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Neurodegeneration with Brain Iron Accumulation Disorders Overview

Synonym: NBIA

, MS, CGC and , MD.

Author Information

Initial Posting: ; Last Revision: April 24, 2014.

Summary

Clinical characteristics.

Neurodegeneration with brain iron accumulation (NBIA) is a group of inherited neurologic disorders in which iron accumulates in the basal ganglia resulting in progressive dystonia, spasticity, parkinsonism, neuropsychiatric abnormalities, and optic atrophy or retinal degeneration. Ten types and their associated genes are recognized. The age of onset ranges from infancy to late adulthood; the rate of progression varies. Cognitive decline occurs in some subtypes, but more often cognition is relatively spared. Cerebellar atrophy is a frequent finding in some subtypes.

Diagnosis/testing.

The diagnosis is usually first suspected when brain MRI findings suggest abnormal brain iron accumulation. Clinical findings and molecular genetic testing establish the diagnosis of specific types. The ten genes known to be associated with types of NBIA are PANK2, PLA2G6, C19orf12, FA2H, ATP13A2, WDR45, COASY, FTL, CP, and DCAF17.

Genetic counseling.

Eight of the ten genetically defined types of NBIA are inherited in an autosomal recessive manner. Exceptions are: beta-propeller protein-associated neurodegeneration (BPAN), caused by a de novo pathogenic variant in WDR45, which is inherited in an X-linked dominant manner with suspected male lethality; and neuroferritinopathy, caused by a pathogenic variant in FTL, which is inherited in an autosomal dominant manner. If the family-specific pathogenic variant(s) are known, carrier testing for family members at risk for the autosomal recessive types and the X-linked type is possible, and prenatal testing for most types is possible.

Management.

Treatment of manifestations: Intrathecal or oral baclofen, oral trihexyphenidyl, intramuscular botulinum toxin, and deep brain stimulation to treat dystonia; services for the blind, educational programs, assistive communication devices; adaptive aids (walkers, wheelchairs) for gait abnormalities.

Prevention of secondary complications: Adequate nutrition through swallowing evaluation, dietary assessment, gastrostomy tube feeding as needed.

Surveillance: Evaluation for treatable causes of pain during episodes of extreme dystonia; monitoring of height and weight; routine ophthalmologic assessment; regular assessments of ambulation and speech abilities.

GeneReview Scope

Neurodegeneration with Brain Iron Accumulation Disorders Overview: Included Disorders
  • Aceruloplasminemia
  • Beta-propeller protein-associated neurodegeneration
  • COASY protein-associated neurodegeneration
  • Fatty acid hydroxylase-associated neurodegeneration
  • Kufor-Rakeb syndrome
  • Mitochondrial membrane protein-associated neurodegeneration
  • Neuroferritinopathy
  • PLA2G6-associated neurodegeneration
  • Pantothenate kinase-associated neurodegeneration
  • Woodhouse-Sakati syndrome

Definition

Neurodegeneration with brain iron accumulation (NBIA) is a group of inherited neurologic disorders characterized by abnormal accumulation of iron in the basal ganglia (most often in the globus pallidus and/or substantia nigra). Generalized cerebral atrophy and cerebellar atrophy are also frequently observed.

The hallmark clinical manifestations of NBIA are progressive dystonia and dysarthria, spasticity, and parkinsonism. Retinal degeneration and optic atrophy are common. Onset ranges from infancy to adulthood. Progression can be rapid or slow with long periods of stability.

Neuropathologic findings include axonal spheroids in the CNS and, in some types, in peripheral nerves.

Types of NBIA

The genetic basis of ten types of NBIA has been established (Table 1).

Table 1.

Types of NBIA: Molecular Genetics

Disease NameGene% of NBIA Attributed to Pathogenic Variants in This GeneInheritance
PKANPANK2 135%-50% 2AR
PLANPLA2G620% 3AR
MPANC19orf126%-10% 4AR
BPANWDR451%-2% 5XLD
FAHNFA2HRare 6AR
Kufor-Rakeb syndromeATP13A2Rare 7AR
NeuroferritinopathyFTL 8RareAD
AceruloplasminemiaCP 9RareAR
Woodhouse-Sakati syndromeDCAF17Rare 10AR
CoPANCOASY 11RareAR

PKAN = pantothenate kinase-associated neurodegeneration

PLAN = PLA2G6-associated neurodegeneration

MPAN = mitochondrial membrane protein-associated neurodegeneration

BPAN = beta-propeller protein-associated neurodegeneration

FAHN = fatty acid hydroxylase-associated neurodegeneration

CoPAN = COASY protein-associated neurodegeneration

1.
2.
3.
4.

MPAN accounts for the largest proportion of NBIA after PKAN and PLAN [Hartig et al 2011, Hogarth et al 2013].

5.

Based on prevalence in the International Registry for NBIA and Related Disorders from the Hayflick laboratory

6.

Documented in seven unrelated families to date [Dick et al 2008, Edvardson et al 2008, Dick et al 2010, Kruer et al 2010]

7.

Pathogenic variants in ATP13A2 were identified in the family originally reported with Kufor-Rakeb syndrome and a handful of other cases worldwide [Behrens et al 2010, Brüggemann et al 2010, Schneider et al 2010, Chien et al 2011, Eiberg et al 2012].

8.
9.
10.

Described in several Saudi Arabian families [Woodhouse & Sakati 1983, Al-Semari & Bohlega 2007]

11.

The clinical findings of the ten genetically defined NBIA types are detailed below. The distinctive neuroimaging findings of these types discussed below are summarized in Table 2.

Pantothenate Kinase-Associated Neurodegeneration (PKAN)

Phenotypes. The phenotypic continuum includes classic PKAN (early onset and rapid progression) and atypical PKAN (later onset and slower progression). Children with PKAN typically manifest gait abnormalities around age three years and later develop progressive dystonia, dysarthria, rigidity, spasticity, hyperreflexia, and extensor toe signs. Individuals with later-onset PKAN are likely to present with speech difficulty; psychiatric symptoms are more frequent in the later onset form. Retinal degeneration, a common finding in PKAN, may be detected by electroretinography several years before the onset of visual symptoms.

Brain MRI. The eye-of-the-tiger sign, T2-weighted hypointense signal in the globus pallidus with a central region of hyperintensity, is virtually pathognomonic for PKAN [Hayflick et al 2003].

Other. The eponym Hallervorden-Spatz syndrome (HSS) is no longer favored in view of the unethical activities of these two German neuropathologists before and during World War II [Shevell 2003].

HARP syndrome (hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration) is now considered part of the PKAN disease spectrum.

PLA2G6-Associated Neurodegeneration (PLAN)

Phenotypes. Three phenotypes are observed: infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (NAD), and PLA2G6-related dystonia-parkinsonism [Morgan et al 2006, Paisán-Ruiz et al 2009].

  • INAD. Manifestations usually begin between ages six months and three years with developmental regression, initial hypotonia, progressive psychomotor delay, and progressive spastic tetraparesis.
  • Atypical NAD. Less common than INAD; manifestations begin later in childhood with slower progression; dystonia and spastic tetraparesis are common. Patients often present with speech delay and diminished social interactions.
  • PLA2G6-related dystonia-parkinsonism. Subacute onset of dystonia-parkinsonism occurs in late adolescence/early adulthood. Findings include eye movement abnormalities, pyramidal tract signs, and marked cognitive decline.

Brain MRI. In both INAD and atypical NAD, cerebellar atrophy and optic atrophy are hallmark features. In about half of cases, brain iron accumulation is also observed, usually in the globus pallidus [Morgan et al 2006, Kurian et al 2008].

Abnormal iron accumulation in the globus pallidus and substantia nigra reported in some individuals with PLA2G6-related dystonia-parkinsonism appears to be variable, as it is in INAD.

Other. INAD is typically associated with PLA2G6 null variants. PLAN may also be referred to as Parkinson disease 14 or PARK14 [Paisán-Ruiz et al 2012].

Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN)

Phenotypes. Defining features of MPAN include spasticity that is more prominent than dystonia, optic atrophy, a motor neuronopathy with early upper-motor neuron findings followed later by signs of lower-motor neuron dysfunction, and a slowly progressive course with survival well into adulthood. Unlike most NBIA, the vast majority of individuals with MPAN develop progressive cognitive decline. Other findings are paraparesis or tetraparesis and neuropsychiatric changes. Onset generally occurs in childhood to early adulthood with slow progression and survival well into adulthood.

Brain MRI. Iron accumulation is observed in both the globus pallidus and substantia nigra; cortical and cerebellar atrophy are common. On T2-weighted images 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.

Other. A common founder variant, C19orf12 (NM_001031726.3: c.204_214del11; NP_001026896.2: p.Gly69ArgfsTer10), has been observed in persons of central European descent (mainly Polish).

Beta-Propeller Protein-Associated Neurodegeneration (BPAN)

Phenotype. Affected individuals have global developmental delay during childhood with slow motor and cognitive gains; however, during adolescence or adulthood, they experience a relatively sudden onset of progressive dystonia-parkinsonism and dementia [Haack et al 2012].

Brain MRI. Imaging studies (usually performed because of the onset of movement disorder) typically reveal iron accumulation in the globus pallidus and substantia nigra. T1-weighted signal hyperintensity with a central band of hypointensity in the substantia nigra has also been observed.

Other. To date, all reported affected individuals have been simplex cases (i.e., a single occurrence in a family). The majority are females, indicating that pathogenic variants are de novo and suggesting that they are lethal in most males.

Fatty Acid Hydroxylase-Associated Neurodegeneration (FAHN)

Phenotype. FAHN typically begins in childhood and is slowly progressive with focal dystonia in the legs and feet and/or corticospinal tract involvement that often contributes to gait disturbance. Ataxia, dysarthria, and progressive tetraparesis develop later, along with optic atrophy leading to progressive loss of visual acuity. Progressive intellectual decline is reported in most affected individuals.

Brain MRI. Neuroimaging reveals iron accumulation in the globus pallidus, and to a lesser extent in the substantia nigra. White matter changes and cerebellar and brain stem atrophy increase over time and may be profound.

Kufor-Rakeb Syndrome

Phenotype. Kufor-Rakeb syndrome is characterized by juvenile-onset parkinsonism, dementia, pyramidal signs, supranuclear gaze palsy, facial-faucial-finger myoclonus, visual hallucinations, and oculogyric dystonic spasms [Williams et al 2005].

Brain MRI. Of the limited number of affected individuals reported, two had evidence of brain iron accumulation in the caudate [Behrens et al 2010, Schneider et al 2010]. Similar to PLAN, it has been suggested that only a portion of cases may have iron accumulation, it may develop late in disease course, or it may only be associated with more severe pathogenic variants [Chien et al 2011].

Other. Kufor-Rakeb syndrome was proposed to be an NBIA based on findings described by Schneider et al [2010] in a family originally reported in 1994. It is also called Parkinson disease 9 or PARK9 [Williams et al 2005].

Neuroferritinopathy

Phenotype. Presentation can be similar to Huntington disease with adult-onset chorea or dystonia and cognitive changes [Wild et al 2008]. Neuroferritinopathy progresses from extremity involvement to a more generalized movement disorder; most affected individuals develop a characteristic orofacial action-specific dystonia related to speech [Crompton et al 2005].

Brain MRI. Brain MRI shows excess iron in the basal ganglia. The later development of cystic changes and cavitation in the caudate and putamen are unique to neuroferritinopathy [McNeill et al 2008].

Other. A common FTL pathogenic variant in exon 4 has been found in approximately 80% of affected individuals.

Aceruloplasminemia

Phenotype. Unlike other forms of NBIA, aceruloplasminemia is characterized by iron accumulation in both the brain and viscera. The clinical triad of retinal degeneration, diabetes mellitus, and neurologic disease manifests in adulthood (25-60 years) [Miyajima et al 2003]. Neurologic changes include facial and neck dystonia, dysarthria, tremors, chorea, ataxia, and blepharospasm.

MRI

  • Brain MRI shows hypointense signal in the globus pallidus, striatum, thalamus, and dentate nucleus on T2-weighted images.
  • Abnormal hypointensities in the liver are also common; iron content is greater in the liver than in the basal ganglia.

Other. Low serum concentrations of copper and iron and high serum concentrations of ferritin can distinguish aceruloplasminemia from other forms of NBIA.

Woodhouse-Sakati Syndrome (Hypogonadism, Alopecia, Diabetes Mellitus, Intellectual Disability, and Extrapyramidal Syndrome)

Phenotype. Neurologic findings include a progressive extrapyramidal disorder, generalized dystonia and focal dystonia, dysarthria, and cognitive decline. Endocrine abnormalities include hypogonadism, alopecia, and diabetes mellitus.

Brain MRI. Decreased signal in the globus pallidus, substantia nigra, and other regions of the basal ganglia on T2-weighted images are consistent with iron accumulation. White matter disease is common.

Other. A founder pathogenic variant in DCAF17 accounts for the cases in the Saudi Arabian population [Alazami et al 2008].

COASY Protein-Associated Neurodegeneration (CoPAN)

Phenotype. The CoPAN phenotype will continue to evolve as additional cases are recognized. The few subjects described to date presented with early-onset spastic-dystonic paraparesis and later development of oro-mandibular dystonia, dysarthria, axonal neuropathy, parkinsonism, cognitive impairment and obsessive-compulsive behavior. The affected individuals had slow progression and were alive in their third decades, although they could no longer walk.

Brain MRI. Decreased signal in the globus pallidus and substantia nigra on T2-weighted imaging is consistent with iron accumulation. In one case early in disease, T2-weighted sequences also showed hyperintense and swollen caudate nuclei and putamina and mild hyperintensity in the medial and posterior thalami, which may help distinguish CoPAN from other NBIA disorders if these features are observed in additional cases. The striatal and thalamic changes were not observed later in disease when pallidal hypointensity predominated. In a different case, central hyperintensity (surrounded by hypointensity) in the globus pallidus was suggestive of an eye-of-the-tiger sign. However, axial CT suggested that the hyperintensities were consistent with calcifications, which is not the case in PKAN.

Other. Individuals studied have survived into their third decades despite a severe neurologic phenotype, suggesting the presence of a residual amount of CoA enzymatic activity [Dusi et al 2014].

Idiopathic NBIA

A significant portion of individuals with clinical, radiographic, and sometimes pathologic evidence of NBIA do not have an alternate diagnosis or mutation of one of the ten known NBIA-associated genes [Hogarth et al 2013] (see Figure 1). For the most part, these individuals do not stratify into clear phenotypic groups.

Figure 1. . NBIA Subtypes PKAN = pantothenate kinase-associated neurodegeneration PLAN = PLA2G6-associated neurodegeneration MPAN = mitochondrial membrane protein-associated neurodegeneration BPAN = beta-propeller protein-associated neurodegeneration Minor forms include those associated with pathogenic variants in ATP13A2, FA2H, FTL, CP, and DCAF17.

Figure 1.

NBIA Subtypes PKAN = pantothenate kinase-associated neurodegeneration PLAN = PLA2G6-associated neurodegeneration MPAN = mitochondrial membrane protein-associated neurodegeneration BPAN = beta-propeller protein-associated neurodegeneration Minor forms (more...)

Differential Diagnosis of NBIA

Refer to individual GeneReviews PKAN, PLAN, MPAN, BPAN, FAHN, neuroferritinopathy, aceruloplasminemia , and Woodhouse-Sakati syndrome for information on the differential diagnoses for these disorders.

Establishing a Diagnosis of a Specific NBIA Disorder

Brain MRI findings. Because brain MRI findings in NBIA evolve over time, it may be difficult to determine the diagnosis and establish the specific NBIA disorder, even years after the onset of symptoms. Once abnormal brain iron accumulation is identified, the various types of NBIA can then be considered (see Table 2).

Table 2.

Patterns of Iron Distribution by NBIA Subtype

Disease NamePattern of Iron DistributionOther Key Radiographic Features
PKANGP, SNEye-of-the-tiger sign in GP
PLANVariable GP, SN (some cases have no iron accumulation)Cerebellar atrophy
MPANGP, SNCerebellar and cortical atrophy; on T2-weighted images hyperintense streaking of the medial medullary lamina between the globus pallidus interna and externa
BPANGP, SNT1-weighted signal hyperintensity with a central band of hypointensity in the SN; SN iron > GP iron
FAHNGP, SNPontocerebellar atrophy
Kufor-Rakeb syndromeVariable GP, putamen, caudate (some cases have no iron accumulation)Cerebral, cerebellar, and brain stem atrophy
NeuroferritinopathyGP, putamen, caudate, dentate, thalamusCystic cavitation; mild cortical and cerebellar atrophy
AceruloplasminemiaGP, putamen, caudate, thalamus, RN, dentateCerebellar atrophy
Woodhouse-Sakati syndromeGPNo additional key features
CoPANGP, SNT2-weighted images: hyperintense caudate, putamina, medial and posterior thalami in early disease; GP calcifications

Note: For a more comprehensive overview of the radiographic findings in NBIA, see Kruer et al [2012].

GP= globus pallidus

SN= substantia nigra

RN= red nucleus

Clinical Molecular Genetic Testing

Ideally the diagnosis of an NBIA disorder is confirmed with molecular genetic testing: Single gene testing by NBIA type or an NBIA multi-gene panel may be used.

Single gene testing by NBIA type. Molecular genetic testing of PANK2 identifies biallelic pathogenic variants in the majority of individuals with the eye-of-the-tiger sign on MRI.

Note: (1) Glutaric aciduria I, pyruvate dehydrogenase deficiency/Leigh encephalopathy, and fucosidosis can manifest T2-weighted hyperintensity in the globus pallidus reminiscent of early PKAN and, thus, should be considered when causative pathogenic variants are not identified in PANK2 and/or when globus pallidus hyperintensity is not accompanied by the surrounding hypointensity indicative of iron accumulation. Carbon monoxide and bilirubin are toxins that selectively damage the pallidi and may lead to an MRI pattern that mimics that seen in early PKAN (2) Persons with MPAN occasionally exhibit hyperintense streaking between the globus pallidus interna and externa, which may resemble an eye-of-the-tiger sign [Hogarth et al 2013]

In both PLAN and Kufor-Rakeb syndrome, iron accumulation only develops in a portion of cases or may present later in the disease course:

  • The combination of cerebellar atrophy plus optic atrophy in childhood in the absence of high brain iron should suggest the infantile and atypical forms of PLAN.
  • Onset of parkinsonism in late adolescence/early adulthood, which may be accompanied by dystonia, suggests PLAN or Kufor-Rakeb syndrome.

Some of the rarest forms of NBIA should be readily distinguishable based on findings unique to that subtype:

  • Spasticity more prominent than dystonia, optic atrophy, motor neuronopathy, and a slowly progressive course with cognitive decline are more specific to MPAN.
  • Developmental delay in childhood with adult-onset dystonia-parkinsonism and dementia are specific to BPAN.
  • FAHN is also slowly progressive; severe pontocerebellar atrophy helps distinguish it from MPAN.
  • CoPAN is also slowly progressive. There are too few cases to be confident in distinguishing features; if the MRI findings hold true in future cases, these will be useful for narrowing the diagnosis to CoPAN.
  • Pedigree analysis may help identify autosomal dominant neuroferritinopathy. Of note, some individuals have a de novo pathogenic variant and others have limited family history information. Cystic degeneration in the pallidi and putamen, which are unique to neuroferritinopathy, do not develop until later in the disease course.
  • Aceruloplasminemia should be distinguished based on the findings of diabetes mellitus and iron accumulation in the liver.
  • The endocrine abnormalities observed in Woodhouse-Sakati syndrome are not observed in other types of NBIA.

NBIA multi-gene panels. A multi-gene panel that includes genes known to be associated with NBIA is likely to be the most cost-effective testing option for many situations.

Research Molecular Genetic Testing

Because new technologies may facilitate gene identification in the near future, participation in research studies may be useful for individuals in whom a specific type of NBIA cannot be established.

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.

Modes of Inheritance

Eight of the ten genetically defined types of NBIA are inherited in an autosomal recessive manner.

BPAN, caused by de novo pathogenic variants in WDR45, is inherited in an X-linked dominant manner. To date, all reported affected individuals have been simplex cases (i.e., a single occurrence in a family); the majority are females, indicating that pathogenic variants are de novo and suggesting that they are lethal in most males.

Neuroferritinopathy, caused by pathogenic variants in FTL, is inherited in an autosomal dominant manner.

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 mutated allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception each sib of an affected individual has a 25% chance of being affected at conception, 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 being a carrier is 2/3.

Offspring of a proband

  • Individuals with autosomal recessive forms of NBIA reproduce rarely due to the severity of the condition.
  • Those with later onset, atypical disease may have offspring; all such offspring will be obligate carriers.

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

Carrier Detection

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

Risk to Family Members — X-Linked Inheritance

Parents of a proband

Sibs of a proband

  • The risk to sibs depends on the genetic status of the parents.
  • To date, all affected individuals have had a de novo pathogenic variant, suggesting a low risk to sibs. However, because of the possibility of germline mosaicism in a parent, the risk is greater than in the general population.

Offspring of a proband. Individuals with BPAN have never reproduced. If an affected individual were to reproduce, each child of an affected individual would have a 50% chance of inheriting the pathogenic variant. Male fetuses are less likely to survive than females.

Other family members of a proband. Because all affected individuals reported to date have had a de novo pathogenic variant, the risk to other family members is likely not increased.

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

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 with neuroferritinopathy is also affected, the risk to the sibs is 50%.
  • If the pathogenic variant found in the proband cannot be detected in the DNA of either parent, the risk to the 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 affected individual has a 50% chance of inheriting the pathogenic variant.

Other family members of a proband

  • The risk to other family members depends on the genetic status of the proband’s parents.
  • If a parent has the pathogenic variant, his or her family members are at risk.

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.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the pathogenic variant(s) have been identified in an affected family member, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic diagnosis for neurodegeneration with brain iron accumulation 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
  • 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

Management

Evaluations Following Initial Diagnosis

To establish the extent of the disease and needs of an individual diagnosed with neurodegeneration with brain iron accumulation (NBIA), the following should be considered:

  • Neurologic examination for dystonia, spasticity, parkinsonism, and other neurologic findings, including evaluation of ambulation and speech.
  • Consider consultation with a movement disorders specialist
  • Physical therapy, occupational therapy, and/or speech therapy assessments
  • Thorough ophthalmologic examination (if not performed during the diagnostic evaluation)
  • Dietary assessment
  • Clinical genetics consultation

Note: The extent of disease in an affected individual is often well characterized during the diagnostic work up, which frequently includes neurophysiologic studies (EEG, EMG, electroretinogram, and/or visual evoked potentials) and brain MRI.

Treatment of Manifestations

Treatments for NBIA are palliative. The following treatments should be considered (some do not apply to all subtypes of NBIA):

  • Pharmacologic treatment of spasticity and seizures
  • Trial of oral or intrathecal baclofen for those with significant dystonia
  • Botulinum toxin for those with focal dystonia
  • L-DOPA treatment, which is beneficial in rare cases. Note: Some will have an initially dramatic response that usually diminishes over time; some will develop prominent dyskinesias early in the treatment
  • Deep brain stimulation, used clinically for dystonia with increasing frequency; shows some evidence of benefit (see Therapies Under Investigation).
  • Psychiatric treatment for those with a later-onset, more protracted course accompanied by neuropsychiatric symptoms

As NBIA progresses, many affected individuals may experience episodes of extreme dystonia lasting for day or weeks. It is especially important during these episodes to evaluate for treatable causes of pain, which may include occult GI bleeding, urinary tract infections, and occult bone fractures. The combination of osteopenia in a non-ambulatory person with marked stress on the long bones from dystonia places many individuals with NBIA at high risk for fractures without apparent trauma.

Prevention of Secondary Complications

Swallowing evaluation and regular dietary assessments are indicated to assure adequate nutrition

Once the individual can no longer maintain an adequate diet orally, gastrostomy tube placement is indicated

Gastric feeding tube and/or tracheostomy is appropriate as needed to prevent aspiration pneumonia.

Over-the-counter fiber supplements and/or stool softeners are indicated to treat constipation, which is likely caused by a combination of immobility, diet, and medications.

Surveillance

The following should be performed on a regular basis:

  • Monitoring of height and weight using appropriate growth curves to screen children for worsening nutritional status
  • Ophthalmologic assessment
  • Assessment of ambulation and speech abilities

Therapies Under Investigation

Deep brain stimulation (DBS). As DBS has become a common treatment for primary dystonia, it is also being used more frequently to attempt to treat the secondary dystonia seen in NBIA, most often in individuals with PKAN. Because a limited number of persons with PKAN have undergone such treatment and care has been provided at a variety of centers, it is not possible to evaluate the efficacy of DBS for this population.

  • The largest cohort studied at the same center included six individuals with PKAN. Those treated with DBS showed overall improvements in writing, speech, walking, and global measures of motor skills [Castelnau et al 2005]. However, at publication the length of follow-up time varied from only six to 42 months.
  • Another study of four individuals with PKAN suggested that DBS had decreasing benefit when measured at both six and 12 months following the procedure [Lim et al 2012].
  • Additional case reports with varying follow-up times and anecdotal reports from families with PKAN also support that DBS can provide benefit in some cases [Krause et al 2006, Shields et al 2007, Isaac et al 2008, Mikati et al 2009].

Even with these limitations, these studies suggested that DBS may hold more promise than previously recognized. Larger prospective studies may improve understanding of the factors that influence the outcomes of DBS use in NBIA [Pauls & Timmermann 2012].

Baclofen is one of the mainstay drugs, used both orally and intrathecally, to treat dystonia in NBIA. In 2009 Albright and Ferson reported favorable outcomes from a new technique used to deliver intraventricular baclofen in nine children and one adult with secondary dystonia, including one child with PKAN [Albright & Ferson 2009]. Additional studies are necessary to determine the optimal dose and efficacy in PKAN and other NBIAs. Intraventricular delivery of baclofen is of interest because delivery at this site may better treat upper-body and facial dystonia (e.g., blepharospasm) and may result in higher baclofen concentrations over the cortex.

Iron chelation. Interest in iron chelation has reemerged as data on deferiprone (Ferriprox®) have accumulated in several patient populations. Iron chelating agents have been tried in the past without clear benefit [Dooling et al 1974]. Until recently, trials were limited by the development of systemic iron deficiency before any clinical neurologic benefits were evident. Unlike earlier drugs, deferiprone crosses the blood-brain barrier and removes intracellular iron.

Case reports suggest regression of symptoms in two adults with NBIA of unknown cause (i.e., non-PKAN NBIA) [Forni et al 2008, Kwiatkowski et al 2012].

A Phase II pilot trial in Italy with ten persons with PKAN found that deferiprone treatment was able to reduce brain iron levels; over the six-month treatment period there were no serious adverse events but also no significant changes in clinical status, suggesting that a longer treatment period is necessary to determine the utility of this drug [Zorzi et al 2011].

A clinical trial that has received FDA approval in the US is currently enrolling.

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

References

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Chapter Notes

Revision History

  • 24 April 2014 (aa) Revision: COASY protein-associated neurodegeneration added
  • 28 February 2013 (me) Review posted live
  • 23 April 2012 (ag) Original submission
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