Disease characteristics. Neuroferritinopathy typically presents with progressive adult-onset chorea or dystonia affecting one or two limbs, and subtle cognitive deficits. The movement disorder involves additional limbs within five to ten years and becomes more generalized within 20 years. When present, asymmetry remains throughout the course of the disorder. The majority of individuals develop a characteristic orofacial action-specific dystonia related to speech that leads to dysarthrophonia. Frontalis overactivity and orolingual dyskinesia are common. Cognitive deficits and behavioral issues become major problems with time.
Diagnosis/testing. The diagnosis of neuroferritinopathy is based on clinical findings including adult-onset chorea or dystonia and T2* MRI showing excess iron storage or cystic degeneration. FTL is the only gene in which mutations are known to cause neuroferritinopathy.
Management. Treatment of manifestations: Standard doses of levodopa, tetrabenazine, orphenadrine, benzhexol, sulpiride, diazepam, clonazepam, and deanol for the movement disorder; botulinum toxin for painful focal dystonia.
Prevention of secondary complications: Adequate caloric intake; physiotherapy to maintain mobility and prevent contractures.
Agents/circumstances to avoid: Iron supplements are not recommended.
Genetic counseling. Neuroferritinopathy is inherited in an autosomal dominant manner with 100% penetrance. Most individuals diagnosed with neuroferritinopathy have an affected parent; the proportion of cases caused by de novo mutations is unknown. Each child of an individual with neuroferritinopathy has a 50% chance of inheriting the mutation. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation in the family is known.
Neuroferritinopathy is suspected in individuals with the following:
- Adult-onset progressive movement disorder (either chorea or dystonia)
- Family history consistent with autosomal dominant transmission
- Evidence of excess iron storage on brain MRI, and in advanced cases, cystic degeneration apparent on MRI (see Figure 1)
Pathologic diagnosis. Neuroferritinopathy may be diagnosed post mortem based on the characteristic basal ganglia cavitation, iron deposition, and ferritin deposition accompanying neuronal loss.
Serum ferritin concentration may be low.
- Normal range varies according to gender and whether a female is pre- or postmenopausal.
- Each laboratory has its own reference range.
Molecular Genetic Testing
Gene. FTL is the only gene in which mutations are known to cause neuroferritinopathy.
- Sequence analysis. To date six of the seven identified mutations lie in exon 4 and the other in exon 3; six are insertions (460insA, 458insA, 498-499insTC, 646insC, c.469_484dup16nt and c.641_642GACC) and one is a missense mutation (474G>A) (see Table 3) [Curtis et al 2001, Vidal et al 2004, Maciel et al 2005, Mancuso et al 2005, Devos et al 2009, Kubota et al 2009].
The common adenine insertion in exon 4 (c.460dupA) observed in 10/12 families (~80%) [Curtis et al 2001, Chinnery et al 2007] and unique mutations found in other individuals with neuroferritinopathy (see Molecular Genetics) can be detected by sequence analysis of FTL.
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
To confirm the diagnosis in a proband, molecular testing for the c.460dupA mutation is the first step, followed by complete sequence analysis of exon 4 of FTL.
Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.
Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.
Genetically Related (Allelic) Disorders
Mutations in the iron-responsive element of FTL have been identified in hereditary hyperferritinemia cataract syndrome (OMIM 600886) [Beaumont et al 1995], in which an increase in the serum ferritin concentration is associated with bilateral cataracts developing in childhood or early adult life, but not with excess iron storage in the brain.
Neuroferritinopathy typically presents in adult life (mean age 40 years), although onset in early teenage years and in the sixth decade has been reported. The two presenting phenotypes are typically chorea or dystonia affecting one or two limbs, although one individual presented with late-onset parkinsonism [Curtis et al 2001, Burn & Chinnery 2006, Chinnery et al 2007] and two families with cerebellar features [Vidal et al 2004, Devos et al 2009].
The movement disorder is progressive, involving additional limbs in five to ten years and becoming more generalized within 20 years [Crompton et al 2005]. Some individuals have striking asymmetry, which remains throughout the course of the disorder. The majority of individuals develop a characteristic orofacial action-specific dystonia related to speech and leading to dysarthrophonia. Frontalis overactivity is common, as is orolingual dyskinesia [Crompton et al 2005]. Eye movements are well preserved throughout the disease course. (See Table 2.)
Subtle cognitive deficits are apparent in most individuals from the outset [Crompton et al 2005]. Formal neuropsychometry reveals frontal/subcortical deficits [Wills et al 2002] that are not as prominent as those seen in Huntington disease. The cognitive and behavioral component eventually becomes a major problem.
Neuroimaging. From the outset, all affected individuals have evidence of excess brain iron accumulation on T2* MRI. The iron deposition may be missed on other MR sequences in early stages of the disease. Later stages are associated with high signal on T2 MRI in the caudate, globus pallidus, putamen, substantia nigra, and red nuclei, followed by cystic degeneration in the caudate and putamen. Neuroferritinopathy has a characteristic appearance, distinguishing it from other disorders associated with brain iron accumulation [McNeill et al 2008].
Histopathologic examination of three individuals with 460dupA confirmed evidence of abnormal iron accumulation throughout the brain and particularly in the basal ganglia [Hautot et al 2007]. Affected regions contain iron and ferritin-positive spherical inclusions, often co-localizing with microglia, oligodendrocytes, and neurons. Axonal swellings (neuroaxonal spheroids) that were immunoreactive to ubiquitin, tau, and neurofilaments were also present. Mancuso et al  report neuropathology in a person with c.442dupC in FTL.
Serum ferritin. Serum ferritin concentrations were low (<20 µg/L) in the majority of males and postmenopausal females but within normal limits for premenopausal females [Chinnery et al 2007].
A male with a 2-bp insertion in exon 4 of FTL (c.497_498dupTC) presented at age 20 years with tremor followed by cerebellar signs at age 47 years (dysarthria and ataxia, but no nystagmus), frontal/subcortical cognitive impairment, dyskinesia (described as involuntary movement of the face, resembling tardive dyskinesia, evolving into dystonic posturing and buccolingual dyskinesia), brisk tendon reflexes, and Babinski signs [Vidal et al 2004].
The p.Ala96Thr mutation was found in a man with mild non-progressive intellectual disability who developed a gait disturbance at age 13 years, followed by episodes of psychosis, which was treated with neuroleptics. He subsequently developed an akinetic-rigid syndrome, ataxia, and pyramidal signs. His 40-year-old mother, who had the same missense mutation, was asymptomatic [Maciel et al 2005].
Cerebellar and psychiatric features were also noted in persons with the 458dupA FTL mutation [Devos et al 2009].
With the exception of the reported cerebellar signs, the clinical presentation of the persons with the c.497_498dupTC and c.442dupC, and 458dupA mutations fall within the spectrum seen in individuals with the c.460dupA mutation [Chinnery et al 2007]. The clinical picture was different in the individual with a missense mutation, raising the possibility that missense mutations cause a different phenotype, although neuroleptic medication may have complicated the picture.
Despite the clinical differences, the neuroimaging was similar across individuals who had the four different FTL mutations.
Based on current data, penetrance is 100% [Chinnery et al 2007].
Anticipation has not been reported.
Prevalence is unknown. Fewer than 100 cases have been described. The majority of individuals described to date have the same mutation in FTL. Evidence suggests that they have descended from a common founder [Chinnery et al 2003], although the recent identification of a person from the state of Texas with German ancestry raises the possibility of a recurrent 460dupA mutation [Ondo et al 2010].
In simplex cases (i.e., only one affected individual in a family) and in individuals with a family history consistent with autosomal dominant inheritance, Huntington disease and spinocerebellar ataxia type 17 should be considered; however, neither has the characteristic findings of neuroferritinopathy on neuroimaging.
The phenotype in some individuals with neuroferritinopathy is strikingly similar to that seen in early-onset primary dystonia (DYT1), torsion dystonia caused by the c.904_906delGAG (NM_000113.2) mutation in TOR1A [Crompton et al 2005].
The orofacial dyskinesia seen in neuroferritinopathy resembles that seen in choreoacanthocytosis and McLeod neuroacanthocytosis syndrome; however, in contrast to these two disorders, the reflexes are preserved in neuroferritinopathy.
In simplex and autosomal recessive cases, early-onset movement disorders including Parkin-type of juvenile-onset Parkinson disease, aceruloplasminemia, and Neimann-Pick type C should be considered. These disorders do not show the characteristic neuroimaging of neuroferritinopathy, but very similar MRI findings are found in pantothenate kinase-associated neurodegeneration (PKAN, formerly known as Hallervorden-Spatz disease, and also known as neurodegeneration with brain iron accumulation type 2). Individuals with neuroferritinopathy also show the "eye of the tiger" sign.
Basal ganglia abnormalities on MRI are also seen in mitochondrial disorders, which should thus be considered in the differential diagnosis (see Mitochondrial Disease Overview).
Neuroferritinopathy shares similar MRI appearances and clinical presentation of several other neurodegenerative disorders with brain iron accumulation (NBIA) including pantothenate kinase-associated neurodegeneration (PKAN, formerly known as Hallervorden-Spatz disease, and also known as neurodegeneration with brain iron accumulation type 2), aceruloplasminemia, and infantile neuroaxonal dystrophy. However, the age of onset, inheritance pattern, and T2* MRI results can be used to distinguish these disorders [McNeill et al 2008]. Individuals with neuroferritinopathy also show the "eye of the tiger" sign.
Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with neuroferritinopathy, the following evaluations are recommended:
- Psychometric assessment
- Physiotherapy assessment
- Speech therapy assessment
- Dietary assessment
Treatment of Manifestations
The movement disorder is particularly resistant to conventional therapy, but some response has been recorded with levodopa, tetrabenazine, orphenadrine, benzhexol, sulpiride, diazepam, clonazepam, and deanol in standard doses [Chinnery et al 2007, Ondo et al 2010]
Botulinum toxin is helpful for painful focal dystonia.
Prevention of Secondary Complications
Dietary assessment is helpful; affected individuals should maintain caloric intake.
Physiotherapy helps to maintain mobility and prevent contractures.
Agents/Circumstances to Avoid
Iron supplements are not recommended for affected individuals and those at risk. This recommendation is empiric [Chinnery et al 2007] Iron replacement therapy with careful monitoring may be required if affected individuals develop coincidental iron deficiency anemia.
Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Current treatments under evaluation:
- Iron chelation with deferiprone
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
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
Neuroferritinopathy is inherited in an autosomal dominant manner.
Risk to Family Members
Parents of a proband
- Most individuals diagnosed with neuroferritinopathy have an affected parent.
- The possibility of a single founder suggests that most probands are related genetically, although the family history may be unknown because older affected relatives died at a young age [Chinnery et al 2003].
- A proband with neuroferritinopathy may have the disorder as the result of a de novo mutation. The proportion of cases caused by de novo mutations is unknown.
- The disorder may present in late adult life (the oldest diagnosed individual on record presented at age 61 years), and thus unaffected parents who have the disease-causing mutation may have affected offspring.
- Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include brain MRI, measurement of serum ferritin concentration, and molecular genetic testing if the FTL mutation has been identified in the proband.
Note: Although most individuals diagnosed with neuroferritinopathy have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.
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 or has a disease-causing mutation, the risk to the sibs is 50%.
- If the disease-causing mutation found in the proband cannot be detected in the DNA of the either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.
Offspring of a proband. Each child of an individual with neuroferritinopathy has a 50% chance of inheriting the mutation.
Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected or has a disease-causing mutation, his or her family members are at risk.
Related Genetic Counseling Issues
Testing of at-risk asymptomatic adults. Testing of at-risk asymptomatic adults for neuroferritinopathy possible using the techniques described in Molecular Genetic Testing. Such testing is not useful in accurately predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. When testing at-risk individuals for neuroferritinopathy, an affected family member should be tested first to confirm the molecular diagnosis in the family.
Testing for the disease-causing mutation in the absence of definite symptoms of the disease is predictive testing. At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations including simply the "need to know." Testing of asymptomatic at-risk adult family members usually involves pre-test interviews in which the motives for requesting the test, the individual's knowledge of neuroferritinopathy, the possible impact of positive and negative test results, and neurologic status are assessed. Those seeking testing should be counseled about possible problems they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow up and evaluations.
Molecular genetic testing of asymptomatic children (in the US defined as individuals younger than age 18 years) who are at risk for adult-onset disorders for which no treatment exists is not considered appropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
Genetic testing is always indicated in affected or symptomatic individuals in a family with established neuroferritinopathy regardless of age.
For more information, see also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.
Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has a disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.
- The optimal time for determination of genetic risk 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 or at risk.
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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.
If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.
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 Association2082 Monaco CourtEl Cajon CA 92019-4235Phone: 619-588-2315Fax: 619-588-4093Email: info@NBIAdisorders.org
- NBIA Disorders Association Research Registry and Treat Iron-Related Childhood-Onset Neurodegeneration (TIRCON) RegistryCA 92019-4235Phone: 619-588-2315Fax: 619-588-4093Email: firstname.lastname@example.org
- Registry for NBIA and Related DisordersOregon Health & Science UniversityPhone: 503-494-4344Fax: 503-494-6886Email: email@example.com
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
Normal allelic variants. FTL has four exons.
Pathologic allelic variants. Variants include the common mutation c.460dupA [Curtis et al 2001, Chinnery et al 2003, Crompton et al 2005, Chinnery et al 2007] and three others, each found in a single individual/family with neuroferritinopathy: c.497_498dupTC [Vidal et al 2004], c.442dupC [Mancuso et al 2005], and the missense mutation p.Ala96Thr [Maciel et al 2005].
Normal gene product. Ferritin has two main subunits, H and L, and is involved in the storage and detoxification of iron. A functional ferritin molecule can store up to 4,500 iron molecules. The proportion of H and L subunits varies among tissues.
Abnormal gene product. The adenine insertion in exon 4 (c.460dupA) of FTL is predicted to alter 22 C-terminal residues (the D-helix, the DE loop, and the E-helix) of the ferritin molecule, extending the polypeptide by four additional amino acids. This is predicted to alter its iron storage capacity, possibly leading to the excess release of toxic iron within neurons through a dominant-negative effect; mitochondrial respiratory chain function may also be involved, as abnormal mitochondrial respiratory function has been documented in numerous individuals with neuroferritinopathy.
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- 23 December 2010 (me) Comprehensive update posted live
- 8 August 2007 (me) Comprehensive update posted to live Web site
- 30 November 2006 (pfc) Revision: sequence analysis clinically available; addition of relevant material from author's new paper, Chinnery et al 2007
- 25 April 2005 (me) Review posted to live Web site
- 1 September 2004 (pfc) Original submission
University of Newcastle upon Tyne
Newcastle upon Tyne, United Kingdom
Initial Posting: April 25, 2005; Last Update: December 23, 2010.
University of Washington, Seattle, Seattle (WA)
Chinnery PF. Neuroferritinopathy. 2005 Apr 25 [Updated 2010 Dec 23]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.