Neuroferritinopathy

Clinical characteristics.

Neuroferritinopathy typically presents with progressive adult-onset chorea or dystonia affecting one or two limbs, and subtle cognitive deficits. The movement disorder affects 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 established in a proband with typical clinical findings and/or identification of a heterozygous pathogenic variant in FTL by molecular testing.

Management.

Treatment of manifestations: While the movement disorder is particularly resistant to conventional therapy, some response has been recorded with levodopa, tetrabenazine, orphenadrine, benzhexol, sulpiride, diazepam, clonazepam, and deanol in standard doses; botulinum toxin may be helpful 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 pathogenic variants is unknown. Each child of an individual with neuroferritinopathy has a 50% chance of inheriting the pathogenic variant. Prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible if the FTL pathogenic variant in the family is known.

Suggestive Findings

Neuroferritinopathy should be 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)

Figure 1

a. Non-contrast brain CT symmetric low signal in the putamina b. T₂-weighted MRI image showing cystic change involving the putamina and globus pallidi and with increased signal in the heads of the caudate nuclei [Crompton et al 2005]

Establishing the Diagnosis

The diagnosis of neuroferritinopathy is established in a proband with typical clinical findings and/or identification of a heterozygous pathogenic variant in FTL by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

• Single-gene testing. Sequence analysis of FTL is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
  Note: Since neuroferritinopathy is thought to occur through a gain-of-abnormal-function mechanism and large intragenic deletion or duplication has not been reported, testing for intragenic deletions or duplication is unlikely to identify a disease-causing variant.
  Targeted analysis for pathogenic variants can be performed first in individuals of United Kingdom (UK) ancestry.
• A multigene panel that includes FTL and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

Presentation and progression. Neuroferritinopathy typically presents in adult life (mean age 40 years) [Chinnery et al 2007], 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] (see Table 2). Unusual presentations have also been described, related to an underlying dystonic gait [Keogh et al 2011, Nishida et al 2014].

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.

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^*-weighted 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-weighted 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] and associated with progressive iron accumulation on MRI [McNeill et al 2012], including the "eye of the tiger" sign [McNeill et al 2012] and other radiologic features [Batla et la 2015].

Histopathologic examination of three individuals with the 460dupA pathogenic variant 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 [2005] report similar neuropathologic findings 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].

Penetrance

Penetrance is 100% [Chinnery et al 2007].

Prevalence

Prevalence is unknown. The majority of individuals described to date have the same pathogenic variant in FTL. Evidence suggests that they have descended from a common UK founder [Chinnery et al 2003], although the identification of a person from the state of Texas with German ancestry raises the possibility of a recurrent 460dupA pathogenic variant [Ondo et al 2010].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with neuroferritinopathy, the following evaluations are recommended if they have not already been completed:

• Psychometric assessment
• Physiotherapy evaluation
• Speech therapy assessment
• Dietary assessment because weight loss may develop in the late stages of the disorder
• Consultation with a clinical geneticist and/or genetic counselor

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]. However, no formal treatment trials have been carried out. Specific drugs are tried empirically based on the predominant symptoms. It is important to note that the predominant symptoms will change over time, requiring an adjustment of the medication. Such treatment is best managed by a clinician with expertise in movement disorders.

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. There is no evidence to support avoidance of iron-rich foods by affected individuals [Author, personal observation].

Evaluation of Relatives at Risk

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

Therapies Under Investigation

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. Note: There may not be clinical trials for this disorder.