Disorder of iron metabolism and transport
-Rare genetic disease
Huntington disease-like syndrome
-Rare genetic disease
-Rare neurologic disease
Neurodegeneration with brain iron accumulation
-Rare genetic disease
-Rare neurologic disease
Neurodegeneration with brain iron accumulation is a genetically heterogeneous disorder characterized by progressive iron accumulation in the basal ganglia and other regions of the brain, resulting in extrapyramidal movements, such as parkinsonism and dystonia. Age at onset, cognitive ... Neurodegeneration with brain iron accumulation is a genetically heterogeneous disorder characterized by progressive iron accumulation in the basal ganglia and other regions of the brain, resulting in extrapyramidal movements, such as parkinsonism and dystonia. Age at onset, cognitive involvement, and mode of inheritance is variable (review by Gregory et al., 2009).
Curtis et al. (2001) described a dominantly inherited late-onset basal ganglia disease variably presenting with extrapyramidal features similar to those of Huntington disease (143100) or parkinsonism. The disorder typically presented with involuntary movements at 40 to 55 years ... Curtis et al. (2001) described a dominantly inherited late-onset basal ganglia disease variably presenting with extrapyramidal features similar to those of Huntington disease (143100) or parkinsonism. The disorder typically presented with involuntary movements at 40 to 55 years of age. Symptoms of extrapyramidal dysfunction included choreoathetosis, dystonia, spasticity, and rigidity, sometimes showing acute progression but not associated with significant cognitive decline or cerebellar involvement. MRI scan showed cavitation of the basal ganglia confirmed by brain pathology. Surviving affected family members lived within a 40-km radius of the home of the earliest founder that was traced (from records circa 1790), a member of a local family from the Cumbrian region of northern England. Patients had low serum ferritin levels and abnormal aggregates of ferritin and iron in the brain. Curtis et al. (2001) noted that iron deposition in the brain increases normally with age, especially in the basal ganglia, and is a suspected causative factor in several neurodegenerative diseases in which it correlates with visible pathology, possibly by its involvement in toxic free-radical reactions. Known neurologic disorders were excluded by routine diagnostic tests. Chinnery et al. (2003) reported a French family in which 7 members developed dystonia between the ages of 24 and 58 years of age. Inheritance was autosomal dominant. Additional clinical features included dysarthria, chorea, parkinsonism, blepharospasm, and cerebellar signs. Two affected members had a frontal lobe syndrome, and 1 had dementia. MRI of 3 affected family members showed cystic changes in the basal ganglia. Skeletal muscle biopsy from 4 patients showed abnormalities of the mitochondrial respiratory chain. Devos et al. (2009) provided further information on 4 of the affected members from the French family reported by Chinnery et al. (2003). These patients developed symptoms between 24 and 44 years of age. Presenting features included dystonia, causing writing difficulties or a gait disorder, followed by rapid progression to orofacial, pharyngeal, and laryngeal dystonia. L-dopa was not effective. None developed spasticity, abnormal reflexes, or marked tremor. Three deceased family members developed cerebellar ataxia. All developed a moderate subcortical/frontal dementia. Other atypical features included a limitation of vertical eye movements and mild dysautonomia, including orthostatic hypotension, constipation, and urinary incontinence. Brain imaging showed iron deposition and cystic cavitation of the basal ganglia. Serum ferritin levels were decreased. Vidal et al. (2004) reported a large 5-generation French family in which 11 members had neuroferritinopathy inherited in an autosomal dominant pattern. Six affected family members were living at the time of the report. The proband first developed tremor at age 20 years. Thereafter, she had a progressive neurologic decline, characterized by frontal and subcortical cognitive impairment and involuntary movements in her mid-fifties, and pyramidal signs in her late fifties. She had dyskinesias, rigidity, hypertonicity, buccolingual dyskinesia, and dystonic posturing of the hands and feet. She became wheelchair-bound, was unable to feed herself, and died in a comatose state. Neuropathologic examination showed cerebellar and cerebral atrophy, cavitation of the putamen, and widespread ferritin inclusions in neurons and glia throughout the brain. Ferritin inclusions were also seen in extraneural tissue, including skin, muscle, and kidney. Serum ferritin was not measured. Vidal et al. (2004) noted the earlier age at onset in this family compared to the family reported by Curtis et al. (2001), as well as the prominent tremor and cognitive decline in the French family. Maciel et al. (2005) reported a 19-year-old man with parkinsonism, ataxia, and corticospinal signs consistent with neuroferritinopathy. Genetic analysis detected a mutation in the FTL gene (A96T; 134790.0013) in the patient, his asymptomatic mother, and his asymptomatic 13-year-old brother. MRI showed bilateral pallidal necrosis in the patient and his mother, and all 3 mutation carriers had decreased serum ferritin. The patient also had mild nonprogressive cognitive deficit and episodic psychosis, which may have been unrelated since a noncarrying uncle had schizophrenia. Chinnery et al. (2007) reported the clinical features of 41 individuals with neuroferritinopathy due to a 460insA mutation in the FTL gene (134790.0010). The mean age of onset was 39.4 years (range, 13-63), presenting with chorea in 50%, focal lower limb dystonia in 42.5%, and parkinsonism in 7.5%. Other variable features included writer's cramp, blepharospasm, and palatal tremor. The disease showed progression over 5 to 10 years, resulting in a generalized disorder with severe asymmetric motor disability and dystonia, dysphagia, and aphonia, although most remained ambulatory. None developed overt spasticity, ophthalmologic changes, or seizures. The majority of patients had normal psychometric profiles and no cognitive dysfunction except for defects in verbal fluency, even after 10 years. Two patients had evidence of a frontal/subcortical dementia after 10 years, but 1 had normal cognition 36 years after onset. Overall, however, many had subtle features of disinhibition and emotional lability. Five of 6 studied had mitochondrial chain respiratory defects in skeletal muscle biopsies. Laboratory studies showed low levels in most males and postmenopausal females, but normal levels in premenopausal females. Brain imaging showed iron deposition predominantly in the basal ganglia in all affected individuals and in 1 presymptomatic carrier. Some with advanced disease showed cystic degenerative changes. The majority of patients reported a family history of a movement disorder, which was often misdiagnosed as Huntington disease, and admission to a psychiatric institution. Treatment with iron depletion therapy did not provide any benefit, at least in the short term. Chinnery et al. (2007) concluded that isolated parkinsonism is unusual in neuroferritinopathy, and that cognitive changes are absent or subtle in the early stages. Devos et al. (2009) noted that 3 French patients reported by Chinnery et al. (2007) were found to carry a different mutation in the FTL gene (458dupA; 134790.0016). Ohta et al. (2008) reported a Japanese mother and son with neuroferritinopathy confirmed by genetic analysis (134790.0015). The son developed hand tremors in his mid-teens and foot dragging at age 35. By age 42, he had generalized hypotonia, hyperextensibility, unsteady gait, aphonia, micrographia, hyperreflexia, and cognitive impairment. Rigidity, spasticity, dystonia, and chorea were not observed. His mother had hand tremors at age 10, difficulty walking at age 35, developed cognitive impairment and akinetic mutism, and died at age 64. Brain imaging in both patients showed symmetric cystic changes in the basal ganglia. The son had hyperintense lesions in the basal ganglia and substantia nigra on MRI. Ohta et al. (2008) suggested that the mutant FTL protein was unable to retain iron, which was released in the nervous system, causing oxidative damage. Keogh et al. (2012) found that 3 asymptomatic descendants of known FTL mutation carriers who themselves were carriers of a mutation (460insA; 134790.0010) had evidence of iron deposition on brain imaging. In each case, the signal abnormalities were visible on T2*-weighted MRI. The abnormalities increased with age: 1 patient between 6 and 16 years had involvement of the substantia nigra, globus pallidus, and motor cortex; a patient between 17 and 25 years had additional involvement of the red nucleus and thalamus, but not the motor cortex; and the third patient, between 26 and 36 years, had additional involvement of the caudate. The findings indicated that iron deposition in neuroferritinopathy can begin decades before symptomatic presentation, and suggested that iron deposition initiates neurodegeneration.
In an individual with adult-onset basal ganglia disease and in 5 apparently unrelated subjects with similar extrapyramidal symptoms, Curtis et al. (2001) identified an insertion mutation in the FTL gene (134790.0010). Curtis et al. (2001) proposed a dominant-negative ... In an individual with adult-onset basal ganglia disease and in 5 apparently unrelated subjects with similar extrapyramidal symptoms, Curtis et al. (2001) identified an insertion mutation in the FTL gene (134790.0010). Curtis et al. (2001) proposed a dominant-negative or dominant gain-of-function effect rather than haploinsufficiency. An abnormality in ferritin strongly indicated a primary function for iron in the pathogenesis of this disease, for which they proposed the name 'neuroferritinopathy.' In affected members of a French family with neuroferritinopathy reported by Chinnery et al. (2003), Devos et al. (2009) identified a mutation in the FTL gene (458dupA; 134790.0016). The family had originally been thought to have a different mutation (134790.0010) (Chinnery et al., 2003). In a healthy 52-year-old woman who was a control subject in a genetic study of hyperferritinemia-cataract syndrome, Cremonesi et al. (2004) identified a heterozygous mutation in the ATG start codon of the FTL gene, predicted to disable protein translation and expression. She had no history of iron deficiency anemia or neurologic dysfunction. Hematologic examination was normal except for decreased serum ferritin. The findings suggested that L-ferritin has no effect on systemic iron metabolism and also indicated that neuroferritinopathy is not a consequence of haploinsufficiency of L-ferritin, but likely results from gain-of-function mutations in the FTL gene. Vidal et al. (2004) identified a mutation in the FTL gene (498insTC; 134790.0014) in affected members of a French family with neuroferritinopathy.
In a nationwide survey of Japanese patients, Hirayama et al. (1994) estimated the prevalence of all forms of spinocerebellar degeneration to be 4.53 per 100,000. Of these, 1.5% were thought to have striatonigral degeneration, defined by the authors ... In a nationwide survey of Japanese patients, Hirayama et al. (1994) estimated the prevalence of all forms of spinocerebellar degeneration to be 4.53 per 100,000. Of these, 1.5% were thought to have striatonigral degeneration, defined by the authors as a sporadic disorder with onset after middle age with mainly parkinsonian signs and occasionally accompanied by cerebellar ataxia, autonomic disturbance, and cerebellar atrophy on scanning.
Neuroferritinopathy is suspected in individuals with the following:...
DiagnosisClinical DiagnosisNeuroferritinopathy 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) FigureFigure 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 (more...)Pathologic diagnosis. Neuroferritinopathy may be diagnosed post mortem based on the characteristic basal ganglia cavitation, iron deposition, and ferritin deposition accompanying neuronal loss. TestingSerum 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 TestingGene. FTL is the only gene in which mutations are known to cause neuroferritinopathy. Clinical testing 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. Table 1. Summary of Molecular Genetic Testing Used in NeuroferritinopathyView in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityFTLSequence analysisSequence variants 280% 3Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions (including the common adenine insertion in exon 4) and missense, nonsense, and splice site mutations.3. The detection rate for simplex cases (i.e., a single occurrence in a family) is significantly lower.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo 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) DisordersMutations 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]. ...
Natural HistoryNeuroferritinopathy 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.Table 2. Clinical Findings in Individuals with NeuroferritinopathyView in own windowClinical FindingNumberPercentPresentingphenotypeChorea20/4050%Dystonia17/4042.5%Parkinsonism3/407.5%Asymmetry25/4062.5%Speech and swallowingDysarthria31/4077.5%Dysphonia19/4047.5%Orolingual dyskinesia26/4065%Dysphagia16/4040%EyesAbnormal EOM3/407.5%Abnormal fundi0/400%MotorBradykinesia14/4035.5%Tremor0/400%Dystonia33/4082.5%Chorea28/4070%Spasticity0/400%Normal strength in nondystonic limbs40/40100%Increased tendon reflexes7/4017.5%Babinski reflex0/400%Ataxia0/400%In 40 individuals with the FTL c.460dupA mutation [Chinnery et al 2007]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 [2005] 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].
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. ...
Differential DiagnosisIn 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. Other dominantly inherited spinocerebellar ataxias with extrapyramidal features, including SCA2 and SCA3, should also be considered.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. See Neurodegeneration with Brain Iron Accumulation Disorders Overview.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).
To establish the extent of disease in an individual diagnosed with neuroferritinopathy, the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo 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 ManifestationsThe 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 ComplicationsDietary assessment is helpful; affected individuals should maintain caloric intake. Physiotherapy helps to maintain mobility and prevent contractures.Agents/Circumstances to AvoidIron 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 RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationCurrent treatments under evaluation: Venesection Iron chelation with deferiproneCoenzyme Q10 (ubiquinone); the therapeutic role is being evaluated based on evidence of mitochondrial respiratory chain dysfunction in neuroferritinopathy [Caparros-Lefebvre et al 1997, Chinnery et al 2003]. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Neuroferritinopathy: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDFTL19q13.33Ferritin light chainFTL homepage - Mendelian genesFTLData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Neuroferritinopathy (View All in OMIM) View in own window 134790FERRITIN LIGHT CHAIN; FTL 606159NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 3; NBIA3Normal 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]. Table 3 Selected FTL Pathologic Allelic VariantsView in own windowDNA Nucleotide Change (Alias 1)Protein Amino Acid ChangeReference Sequencesc.474G>Ap.Ala96ThrNM_000146.3 NP_000137.2c.442dupC (c.646_647insC)p.His148Profs*33c.497_498dupTC (498insTC)p.Phe167Serfs*26c.460dupA (c.460_461insA)p.Arg154Lysfs*27See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Variant designation that does not conform to current naming conventionsNormal 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.