Neuroferritinopathy

Neuroferritinopathy is a genetically dominant form of NBIA. That means it can be inherited if only one parent has the mutated gene. Although the prevalence is unknown, only about 100 cases have been reported, and most share the same gene change, suggesting a common ancestor. It is caused by mutations in the FTL gene, which stands for ferritin light. This is one of two sub-proteins that make up ferritin, a protein in the body that helps store and detoxify iron. MRIs are different from those of other NBIA patients.

Clinical Diagnosis

The effects of neuroferritinopathy typically begin around age 40, although onset in the early teenage years and in the sixth decade have been recorded. A family history consistent with autosomal dominant transmission are indicative of this disorder.

Individuals with neuroferritinopathy typically present with either dystonia or chorea. Dystonia is a movement disorder in which involuntary sustained or intermittent muscle contractions cause twisting and repetitive movements, abnormal postures, or both. Chorea is an ongoing random-appearing sequence of one or more discrete involuntary movements or movement fragments. This usually affects one or two limbs. Mild changes in thinking (cognitive effects) can also occur at this time.

Within 20 years of onset, neuroferritinopathy usually begins to affect movement in all the limbs. It also causes difficulty speaking and resembles Huntington’s disease. Cognitive deficits and behavioral issues worsen over time.

Serum ferritin concentration may be low. Eye movements are usually not affected throughout the disease course. Axonal swellings (neuroaxonal spheroids) may be present.

From the onset, all affected individuals have evidence of excess brain iron accumulation on T2-weighted MRI views of the brain. Later stages are associated with high signal on T2-weighted MRI in the caudate, globus pallidus, putamen, substantia nigra and red nuclei. This is followed by cystic degeneration in the caudate and putamen.

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]

Table taken from Neuroferritinopathy - GeneReviews® - NCBI Bookshelf

Evaluations Following Initial Diagnosis

Psychometric, physiotherapy, speech therapy and dietary assessments should be made.

Management

The movement disorder is particularly resistant to conventional therapy, but records show some patients have responded to 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.

Dietary assessment is helpful. Affected individuals should be evaluated to ensure that they maintain caloric intake. Physiotherapy can help maintain mobility and prevent tightening of muscles, ligaments or skin.

Genetics

Because neuroferritinopathy is inherited in an autosomal dominant manner, a person affected with neuroferritinopathy has one working copy of the affected gene and one copy that has a change or mutation. This single mutation is enough to cause the disease. There is a one in two chance (50%) that an affected individual will pass the gene change on to his or her children. Most individuals diagnosed with neuroferritinopathy have one affected parent. The proportion of cases caused by de novo (new) mutations is unknown.

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk can be done. In one test, DNA is extracted from fetal cells obtained by amniocentesis, usually at 15 to 18 weeks’ gestation, and analyzed. Or, sampling is done of the chorionic villus, the tiny finger-like projections on the edge of the placenta, usually at 10 to 12 weeks’ gestation.

Embryo screening, known as preimplantation genetic diagnosis, may be an option for some families in which the disease-causing mutations have been identified.

Note

A main resource for this clinical information is Neuroferritinopathy - GeneReviews® - NCBI Bookshelf. GeneReviews is primarily used by genetics professionals so the terminology and information may be difficult for the general public to understand.

TIRCON International NBIA Registry

The TIRCON International NBIA Registry is housed at Ludwig Maximilian University of Munich, Germany, and was created under an EU grant from 2011-2015 called Treat Iron-Related Childhood-Onset Neurodegeneration.

The NBIA Alliance and other sources have provided funding since 2015. Clinical centers from 16 countries have provided patient clinical data. There are over 750 entries consisting of NBIA patients and controls as of September 2015. Clinical centers seeing at least five NBIA patients are eligible to participate. Clinical and natural history data are available to researchers studying NBIA disorders. Contact Anna Baur-Ulatowska at Anna.Baur@med.uni.muenchen.de for more information on this registry.

Clinical Trials

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies.

Neuroferritinopathy Research Publications and Articles

Other research articles and studies can be found at Pub Med Central.

Following is a list of recent Neuroferritinopathy research articles:

2021 - Pathogenic mechanism and modeling of neuroferritinopathy

2021 - New Insights into the Role of Ferritin in Iron Homeostasis and Neurodegenerative Diseases

2020 - Neuropathological and biochemical investigation of Hereditary Ferritinopathy cases with ferritin light chain mutation: Prominent protein aggregation in the absence of major mitochondrial or oxidative stress

2019 - Stem Cell Modeling of Neuroferritinopathy Reveals Iron as a Determinant of Senescence and Ferroptosis during Neuronal Aging

2016 - Effect of Systemic Iron Overload and a Chelation Therapy in a Mouse Model of the Neurodegenerative Disease Hereditary Ferritinopathy

2016 - Neuroferritinopathy: Pathophysiology, Presentation, Differential Diagnoses and Management

2015 - Neuroferritinopathy: From ferritin structure modification to pathogenetic mechanism

Aceruloplasminemia

Aceruloplasminemia was first described in 1987 as an autosomal recessive disease, meaning that an affected individual has inherited the defective gene from both parents. The disorder is caused by a mutation of the ceruloplasmin gene (CP), which is inactivated. The estimated prevalence of this disease is about one in 2 million. It has been mainly studied in Japan, where it is most prevalent.

While other NBIA disorders cause iron accumulation in the brain, aceruloplasminemia is unique in that it causes iron overload not only in the brain but also in other organs such as the liver, pancreas and heart.

The main symptoms are retinal degeneration, diabetes and neurologic disease related to iron build-up in the brain’s basal ganglia. Movement problems include face and neck dystonia (involuntary muscle contractions, with repetitive movements or painful postures), blepharospasm (eyelid spasms), tremors and jerky movements.

Clinical Diagnosis

Individuals with aceruloplasminemia often present to doctors with anemia before the onset of diabetes mellitus or neurologic symptoms. Physical traits, known as phenotypic expression, vary, even within families.

The classical disease triad of aceruloplasminemia is diabetes, retinopathy and neuropathy. Diabetes mellitus is considered an early sign. It was reported as the first symptom in 68.5% of patients at a median age of 38.5 years (Vroegindeweij et al., 2015). Retinal symptoms are reported in over 75% of Japanese patients (Kono, 2012). These retinal manifestations do not affect visual acuity.

Neurological symptoms usually appear in the fifth decade of life and vary within a wide spectrum that includes cerebellar ataxia (sudden, uncoordinated muscle movement), involuntary movements, parkinsonism (movement disorder), mood and behavior disturbances, and cognitive impairment.

Physicians may do an MRI to assist in diagnosing patients. The MRI will show signs of iron accumulation in the brain (striatum, thalamus, dentate nucleus) and liver on both T1- and T2-weighted images. The images also will indicate the absence of serum ceruloplasmin, a copper-containing protein, and some combination of the following: low serum copper concentration, low serum iron concentration, high serum ferritin (a protein that enables cells to store iron) concentration and increased iron concentration in the liver. Laboratory blood tests can also test these concentrations.

Age at onset is 25 to 60, and older. Psychiatric problems in patients include depression and cognitive dysfunction in individuals older than 50.

When phenotypic and laboratory findings suggest the diagnosis of aceruloplasminemia, molecular genetic testing can include single gene testing, multigene panels or comprehensive genomic testing.

Evaluations Following Initial Diagnosis

To establish the extent of disease and the individual’s needs, evaluations for the following are recommended:

• Iron deposits. Serum ferritin concentration, brain and abdomen MRI findings, and hepatic (liver) iron and copper content by liver biopsy
• Neurologic findings. Brain MRI and protein concentration in cerebrospinal fluid
• Diabetes mellitus. Blood concentrations of insulin and HbA1c, a test of blood sugar levels
• Retinal degeneration. Examination of the optic fundi, the interior linking of the eyeball, and fluorescein angiography, a test to examine blood vessels in the retina, choroid and iris of the eye
• Anemia. Complete blood count
• Medical genetics consultation

Annual glucose tolerance tests starting at age 15 are recommended to evaluate the onset of diabetes mellitus. A cardiac evaluation should be performed early in the course of the disease and repeated every year. Finally, evaluation of thyroid and liver function and complete blood count are indicated annually starting at the time of diagnosis.

Management

Treatment is focused on reducing iron overload using iron chelating agents, such as desferrioxamine, deferasirox and deferiprone. While iron chelation therapy (ICT) was effective in reducing systemic iron overload, it was not effective on neurological symptoms [Kono 2013; Dusek et al., 2016]. It also must often be discontinued due to iron deficiency anemia.

More research needs to be done on the therapeutic efficacy of ICT in aceruloplasminemia. There is no information on whether it can improve glucose metabolism and retinopathy, and only short-term studies have been done on the effect on neurological symptoms. It is possible that the treatment would be more effective if started in the window between the appearance of the first signs of disease and the neurological symptoms. Zinc sulfate and minocycline have been proposed as alternatives to ICT due to their antioxidant properties. The results are promising but are limited to only two patients [Kuhn et al. 2007; Hayashida et al., 2016].

In some cases, ICT was combined with fresh-frozen plasma (FFP) administration. FFP can partially/temporarily restore circulating ceruloplasmin (Cp). A 2017 case report suggests that the early initiation of combined treatment with FFP and iron chelation may be useful to reduce the accumulation of iron in the central nervous system and improve neurological symptoms.

Genetics

Aceruloplasminemia is inherited in an autosomal recessive manner. Because most of our genes exist in pairs (one coming from the mother and one coming from the father), we normally carry two working copies of each gene. When one copy of a recessive gene has a change or mutation, the person should still have normal health. That person is called a carrier.

Recessive diseases only occur when both parents are carriers for the same condition and then pass their changed genes onto their child. Statistically, there is a one in four chance that two carriers would have an affected child. The chance is one in four that their child will not be a carrier.

Carrier testing for at-risk relatives and prenatal testing for pregnancies at risk are possible if both disease-causing mutations have been identified in an affected family member.

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells through amniocentesis (usually at 15 to 18 weeks’ gestation) or sampling of the chorionic villus - the finger-like projections that emerge from the outer sac surrounding the fetus - (usually at 10 to 12 weeks’ gestation).

Screening embryos before they become implanted may be an option for some families in which the disease-causing mutations have been identified.

Note

A main resource for this clinical information is Aceruloplasminemia - GeneReviews - NCBI Bookshelf. GeneReviews is primarily for the use of genetics professionals so the terminology and information may be difficult to understand for the general public.

TIRCON International NBIA Registry

The TIRCON International NBIA Registry is housed at Ludwig Maximilian University of Munich, Germany, and was created under an EU grant from 2011-2015 called Treat Iron-Related Childhood-Onset Neurodegeneration.

The NBIA Alliance and other sources have provided registry funding since 2015. Clinical centers from 16 countries have provided patient clinical data. There are over 750 entries consisting of NBIA patients and controls as of September 2021. Clinical centers seeing at least five NBIA patients are eligible to participate. Clinical and natural history data are available to researchers studying NBIA disorders. Contact Anna Baur-Ulatowska at Anna.Baur@med.uni-muenchen.de for more information on this registry. 

Clinical Trials

Clinical trial information can be found at ClinicalTrials.gov by searching for aceruloplasminemia. Currently, one study is in the recruitment process at First Affiliated Hospital of Fujian Medical University. More information can be found at Clinical Curative Effect Evaluation Study of Treatment of Oral Deferiprone Tablets in Aceruloplasminemia.

Aceruloplasminemia Research Publications and Articles

Following is a list of recent aceruloplasminemia research articles. Other research articles and studies can be found at Pub Med Central.

2020 - Genetic and Clinical Heterogeneity in Thirteen New Cases with Aceruloplasminemia. Atypical Anemia as a Clue for an Early Diagnosis

2020 - Deferasirox Might Be Effective for Microcytic Anemia and Neurological Symptoms Associated with Aceruloplasminemia: A Case Report and Review of the Literature

2019 - Aceruloplasminemia: A Severe Neurodegenerative Disorder Deserving an Early Diagnosis

2018 - Aceruloplasminemia: Waiting for an Efficient Therapy

2018 - Ceruloplasmin replacement therapy ameliorates neurological symptoms in a preclinical model of aceruloplasminemia

2017 - Is aceruloplasminemia treatable? Combining iron chelation and fresh-frozen plasma treatment

2016 - Iron chelation in the treatment of neurodegenerative diseases

2016 - Aceruloplasminemia With Psychomotor Excitement and Neurological Sign Was Improved by Minocycline (Case Report)

2015 - Combination‐therapy with concurrent deferoxamine and deferiprone is effective in treating resistant cardiac iron‐loading in aceruloplasminaemia

2015 - Aceruloplasminemia presents as Type 1 diabetes in non‐obese adults: a detailed case series

2013 - Aceruloplasminemia: an update

2012 - Aceruloplasminemia

2007 - Treatment of symptomatic heterozygous aceruloplasminemia with oral zinc sulphate

2006 - Molecular and pathological basis of aceruloplasminemia

Cited on Page

Dusek P., Schneider S. A., Aaseth J. (2016). Iron chelation in the treatment of neurodegenerative diseases. J. Trace Elem. Med. Biol. 38 81–92. 10.1016/j.jtemb.2016.03.010 [PubMed]

Hayashida M., Hashioka S., Miki H., Nagahama M., Wake R., Miyaoka T., et al. (2016). Aceruloplasminemia with psychomotor excitement and neurological sign was improved by minocycline (case report). Medicine 95:e3594. 10.1097/MD.0000000000003594 [PubMed]

Kuhn J., Bewermeyer H., Miyajima H., Takahashi Y., Kuhn K. F., Hoogenraad T. U. (2007). Treatment of symptomatic heterozygous aceruloplasminemia with oral zinc sulphate. Brain Dev. 29 450–453. 10.1016/j.braindev.2007.01.001 [PubMed]

Kono S. (2012). Aceruloplasminemia. Curr. Drug Targets 13 1190–1199. 10.2174/138945012802002320 [PubMed]

Kono S. (2013). Aceruloplasminemia: an update. Int. Rev. Neurobiol. 110 125–151. 10.1016/B978-0-12-410502-7.00007-7 [PubMed]

Vroegindeweij L. H., Van Der Beek E. H., Boon A. J., Hoogendoorn M., Kievit J. A., Wilson J. H., et al. (2015). Aceruloplasminemia presents as Type 1 diabetes in non-obese adults: a detailed case series. Diabet. Med. 32 993–1000. 10.1111/dme.12712 [PubMed]

Fatty Acid
Hydroxylase-Associated
Neurodegeneration (FAHN)

FAHN

Fatty Acid Hydroxylase-associated Neurodegeneration (also known as HSP35), is caused by a mutation in the fatty acid 2-hydroxylase (FA2H) gene found on chromosome 16.

FAHN is ultra-rare; with approximately 5% of NBIA Individuals having the diagnosis. Onset usually occurs in childhood, or within the first or second decade of life. FAHN affects the central nervous system (brain and spinal cord) and causes problems with the corticospinal tract, which is the path of communication between the brain and limbs. This communication problem results in spasticity of the limbs.

Ataxia is also common, which is impaired coordination, balance and speech, Ataxia and spasticity share some of the same symptoms. Individuals with spasticity can have difficulty walking and doing other tasks because of muscle stiffness, spasms and contractions. Often, these individuals also experience dystonia, which are involuntary movements and prolonged muscle contractions that result in twisting body motions, tremors and abnormal posture.

Affected FAHN individuals also experience optic atrophy, profound cerebellar atrophy and white matter changes in the brain, in addition to high iron levels in the brain. Later in the disease course, individuals experience progressive intellectual impairment and seizures. Life expectancy varies among individuals.

Clinical Diagnosis

FAHN is diagnosed through an MRI of the brain. A common type of MRI known as a T2-weighted scan will show abnormalities in FAHN individuals: hypointensity (darkness) of the globus pallidus and possibly variable unilateral or bilateral symmetric white matter hyperintensity (brightness). There may be progressive atrophy (wasting away or diminution) of various regions of the brain and spinal cord, as well as thinning of the corpus callosum, which is the thin separation between the brain’s two hemispheres. Bone marrow biopsy, although not necessary for diagnosis, may demonstrate accumulation of granular histiocytes, which are immune cells.

The diagnosis of FAHN may be suspected in individuals with the onset of hallmark features in the first or second decade: spasticity, ataxia, dystonia, optic atrophy, eye movement abnormalities early in the disease course and progressive intellectual impairment and seizures later in the disease course. Other features are spastic paraplegia or quadriplegia and pyramidal tract signs (problems, such as spasticity, caused by dysfunction of the motor neurons that originate in the cerebral cortex and terminate in the spinal cord); dysarthria (difficulty pronouncing words); and dysphagia (difficulty swallowing).

Note: Because very few individuals with FAHN have been documented, the phenotype (disease characteristics) is likely to expand as more cases are ascertained, and thus the designation of any phenotypic feature as ‘hallmark’ may be premature.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with FAHN, the following evaluations may be useful:

• Neurologic examination for dystonia, ataxia and spasticity, including formal evaluation of ambulation, speech and feeding
• Ophthalmologic assessment for evidence of optic atrophy or eye movement abnormalities
• Screening developmental assessment, with referral for more formal testing if developmental delay is observed or suspected
• Assessment for physical therapy, occupational therapy, and/or speech therapy and appropriate assistive devices

Management

Symptomatic treatment is aimed primarily at the dystonia, which can be debilitating. Therapies used with varying success include the oral medications baclofen, anticholinergics, tizanidine and dantrolene; focal injection of botulinum toxin; intrathecal baclofen; and deep brain stimulation.

More information on these therapies can be found in the Medical Information section of our website.

Attention should be given to diet and swallowing to prevent aspiration. Children with FAHN should have regular measurement of height and weight to assure adequate nutrition, with gastrostomy tube placement as needed. Assessment of ambulation and speech and communication needs, and ophthalmologic examination also are recommended.

Since most individuals with FAHN lose the ability to walk and speak, independence should be encouraged when possible. Adaptive equipment and devices that can help include walkers or wheelchairs and augmentative communication aids.

Genetics

FAHN is inherited in an autosomal recessive manner. Because most of our genes exist in pairs (one coming from the mother and one coming from the father), we normally carry two working copies of each gene. When one copy of a recessive gene has a change, or mutation, the person should still have normal health. That person is called a carrier.

Recessive diseases only occur when both parents are carriers for the same condition and then pass their mutated genes onto their child. Statistically, there is a one in four chance that two carriers would have an affected child. There is a two in four chance the parents will have a child who is also a carrier. The chances are one in four that the child will not have the gene mutation. Carrier testing for at-risk relatives and prenatal testing for pregnancies at risk are suggested if both disease-causing mutations have been identified in an affected family member.

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk can be done. In one test, DNA is extracted from fetal cells obtained by amniocentesis, usually at 15 to 18 weeks’ gestation, and analyzed. Or, sampling is done of the chorionic villus, the tiny finger-like projections on the edge of the placenta, usually at 10 to 12 weeks’ gestation.

Embryo screening, known as preimplantation genetic diagnosis, may be an option for some families in which the disease-causing mutations have been identified.

Note

A main resource for the clinical information provided here is FAHN - GeneReviews® - NCBI Bookshelf. GeneReviews is primarily used by genetics professionals so the terminology and information may be difficult to understand for the general public.

Research

Research grants have been awarded to various studies to help understand the disease. A focus of the research has been creating disease models which will allow scientists to perform studies testing possible drug therapies to see if effective in the disease models. It is important that the model mimic the condition seen in patients with FAHN.

A successful mouse model has been created to study the disease and research is underway to create a stem cell model. To develop these stem cells in the lab, cells will be taken from the connective tissue of FAHN patients. Researchers will then use a gene editing technology, CRISPR/Cas9, to add copies of certain genes to the cells, endowing them with a stem cell’s special characteristics. They can develop into central nervous system cells that may be affected by FAHN.

As research moves forward, these disease models could provide scientists important clues on the cause of disease as well as help develop and test potential treatments through drug screeningthat can be later used in clinical trials. trials.

Researchers are also gathering data to create a natural history of FAHN and are analyzing clinical, genetic and imaging data.

Natural History Studies

TIRCON International NBIA Registry

The TIRCON International NBIA Registry was created under a European Union grant called Treat Iron-Related Childhood-Onset Neurodegeneration. Grant funding ran from 2011 to 2015, and the project is housed at Ludwig Maximilian University of Munich, Germany. The NBIA Alliance and other sources have provided registry funding since 2015. Clinical centers from 12 countries take part in the registry by entering their patient data. There were over 750 entries consisting of NBIA patients and controls as of September 2021. Clinical centers seeing at least five NBIA patients are eligible to participate. Clinical and natural history data is available to researchers studying NBIA disorders. For more information on the registry, contact Anna Baur-Ulatowska at Anna.Baur@med.uni-muenchen.de

Research Publications and Articles

Following is a list of some recent research articles. Others can be found at Pub Med Central.

2022 - Generation of the human iPSC line AKOSi010-A from fibroblasts of a female FAHN patient, carrying the compound heterozygous mutation p.Gly45Arg/p.His319Arg

2018 - Hereditary Spastic Paraplegia Type 35 with a Novel Mutation in Fatty Acid 2-Hydroxylase Gene and Literature Review of the Clinical Features