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 (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 typically established in a proband with suggestive findings and biallelic pathogenic variants (or less commonly a heterozygous pathogenic variant) in C19orf12 identified by molecular genetic testing.

Management.

Treatment of manifestations: Pharmacologic treatment of spasticity, dystonia, and parkinsonism; psychiatric treatment of significant neuropsychiatric manifestations; physical, occupational, speech, and other therapies as indicated; nutritional supplements and gastric tube 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 individuals who are more stable); routine monitoring by occupational therapy / physical therapy, mental health providers, ophthalmology, speech and language therapy, and feeding team is recommended; routine assessment of educational needs and social support.

Genetic counseling.

MPAN is inherited in an autosomal recessive or (less commonly) autosomal dominant manner.

• Autosomal recessive MPAN. If both parents are known to be heterozygous for an C19orf12 pathogenic variant, each sib of an affected individual has at conception 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.
• Autosomal dominant MPAN. Each child of an affected individual has a 50% chance of inheriting the C19orf12 pathogenic variant.

Once the C19orf12 pathogenic variant(s) in the family have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

Mitochondrial membrane protein-associated neurodegeneration (MPAN) should be considered in individuals with the following findings.

Imaging findings

Brain MRI revealing iron accumulation in both the globus pallidus and substantia nigra (Figure 1B) is observed in most molecularly confirmed MPAN.* Because most affected individuals are identified following abnormal brain MRI studies, this strong correlation may reflect ascertainment bias.

Figure 1.

T₂-weighted imaging in MPAN A. Typical eye-of-the-tiger sign seen in PKAN

*Exceptions include (1) affected sisters homozygous for the pathogenic variant c.187G>C; p.Ala63Pro in whom brain MRI did not reveal any evidence of iron accumulation [Landouré et al 2013], despite observation of brain iron accumulation in at least two other families with affected individuals with the same pathogenic variant, and (2) instances in which brain iron accumulation was not appreciated on early imaging studies but was identified later in the disease course [Kim et al 2016, Skowronska et al 2017].

Serial MRI studies show that iron accumulation and brain atrophy progress with the disease course.

On T₂-weighted brain MRI many individuals have isointense streaking of the medial medullary lamina between the hypointense globus pallidus interna and externa that could be mistaken for an eye-of-the-tiger sign (Figures 1A and 1C).

Other less frequent MRI abnormalities

• Generalized cortical atrophy and cerebellar atrophy [Hogarth et al 2013, Schottmann et al 2014]
• T₁-weighted hyperintensity in the caudate nucleus and putamen [Schulte et al 2013]. White matter hyperintensities may be observed; they are usually localized to the periventricular region [Skowronska et al 2017].
• Hydrocephalus has also been reported in one adult with MPAN and may be a rare finding [Bayram et al 2019].

Establishing the Diagnosis

The diagnosis of MPAN is typically established in a proband with suggestive findings and either biallelic pathogenic variants (approximately 60% of cases [Author, personal observation]) or less commonly a heterozygous pathogenic variant in C19orf12 identified by molecular genetic testing (see Table 1).

• Autosomal recessive (AR) MPAN. Note: Identification of biallelic C19orf12 variants of uncertain significance (or identification of one known C19orf12 pathogenic variant and one C19orf12 variant of uncertain significance) does not establish or rule out a diagnosis of this disorder.
• Autosomal dominant (AD) MPAN. Note: Identification of a heterozygous C19orf12 variant of uncertain significance does not establish or rule out the diagnosis of this disorder.

Molecular genetic testing approaches can include gene-targeted testing (most commonly multigene panel and less commonly single-gene testing) or comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of MPAN has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is characterized initially by gait changes followed by progressive spastic paresis, progressive dystonia, neuropsychiatric abnormalities, and cognitive decline. Additional early findings can include dysphagia, dysarthria, optic atrophy, axonal neuropathy, parkinsonism, and bowel/bladder incontinence.

Onset of MPAN typically occurs in childhood (3-16 years, considered juvenile onset) to early adulthood (17-24 years, considered adult onset), but onset has been reported as late as age 55 years [Gregory et al 2019]. Among affected sibs the age of onset is similar. The disease course is similar across age groups, with the exception of some adult-onset, rapidly progressive cases described below.

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. Early gait changes are typically followed by the onset of progressive spastic paresis.

Some individuals present with vision impairment associated with optic atrophy, which is more common in childhood-onset than adult-onset MPAN.

The progression of MPAN is usually slow with survival well into adulthood. However, rare individuals have had abrupt adult onset and rapid progression [Dogu et al 2013, Hogarth et al 2013].

The terminal 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 manifestations of seizures. Death typically occurs secondary to complications such as aspiration pneumonia.

Fewer than 200 affected individuals have been described to date; thus, the phenotypic spectrum of MPAN is likely to broaden as more affected individuals are described.

The phenotypes associated with autosomal recessive (AR) MPAN and autosomal dominant (AD) MPAN are indistinguishable [Gregory et al 2019].

Progressive cognitive decline is the norm in MPAN and ends with severe dementia. Cognitive decline may present initially as learning difficulties or memory impairment, later becoming more global [Hogarth et al 2013, Gregory et al 2019].

Neuropsychiatric changes are frequent and varied, often occurring early in the disease course. Neuropsychiatric findings can include depression, anxiety, emotional lability, compulsions, hallucinations, perseveration, impulsivity, inattention, and hyperactivity.

Lower motor neuron involvement (muscle weakness and atrophy, hyporeflexia, fasciculations). Lower motor neuron signs emerge later in the disease course as loss of deep tendon reflexes progressing from distal to proximal, variably accompanied by muscle atrophy. Motor axonopathy with a pattern of distal denervation observed on electromyography and nerve conduction studies are consistent with these clinical findings. In four 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 2014, Kim et al 2016].

Upper motor neuron involvement (spasticity, hyperreflexia, Babinski sign). The lower limbs are usually affected earlier and more significantly than the upper limbs. In some instances, progressive spastic paraparesis early in the disease course before emergence of other manifestations of MPAN can lead to the erroneous diagnosis of hereditary spastic paraparesis [Selikhova et al 2017].

Dysarthria, reported in most affected individuals, usually progresses to anarthria during end-stage disease.

Dysphagia, also common, often requires dietary adaptions and eventual placement of a feeding tube.

Dystonia is also common and progressive. It may be limited to the hands and feet or be more generalized.

Optic atrophy. While affected individuals may or may not report visual symptoms, most have optic atrophy on examination. In a small cohort with the common Polish variant, optic atrophy presented as optic nerve pallor; additional studies showed prolonged visual evoked potentials, thin retinal nerve fiber layers, and normal electoretinograms [Langwinska-Wosko et al 2016]. In another cohort, all 18 individuals with two loss-of-function variants had optic atrophy [Hartig et al 2011].

Parkinsonism also occurs 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.

Bladder incontinence, less often also involving the bowel, may develop early in MPAN while affected individuals are still ambulatory with little cognitive decline [Hogarth et al 2013]. Data from urodynamic studies have not been available to characterize what is likely neurogenic bladder dysfunction.

Neuropathology of MPAN is characterized by increased iron deposition in the globus pallidus and substantia nigra.

Genotype-Phenotype Correlations

The phenotypes of AR and AD MPAN are indistinguishable, both arising from loss of function of the C19orf12 protein.

• AR MPAN. 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 (p.Thr11Met) is associated with later disease onset (mean age 25 years for persons homozygous for c.32C>T vs mean age 10 years for all published cases) [Hartig et al 2013].
  Note: Previous speculation that the variant c.187G>C (p.Ala63Pro) might be correlated with an atypical presentation [Landouré et al 2013] was disproved when this variant was found in individuals with typical MPAN.
• AD MPAN. Heterozygous pathogenic variants that cause autosomal dominant MPAN are located in the last exon of C19orf12. See Molecular Genetics.

Prevalence

The prevalence of MPAN is roughly estimated at less than one in 1,000,000.

The prevalence may be higher in the Turkish population due to the c.32C>T (p.Thr11Met) founder variant [Olgiati et al 2017] (see Table 6).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with mitochondrial membrane protein-associated neurodegeneration (MPAN), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Iron chelation using deferiprone has been investigated in a randomized, double-blind, placebo-controlled trial in a distinct NBIA disorder, PKAN [Klopstock et al 2019]. Results indicate that deferiprone treatment in PKAN did not lead to statistically significant clinical change, although there was a trend towards slower progression on the dystonia scale used. Since other MPAN treatments are symptomatic, some individuals may elect to try deferiprone off label based on these results in a related disorder. Deferiprone treatment in MPAN has been reported in two patients: (1) Two-year treatment in a 13-year-old led to reduction of iron content in the substantia nigra, while pallidal iron depositions and clinical status remained unchanged [Löbel et al 2014]; (2) In another patient with MPAN who received deferiprone, treatment had to be discontinued because of gastrointestinal side effects [Gore et al 2016].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is inherited in an autosomal recessive or, less commonly, an autosomal dominant manner.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one C19orf12 pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a C19orf12 pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent, the following possibilities should be considered:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a C19orf12 pathogenic variant, each sib of an affected individual has at conception 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.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Unless an individual with autosomal recessive 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 of a C19orf12 pathogenic variant.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Rarely, individuals diagnosed with autosomal dominant MPAN have an affected parent.
• More often, a proband with autosomal dominant MPAN has the disorder as a result of a de novo pathogenic variant in exon 3 of C19orf12 (see Molecular Pathogenesis, Mechanism of disease causation) [Gregory et al 2019].
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the C19orf12 pathogenic variant is 50%.
• Because only two multigeneration families with inherited autosomal dominant MPAN have been reported to date, the risk for MPAN in individuals who inherit a C19orf12 pathogenic variant is not clear. Reduced penetrance is suggested in two individuals in the two reported families [Gregory et al 2019]. There may also be differences in the age of onset and rate of progression of the disorder between heterozygous members of the same family.
• If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].

Offspring of a proband

• Each child of an individual with autosomal dominant MPAN has a 50% risk of inheriting the pathogenic variant.
• While physical and cognitive impairment in MPAN reduces the possibility of having children, some individuals with late-onset MPAN will reproduce before the onset of symptoms [Gregory et al 2019].

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected or has the C19orf12 pathogenic variant, his or her family members are at risk.

Predictive testing of at-risk asymptomatic adult family members requires prior identification of the autosomal dominant C19orf12 pathogenic variant in the family.

Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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 or affected.

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.

Prenatal Testing and Preimplantation Genetic Testing

Once the pathogenic C19orf12 variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for MPAN are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

C19orf12 encodes C19orf12, a protein that localizes predominantly to the mitochondria [Hartig et al 2011]. The two protein isoforms in humans have 141 and 152 amino acids, NP_001242976.1 and NP_001026896.2, respectively.

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. C19orf12 is suspected of playing a role in lipid homeostasis [Hartig et al 2011].

Mechanism of disease causation

• AR MPAN. Loss of function
• AD MPAN. It is proposed that loss of function also occurs, through a dominant-negative effect [Gregory et al 2019].

C19orf12-specific laboratory technical considerations. Heterozygous pathogenic variants that cause AD MPAN are located in the last exon of C19orf12 and are predicted to escape nonsense-mediated decay, resulting in a truncated protein after amino acid 79 (with wild type residues 69-76 intact) [Gregory et al 2019]. This finding should help inform interpretation of results by clinical laboratories.

Author Notes

Investigators and clinicians at Oregon Health & Science University have studied the NBIA disorders, including MPAN, for more than 25 years. Our program includes an NBIA Center of Excellence committed to providing comprehensive care for patients with NBIA around the world (nbiacure.org/nbia-clinic). Our multidisciplinary team investigates NBIA disorders broadly, from gene discovery to clinical trials for rational therapeutics, to improve the lives of those with NBIA.

For more information, please contact us:
Phone: 503-494-4344
Fax: 503-494-6886
Email: ude.usho@ayrogerg
Website: nbiacure.org

Acknowledgments

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

Author History

Allison Gregory, MS, CGC (2014-present)
Monika Hartig, MD; Technische Universität München (2014-2021)
Susan J Hayflick, MD (2014-present)
Penelope Hogarth, MD (2014-present)
Thomas Klopstock, MD (2021-present)
Tomasz Kmiec, MD (2014-present)
Holger Prokisch, PhD; Technische Universität München (2014-2021)

Revision History

• 4 March 2021 (bp) Comprehensive update posted live
• 27 February 2014 (me) Review posted live
• 3 September 2013 (ag) Original submission

Literature Cited

• Al Macki N, Rashdi I. A novel deletion mutation of exon 2 of the C19orf12 gene in an Omani family with mitochondrial membrane protein-associated neurodegeneration (MPAN). Oman Med J. 2017;32:66–8. [PMC free article: PMC5187394] [PubMed: 28042406]
• Bayram E, Peker E, Metzger S, Akbostanct M. Myoclonus, hydrocephalus in mitochondrial protein-associated neurodegeneration. Can J Neurol Sci. 2019;46:628–30. [PubMed: 31327327]
• 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]
• Gagliardi M, Annesi G, Lesca G, Broussolle E, Iannello G, Vaiti V, Gambardella A, Quattrone A. C19orf12 gene mutations in patients with neurodegeneration with brain iron accumulation. Parkinsonism Relat Disord. 2015;21:813–6. [PubMed: 25962551]
• Gore E, Appleby BS, Cohen ML, DeBrosse SD, Leverenz JB, Miller BL, Siedlak SL, Zhu X, Lerner AJ. Clinical and imaging characteristics of late onset mitochondrial membrane protein-associated neurodegeneration (MPAN). Neurocase. 2016;22:476–83. [PMC free article: PMC5568540] [PubMed: 27801611]
• Gregory A, Lotia M, Jeong SY, Fox R, Zhen D, Sanford L, Hamada J, Jahic A, Beetz C, Freed A, Kurian MA, Cullup T, van der Weijden MCM, Nguyen V, Setthavongsack N, Garcia D, Krajbich V, Pham T, Woltjer R, George BP, Minks KQ, Paciorkowski AR, Hogarth P, Jankovic J, Hayflick SJ. Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN). Mol Genet Genomic Med. 2019;7:e00736. [PMC free article: PMC6625130] [PubMed: 31087512]
• 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]
• Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519–22. [PubMed: 28959963]
• Kim J, Liao Y, Ionita C, Bale AE, Daras B, Ascadi G. Mitochondrial membrate protein-associated neurodegeneration mimicking juvenile amyotrophic lateral sclerosis. Pediatr Neurol. 2016;64:83–6. [PubMed: 27671242]
• Klopstock T, Tricta F, Neumayr L, Karin I, Zorzi G, Fradette C, Kmiec T, Buchner B, Steele HE, Horvath R, Chinnery PF, Basu A, Kupper C, Neuhofer C, Kalman B, Dusek P, Yapici Z, Wilson I, Zhao F, Zibordi F, Nardocci N, Aguilar C, Hayflick SJ, Spino M, Blamire AM, Hogarth P, Vichinsky E. Safety and efficacy of deperiprone for pantothenate kinase-associated neurodegeneration: a randomised, double-blind, controlled trial and an open-label extension study. Lancet Neurol. 2019;18:631–42. [PubMed: 31202468]
• 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, Accardi J, Landis DM, Gahl WA, Traynor BJ, Marques W Jr, Züchner S, Blackstone C, Fischbeck KH, Burnett BG. Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12. Hum Mutat. 2013;34:1357–60. [PMC free article: PMC3819934] [PubMed: 23857908]
• Langwinska-Wosko E, Skowronska M, Kmiec T, Czlonkowska A. Retinal and optic nerve abnormalities in neurodegeneration associated with mutations in C19orf12 (MPAN). J Neurol Sci. 2016;370:237–240. [PubMed: 27772766]
• Löbel U, Schweser F, Nickel M, Deistung A, Grosse R, Hagel C, et al. Brain iron quantification by MRI in mitochondrial membrane protein-associated neurodegeneration under iron-chelating therapy. Ann Clin Transl Neurol. 2014;1:1041–6. [PMC free article: PMC4284129] [PubMed: 25574478]
• Olgiati S, Doğu O, Tufekcioglu Z, Diler Y, Saka E, Gultekin M, Kaleagasi H, Kuipers D, Graafland J, Breedveld GJ, Quadri M, Sürmeli R, Sünter G, Doğan T, Yalçın AD, Bilgiç B, Elibol B, Emre M, Hanagasi HA, Bonifati V. The p.Thr11Met mutation in c19orf12 is frequent among adult Turkish patients with MPAN. Parkinsonism Relat Disord. 2017;39:64–70. [PubMed: 28347615]
• Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. uycdxTiming, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]
• 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. 2014;85:290–2. [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 neurodegeneration: a novel variant of neurodegeneration with brain iron accumulation. Mov Disord. 2013;28:224–7. [PubMed: 23436634]
• Selikhova M, Fedotova E, Wiethoff S, Schottlaender LV, Klyushnikov S, Illarioshkin SN, Houlden H. A 30-year history of MPAN case from Russia. Clin Neurol Neurosurg. 2017;159:111–3. [PubMed: 28641177]
• Skowronska M, Kmiec T, Jurkiewicz E, Malczyk K, Kurkowska-Jastrzebska I, Czlonkowska A. Evolution and novel radiological changes of neurodegeneration associated with mutations in C19orf12. Parkinsonism Relat Disord. 2017;39:71–76. [PubMed: 28347614]
• Stenson PD, Mort M, Ball EV, Evans K, Hayden M, Heywood S, Hussain M, Phillips AD, Cooper DN. The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum Genet. 2017;136:665–77. [PMC free article: PMC5429360] [PubMed: 28349240]