NBIA Syndromes: A Step Forward from the Previous Knowledge
Keywords: Basal ganglia, dystonia; “eye of the tiger” sign, neurodegeneration with brain iron accumulation, pantothenate kinase
Accumulation of iron within the basal ganglia (BG) and dentate nuclei is a part of normal aging process, but it is also implicated in the pathogenesis of neurodegenerative diseases., Iron is essential as a cofactor in processes of energy production, DNA synthesis and repair, phospholipid metabolism, myelination, and neurotransmitter synthesis., The iron concentration is highest in the BG, suggesting their role in brain iron storage and delivery. A higher concentration in astrocytes supports the idea that these cells have the most important role in the iron regulation.
A group of rare hereditary disorders named Neurodegeneration with Brain Iron Accumulation (NBIA) is directly connected to impaired iron metabolism. Genetic discoveries of NBIAs, and higher accessibility of MRI confirm that NBIAs are not homogenous group of diseases.,, Fifteen different NBIAs have been described to date, with autosomal recessive inheritance found in 13, and a dominant and X-linked dominant inheritance in one disease, respectively. Some NBIAs result from dysfunctional proteins directly involved in the iron metabolism, that interfere with normal cellular transport and iron storage such as CP (ceruloplasmin) and FTL1 (ferritin light chain). The remaining genes are unrelated to iron metabolism. PANK2 (pantothenate kinase type 2) and COASY (CoA synthase) code for enzymes in the essential biochemical pathway responsible for coenzyme A (CoA) production. PLA2G6 (phospholipase A2 group 6), FA2H (fatty acid hydroxylase 2), C19orf12, SCP2 (sterol carrier protein type 2), and CRAT (carnitine acetyltransferase) genes code for proteins involved in the lipid metabolism, membrane integrity, and mitochondrial function. WDR45, ATP13A2, and possibly AP4M1 code for factors involved in the autophagic process. The GTPBP2 gene product plays a role in chain elongation during protein synthesis at the ribosome, REPS1 (RALBP1-associated EPS domain-containing protein 1) is involved in endocytosis and vesicle transport, while the DCAF17 gene encodes for a protein with not yet elucidated cellular localization (possibly in the nucleolus), and with undefined activity [Table 1].
In a view of the rarity of these diseases and extensive variety of their presentations, diagnosis is commonly delayed. It has been recently shown that patients visit five different physicians prior to diagnosis. For the comprehensive information regarding brain iron metabolism, pathogenesis of iron deposition in different NBIAs, genetics, and clinical features of exceedingly rare forms we refer to other review papers.,,,
There are some common characteristics of this set of syndromes. All of them are rare, inherited disorders caused by gene mutations that affect the function of proteins contributing in tissue iron homeostasis. Some of them, but not all, are characterized by severe brain iron deposition. Iron affects mainly the BG- globus pallidus (GP) and substantia nigra (SN) are almost always affected, although other regions including cortex and cerebellum can be involved. Motor symptoms are progressive and complex ranging from early-onset degeneration with premature death to adult-onset parkinsonism and dystonia. In addition, epileptic seizures, pyramidal signs, visual disorders and cognitive deterioration may develop., Rarely, patients may remain asymptomatic until midlife or later. NBIAs are refractory to known therapeutical strategies, although a number of interventions may offer symptomatic relief.
In this review, we discuss the broad clinical presentation of these complex diseases, their genetic and imaging features, and potential therapeutical targets and strategies.
NBIA disorders related to coenzyme a biosynthesis
Mutations in genes coding for the first (PANK2) and the last (COASY) enzyme of the Coenzyme-A (CoA) biosynthetic pathway cause NBIA subtypes known as pantothenate kinase-associated neurodegeneration (PKAN) and CoA synthase protein-associated neurodegeneration (CoPAN), respectively.
Pantothenate kinase-associated neurodegeneration (PKAN), NBIA type 1
PKAN is the most frequent form of NBIA (35%–50% of cases), with a prevalence of 1-3 per 1 000 000. PKAN is a recessively inherited disorder caused by mutations in the pantothenate kinase 2 (PANK2) gene on chromosome 20p13. PANK2 encodes a mitochondrial pantothenate kinase, an essential regulatory enzyme in the biosynthesis of coenzyme A, implicated in energy metabolism, fatty acid synthesis, and degradation., Thus, iron accumulation, is probably not the primary cause of neurodegeneration and a defect in membrane remodeling and/or in signaling pathways involving lipids may underlie the common neuropathological signs. It has been hypothesized that the alteration of ferroportin expression mediated by PANK2 might be the link to the accumulation of iron in the brain. COASY-associated neurodegeneration (CoPAN) is very rare but pathophysiologically strongly related to PKAN.
Mutations, mostly missense, have been detected in all seven exons of the PANK2 gene. The most common mutations are the 1231G > A and 1253C > T, responsible for about one-third of all PKAN cases, while most of the others are “private mutations”., When PKAN is suspected, genetic testing is suggested in symptomatic cases for diagnostic confirmation.
Typical PKAN presents in early childhood before the age of six years with gait difficulty (spastic/dystonic gait), in almost 90% of patients, followed by generalized pyramidal (spasticity, hyperreflexia, extensor toes) and extrapyramidal features (mainly dystonia, with prominent oromandibular involvement) neuropsychiatric symptoms and visual disturbances (pigmentary retinopathy) [Figure 1], [Video 1].,,, Oculomotor abnormalities suggestive of midbrain degeneration are common. Clinical course is progressive and affected children generally become wheelchair-bound within a few years.
Atypical PKAN presents later with less pronounced motor involvement, but cognitive decline and psychiatric features may be prominent. Our patients presented mainly with atypical PKAN and they were included in large cohort published by Hartig et al. Reaching milestones that significantly influence the functional ability and quality of life, generally occurred in the first five years of the disease followed by a rather stable period of slower progression in a long-term follow-up of our patients [Video 1].
PKAN can differ from other forms of NBIA based on the typical brain MRI imaging pattern in the anterior-medial part of the GP characterized by a central hyperintensity within a surrounding area of hypointensity particularly on T2-weighted image due to excessive brain iron accumulation. This typical MRI finding is called “eye of the tiger” sign [Figure 2] and [Table 2]. It was suggested that central hyperintensity reflects edema and gliosis, while the surrounding hypointensities result from iron deposits which develop later into the disease. Hayflick et al. reported there is an absolute correlation between “eye of the tiger” sign and mutations in PANK2., However, this radiological sign can also be detected in other conditions (progressive supranuclear palsy, early-onset levodopa-responsive parkinsonism and cortical–basal ganglionic degeneration). Development of MRI alterations appears to be an active process; characteristic MRI findings might precede clinical symptoms, or may be temporarily present and vanish with time, whereas diffuse GP T2-hypointensity reflecting iron deposition appears later and does not fade away. According to the recently published data, an initial MRI led to the diagnosis in only half of the patients (56.4%). Delgado et al. revealed that only a part of their patients had the typical “eye of the tiger” sign.
Dopamine transporter SPECT imaging is generally normal in PKAN patients, as well as cardiac MIBG uptake. Our transcranial sonography (TCS) study showed that the hyperechogenic areas detected in the TCS study correlate with the hypointense regions detected on MRI examinations. TCS also showed bilateral hyperechogenicity restricted to the lentiform nucleus (LN) and SN. Both TCS and MRI changes were restricted to the LN/GP and the SN. This finding is in line with the pathological findings of the accumulation of iron in GP and SN, suggesting their selective involvement.
In a neuropathological study on genetically confirmed PKAN cases, the involvement mainly of the GP and nearby structures (medial putamen and internal capsule) was reported, while cortical areas, brainstem, rest of deep gray nuclei, optic nerves, and the cerebellum were spared (they were affected in PLA2G6 patients). Intact neurons in the GP express abnormal ubiquitinated protein deposits. Histochemical staining demonstrated granular iron deposits spread through the neuropil and within microglial cells and astrocytes of the GP and SN. Although several studies reported Lewy body pathology in PKAN patients, in the recent series of genetically confirmed cases, Lewy bodies and alpha-synuclein accumulation were absent, contrary to MPAN and PLAN.
PKAN is serious and devastating disease. Most patients experience problems with walking (66.7%), trouble with speaking or being understood (92.3%), problems with vision (69.2%) and problems in school (87.2%). Unfortunatelly, there is no treatment which could modify the evolution of disease. The first-line symptomatic drugs effective in PKAN are trihexyphenidyl, clonazepam, and baclofen. Pratini et al. highlighted the potency of combining intratecal baclofen and oral deferiprone in one patient with classic PKAN. Botulinum toxin is used for treatment of focal dystonia or sialorrhea.
The role of iron depletor has not been clarified. Data from a 4-year follow-up study verified the safety of deferiprone as a chelator agent. One study resulted in 20% reduction of iron quantity, but without clinical improvement. Possible reason for such outcome could be delayed application of therapy. Another study which used deferiprone over a 6-month period resulted in radiological and clinical changes in NBIA patients.
Anesthesia for procedures in individuals with PKAN should be indicated only when absolutely required. Drugs with D2 antagonist activity should be avoided because of their capability to cause acute and tardive dystonia. An early multidisciplinary rehabilitation program is recommended.
Hogarth et al. recommend against a ketogenic diet and a low iron diet. The same study recommends stopping the vitamin B5 (pantothenate) for patients perceiving no benefit from vitamin supplementation.
There is a substantial interest in deep brain stimulation (DBS) for PKAN patients' treatment. In some patients, DBS can have a favorable effect on motor aspect of disease., According to our personal data, DBS improves patients' quality of life, mobility, and symptoms severity. Three out of our five patients had beneficial effects of the GPi-DBS over up to 36 months of follow-up. Two patients who had not reached significant improvement had longer disease duration; therefore, it might be reasonable to recommend GPi-DBS as soon as dystonia becomes disabling
Siudeja et al. showed in a Drosophila model for PKAN that levels of CoA were remarkably decreased and strongly linked to the neurodegenerative phenotype. Their data imply that compounds capable of restoring CoA levels or protein acetylation levels (or their combination) can be used as starting points for development of potential therapies for PKAN.,, Zano et al. published a paper regarding possibility to correct genetic deficiency in pantothenate kinase 1 using phosphopantothenate replacement therapy. It has been also revealed in the Drosophila dPANK/fbl mutants that panthethine, a precursor of CoA, is able to rescue brain degeneration, mitochondrial dysfunction, and locomotor disabilities even in the presence of severely reduced levels of functional pantothenate kinase.,
NBIA disorders related to lipid metabolism
Phospholipase-A2G6 (PLA2G6)-associated neurodegeneration (PLAN), NBIA type 2
Mutations in PLA2G6 gene located on chromosome 22q (17 exons) cause PLAN (NBIA type 2). The PLA2G6 gene plays a role in the synthesis of free fatty acids and lysophospholipids necessary for remodeling of membrane phospholipids, signal transduction, cell proliferation, and apoptosis. Thus, protein dysfunction may result in abnormal lipid composition of the plasma membrane, vesicles, or endosomes.,,
Similar to PKAN an age-dependent phenotype has been documented. PLA2G6-associated diseases could be manifested typically as infantile neuroaxonal dystrophy (INAD) (progressive motor and mental retardation, cerebellar ataxia, marked truncal hypotonia, pyramidal signs, and early visual disturbances due to optic atrophy), atypical neuroaxonal dystrophy (aNAD) (subacute onset of dystonia-parkinsonism combined with pyramidal, signs, eye movement abnormalities, cognitive decline, and psychiatric features) and PLA2G6-related dystonia-parkinsonism with late onset in adults responsive to levodopa with the early development of dyskinesias (PARK14). Cerebellar signs and sensory abnormalities, which are often prominent in the early childhood variant, are absent [Table 1].
Not all INAD patients have signs of iron accumulation in early disease stages but usually develop these later in the disease course., The signal abnormality differs from the eye-of-the-tiger sign in PKAN because central hyperintensity is absent. In late-onset cases iron may be lacking and MRI may even be completely normal. Neuroimaging also shows cerebellar atrophy occurring in the early stages of INAD, but not with late-onset disease [Table 2]. Iron deposits in SN were present in atypical cases.
Neuroaxonal dystrophy and alpha-synuclein pathology with Lewy bodies and Lewy neurites were detected in all postmortem examined cases, while tau pathology was present in some cases., Levodopa responsivenes of parkinsonian features is in line with presence of Lewy body pathology in these disorders.
Fatty-acid 2-hydroxylase-associated neurodegeneration (FAHN)
Similar to PKAN and PLAN, the metabolic pathway of FAHN involves the lipids and ceramides.
FAHN is caused by autosomal recessive mutations in the gene encoding for fatty acid 2-hydroxylase (FA2H). However, mutation in FA2H may result in variable clinical phenotypes including familial leukodystrophy, spastic paraparesis or NBIA with predominant dystonia.,, FAHN is clinicaly characterized by childhood-onset gait impairment, spastic quadriparesis, severe ataxia and dystonia. Seizures and divergent strabismus may also be present [Table 1].
MRI showed severe changes of the white matter, cerebellar atrophy, and thin corpus callosum, bilateral GP T2 hypointensity consistent with iron deposition, prominent pontocerebellar atrophy, and mild cortical atrophy [Table 2].
Mitochondrial protein associated neurodegeneration (MPAN)
MPAN is the third most common type of NBIA, accounting for 6-10% of NBIA cases. Exact MPAN gene function is not known; it is expressed mainly in mitochondria and is co-regulated with genes involved in fatty acid metabolism. It is characterised childhood-onset dysarthria and gait difficulty, followed by the development of spastic paraparesis, extrapyramidal features (dystonia and parkinsonism), neuropathy, optic atrophy and psychiatric symptoms.,
Compared to PKAN, MPAN onset is later and psychomotor regression is more gradual. A slowly progressive gait disorder and cognitive impairment constitute the main features of MPAN. Schulte et al. reported that their patients had progressive psychomotor deterioration, gait impairment, clumsiness, dysarthria, and progressive cognitive deficits. Retinitis pigmentosa, commonly observed in PKAN, was not found. Instead, bilateral atrophy of the optic nerve was present [Table 1].
Iron deposition is present in the GP and SN. In contrast to other subtypes of NBIA, all individuals showed T2 hypointensity of the SN and additional T1 hyperintensity of the caudate nucleus and putamen. In the most severely affected individuals, additional frontotemporal atrophy was present similar to subjects with PLAN., Hyperintense streaking of the medial medullary lamina between the globus pallidus interna and externa (which may resemble the eye of the tiger sign) was found in 20% of patients [Table 2].
Lewy body-like inclusions and tau-positive inclusions were present in various regions of the brain.
NBIA disorders related to iron homeostasis
In diseases caused by mutations that code for proteins directly related to iron metabolism, an early and massive iron deposition is present in the striatum, thalamus, dentate nuclei, and cerebral cortex. Initially, there are good compensatory mechanisms to fight against the iron-induced lesions in the brain. Clinical symptoms begin later, suggesting the toxic effect of iron, which is the principal cause of neurodegeneration.
NFP results from the autosomal dominant mutations in the ferritin light-polypeptide gene. Ferritin is a ubiquitously expressed cytoplasmic iron-storage protein and a source of iron in all cells. Damaged ferritin assembly results in the loss of iron storage capacity within brain cells and subsequent iron-mediated cell injury. Diagnosis is based on the presence of a low serum ferritin level (usually ≤20 μg/dL) and typical iron deposits in the GP, caudate, SN, red nuclei, and putamen. MRI findings are pathognomonic; along with T2 hyperintensive changes in the BG, there are cystic changes, gliosis, and edema in the BG and GP [Table 2].
NFP usually manifests in midlife with psychiatric symptoms (psychosis, anxiety, and depression), frontal lobe dysfunction, dystonia, choreoathetosis, rigidity and spasticity [Table 1]. Extrapyramidal features are similar to those in Huntington's disease or neuroacanthocytosis.
aCP is caused by an autosomal recessive mutation in the ceruloplasmin gene on chromosome 3q, which leads to considerable iron accumulation. Ceruloplasmin plays an essential role in the mobilization of iron from tissues through its ferroxidase activity and carries 95% of plasma copper. Extreme malfunction of ceruloplasmin gives rise to the iron accumulation in the liver, pancreas, retina, BG, thalamus, cerebellum and cerebral cortex. Neurodegeneration may be followed by retinal degeneration.
The classical triad of aCP include young-adult onset diabetes mellitus, retinal degeneration and various neurological symptoms including prominent extrapyramidal features, cognitive impairment and cerebellar ataxia [Table 1]. McNeill et al. reported cognitive impairment (42%) craniofacial dyskinesia (28%), cerebellar ataxia (46%), and retinal degeneration (75%) in their cohort.
Laboratory findings show undetectable ceruloplasmin in the serum, low levels of serum copper and iron and 3- to 40-fold elevated serum ferritin.
Neuroimaging features have been in accordance with pathological iron deposition in BG, thalami, dentate nuclei, and cerebral and cerebellar cortices [Table 2], but also within the retina, pancreas, and liver.
Some studies have reported positive results of treating aceruloplasminemia with iron-chelating agents such as desferrioxamine mesylate and deferasirox.
Other disease with brain iron accumulation
Kufor–Rakeb Disease (PARK9), NBIA type 3
Kufor–Rakeb disease (KRD), a rare autosomal recessive neurodegenerative disease originally described in a consanguineous Jordanian family, results from mutations in the ATP13A2 gene on chromosome 1p.
The clinical phenotype of KRD comprises adult-onset parkinsonism, with pyramidal tract signs. Eye movement abnormalities with incomplete supranuclear up-gaze palsy can be a clue to diagnosis. Slowing of vertical and horizontal saccades and saccadic pursuit has also been described. Cognitive features include visual hallucinations and dementia [Table 1].,, Parkinsonism in KRD is levodopa responsive, with early development of levodopa-induced dyskinesias.
Brain CT and MRI show diffuse moderate cerebral and cerebellar atrophy [Table 2]. Dopamine transporter imaging showed a marked bilateral symmetrical reduction of striatal activity.
Conclusion. NBIA diagnosis is often delayed due to low awareness and broad clinical phenotype. A number of novel NBIA subtypes has been recognized in the past decade suggesting that the clinical and genetic spectrum is still expanding. Neuroimaging is helpful for diagnosis and genetic testing should be done for diagnostic confirmation. In addition to medications that may provide symptomatic relief, multidisciplinary rehabilitation treatment is recommended. There is an increasing evidence that DBS may have a favorable outcome in selected PKAN patients. Ongoing efforts are directed toward a better understanding of molecular and pathophysiological mechanisms in NBIAs. This activity will eventually lead to development of molecules with disease-modifying potential.
Compliance with ethical standards
Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent: Informed consent was obtained from all individual participants included in the study.
Financial support and sponsorship
This work was supported by a grant of Ministry of Education, Science and Technological Development of the Republic of Serbia (ON 175090).
Conflicts of interest
Marina Svetel has received speaker's honoraria from Actavis. Vladimir Kostić has received research grants from the Ministry of Education, Science, and Technological Development, Republic of Serbia and the Serbian Academy of Science and Arts; and speaker honoraria from Actavis and Salveo. Igor Petrović has received speaker's honoraria from Boehringer Ingelheim, GSK, Roche. Aleksandra Tomić, Nataša Dragašević, Ivana Novaković, Iva Stanković and Nikola Kresojević declare no conflict of interest.
[Figure 1], [Figure 2]
[Table 1], [Table 2]