2013;34:1357–60. NIH Intramural Sequencing Center, Accardi J, Landis DM, Gahl WA, Traynor BJ, Marques W Jr, Züchner S, Blackstone C, Fischbeck KH, Burnett BG. [PMC free article: PMC3819934] [PubMed: 23857908]
  • Schottmann G, Stenzel W, Lützkendorf S, Schuelke M, Knierim E. A novel frameshift mutation of C19ORF12 causes NBIA4 with cerebellar atrophy and manifests with severe peripheral motor axonal neuropathy. Clin Genet. 2013 Epub ahead of print. [PubMed: 23521069]
  • Schulte EC, Claussen MC, Jochim A, Haack T, Hartig M, Hempel M, Prokisch H, Haun-Jünger U, Winkelmann J, Hemmer B, Förschler A, Ilg R. Mitochondrial membrane protein associated neurodegenration: a novel variant of neurodegeneration with brain iron accumulation. Mov Disord. 2013;28:224–7. [PubMed: 23436634]
  • Zorzi G, Zibordi F, Chiapparini L, Bertini E, Russo L, Piga A, Longo F, Garavaglia B, Aquino D, Savoiardo M, Solari A, Nardocci N. Iron-related MRI images in patients with pantothenate kinase-associated neurodegeneration (PKAN) treated with deferiprone: results of a phase II pilot trial. Mov Disord. 2011;26:1756–9. [PubMed: 21557313]

Chapter Notes

Acknowledgments

Authors acknowledge funding from the European Commission Seventh Framework Programme (FP7/2007-2013, HEALTH-F2-2011, grant agreement No. 277984, TIRCON).

Revision History

  • 27 February 2014 (me) Review posted live
  • 3 September 2013 (ag) Original submission
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