Goal 1.

Describe the clinical characteristics of neurodegeneration with brain iron accumulation.

Goal 2.

Review the genetic causes of neurodegeneration with brain iron accumulation.

Goal 3.

Provide an evaluation strategy to identify the genetic cause of neurodegeneration with brain iron accumulation in a proband (when possible).

Goal 4.

Inform genetic counseling of family members of an individual with neurodegeneration with brain iron accumulation.

Goal 5.

Review high-level management of neurodegeneration with brain iron accumulation.

Diagnosis of NBIA

The quality of the neuroimaging, including magnet strength and spacing of image slices, can limit the ability to accurately identify abnormal brain iron. Iron-sensitive sequences, such as SWI, GRE, and T₂*, should be used as a first-line diagnostic investigation to identify the characteristic changes in NBIA. By the time clear neurologic features are present, the brain MRI almost always shows characteristic changes, although iron may be visible only later in the disease course.

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

Differential Diagnosis of NBIA

The differential diagnosis of NBIA is usually based on a brain MRI that raises the suspicion of abnormal iron accumulation (Table 1).

Option 1

Single-gene testing (sequence analysis of one gene, followed by gene-targeted deletion/duplication analysis) is useful when the neuroimaging and/or phenotype clearly point toward one NBIA-related gene. For example, an eye-of-the-tiger sign on brain MRI is nearly pathognomonic for PKAN caused by biallelic PANK2 pathogenic variants.

A multigene panel that includes some or all of the genes listed in Table 1 is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. 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. Of note, given the rarity of some of the genes associated with NBIA, some panels may not include all the genes mentioned in this overview. (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.

Option 2

Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) may be considered when clinical/neuroimaging findings have not suggested NBIA. Exome sequencing is most commonly used; genome sequencing is also possible.

If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Note: For individuals in whom a genetic cause of NBIA cannot be established, participation in research studies may be considered as new technologies may facilitate identification of additional NBIA-related genes in the future (see Resources).

Modes of Inheritance

Seven of the ten genetically defined types of neurodegeneration with brain iron accumulation (NBIA) are inherited in an autosomal recessive manner. Exceptions:

• Neuroferritinopathy, an autosomal dominant disorder caused by a pathogenic variant in FTL
• Mitochondrial membrane protein-associated neurodegeneration (MPAN), an autosomal recessive or autosomal dominant disorder caused by mutation of C19orf12 (de novo and inherited pathogenic variants are known to be associated with autosomal dominant MPAN)
• Beta-propeller protein-associated neurodegeneration (BPAN), an X-linked disorder caused by a de novo or inherited pathogenic variant in WDR45 with suspected male lethality (To date, most individuals with BPAN have been female.)

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one NBIA-causing pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

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

Other family members. Each sib of the proband's parents is at 50% risk of being a carrier of an NBIA-causing pathogenic variant.

Carrier detection. Carrier testing for at-risk family members requires prior identification of the pathogenic variants in the family.

X-Linked Inheritance – Risk to Family Members

Parents of a proband

• To date, the vast majority of reported individuals with BPAN have been simplex cases (i.e., a single occurrence in a family) and have had a de novo WDR45 pathogenic variant.
• Rarely, an individual with BPAN has the disorder as the result of an inherited pathogenic variant. In one family, an asymptomatic mother had the same WDR45 pathogenic variant as her sons with significant X-chromosome inactivation skewed toward the normal allele in her leukocyte DNA [Dufke et al 2014].
• Recommended parental molecular genetic testing when a proband has an identified WDR45 pathogenic variant:
  • Female proband. Molecular genetic testing of both parents
  • Male proband. Molecular genetic testing of the mother only; the father of a male proband will neither have the disorder nor be hemizygous for the WDR45 pathogenic variant.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the WDR45 pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. Presumed maternal germline mosaicism has been reported in a family with two affected sibs [Zarate et al 2016].

Sibs of a proband. To date, nearly all affected individuals have had a de novo WDR45 pathogenic variant, suggesting a low risk to sibs.

• The risk to sibs of a female proband depends on the genetic status of the parents. The risk to sibs of a male proband depends on the genetic status of the mother.
• If a proband represents a simplex case (i.e., a single occurrence in a family) and if the WDR45 pathogenic variant cannot be detected in the mother or father's leukocyte DNA (female proband) or in the mother's leukocyte DNA (male proband), the risk to sibs is greater than that of the general population because of the possibility of germline mosaicism [Zarate et al 2016].

Offspring of a proband

• Female proband. Females with the typical BPAN phenotype do not reproduce. In rare cases, a mildly affected female with somatic/germline mosaicism [Haack et al 2012, Zarate et al 2016] or skewed X-chromosome inactivation [Dufke et al 2014] may reproduce (see BPAN, Genetic Counseling for more detailed information).
• Male proband. Affected males do not reproduce.

Other family members. Given that most probands with BPAN reported to date have the disorder as a result of a de novo WDR45 pathogenic variant, the risk to other family members is presumed to be low.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Neuroferritinopathy. Most individuals diagnosed with neuroferritinopathy have an affected parent. More rarely, a proband has the disorder as the result of a de novo pathogenic variant (the proportion of de novo cases in neuroferritinopathy is unknown).
• Autosomal dominant MPAN. Rarely, individuals diagnosed with autosomal dominant MPAN have an affected parent. More often, a proband with autosomal dominant MPAN has the disorder as a result of a de novo pathogenic variant in exon 3 of C19orf12 that leads to a protein truncated after amino acid 79 [Gregory et al 2019].
• Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant in FTL include brain MRI, measurement of serum ferritin concentration, and molecular genetic testing for the pathogenic variant identified in the 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 is affected, the risk to the sibs of inheriting the NBIA-causing pathogenic variant is 50%.
  • Penetrance of neuroferritinopathy is 100%; however, there may be differences in the age of onset and rate of progression in heterozygous sibs.
  • Reduced penetrance is suggested in two individuals in the two families with autosomal dominant MPAN reported to date [Gregory et al 2019].
• If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].

Offspring of a proband. Each child of an individual with neuroferritinopathy or autosomal dominant MPAN has a 50% chance of inheriting the pathogenic variant. There may be differences in the age of onset and rate of progression of the disorder between members of the same family.

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

Predictive testing of at-risk asymptomatic adult family members requires prior identification of the NBIA-causing pathogenic variant in the family. See Neuroferritinopathy, Genetic Counseling for a review of issues related to predictive testing.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.

Prenatal Testing and Preimplantation Genetic Testing

Once the NBIA-causing pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

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

Treatment of Manifestations

Treatments for NBIA disorders are palliative and should be tailored to the specific NBIA disorder and to the affected individual. A consensus management guideline for PKAN has been published [Hogarth et al 2017]. The following treatments should be considered (some do not apply to all genetic types 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.
• Psychiatric treatment for those with a later-onset, more protracted course accompanied by neuropsychiatric symptoms

As NBIA disorders progress, many affected individuals may experience episodes of extreme dystonia lasting for days 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 an NBIA disorder at high risk for fractures without apparent trauma.

Affected individuals benefit from services for the blind, educational programs, and assistive communication devices; adaptive aids (walkers, wheelchairs) may be required for gait abnormalities.

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

Evaluate for treatable causes of pain during episodes of extreme dystonia. 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

Revision History

• 21 October 2019 (bp) Comprehensive update posted live
• 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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