Neurodegeneration with Brain Iron Accumulation: Diagnosis and Management

Imaging findings in PKAN

MRI imaging in PKAN is distinctive enough to be diagnostic in most cases. T2 weighted sequences through the basal ganglia reveal the globus pallidus to be hypointense with an anteromedially-placed region of hyperintensity, the so-called “eye of the tiger” sign (Figure 2). The substantia nigra shows normal to mildly hypointense signal. Although these findings in an individual with characteristic signs on exam are highly predictive of the presence of PANK2 mutations, the finding is not absolutely sensitive or specific: rare mutation-positive cases are described in which there is no “eye of the tiger” on MRI [9,10]. Conversely, “eye of the tiger” mimics may be seen in MPAN, carbon monoxide poisoning survivors, multiple system atrophy, neuroferritinopathy, and other unknown diagnoses [11,12].

Pathology of PKAN

The pathology of PKAN is much more circumscribed than previously thought, being largely limited to the globus pallidus, in contrast to other forms of NBIA [13]. In gross section, the presence of iron is evidenced by a frankly rusty discoloration of the globus pallidus but not other structures; this is confirmed microscopically with iron-specific stains that reveal the iron to have a perivascular distribution. A central area of neuronal depletion and tissue rarefaction corresponds to the “eye of the tiger” seen on MRI. Two populations of ubiquitin-positive spheroids are seen. Larger pleiomorphic structures thought to represent degenerating “ghost” neurons are concentrated in the globus pallidus but are also noted in the putamen and internal capsule. Smaller eosinophil structures represent the classic neuroaxonal spheroid seen in various forms of NBIA; these are sparsely located in the globus pallidus, corpus callosum and subcortical white matter and stain for amyloid precursor protein as well as ubiquitin.

Treatment considerations in PKAN

Currently, treatment is symptomatic. Dystonia and spasticity are usually managed with anticholinergics, benzodiazepines and other anti-spasticity agents such as baclofen, which may be delivered intrathecally. Botulinum toxin injections can also provide targeted relief of dystonia and spasticity. Deep brain stimulation has shown promise, but studies are limited to individual case reports, small case series [14] and a retrospective study [15] which included non-PKAN cases, challenging the generalizability of the results. The ongoing involvement of physical, occupational and speech therapists can delay complications of disease.

One of the most challenging problems for the patient, family and clinician in PKAN is dystonic crisis or “dystonic storm”. This severe exacerbation of dystonia is seen mostly in children with classic disease and can be life-threatening. It can occur without an obvious precipitant, but the child should be screened for infection, fecal impaction, and occult fractures to be certain there is not a treatable cause. The torsional stress created by the severe dystonia of classic PKAN can result in occult fractures of long bones, especially in children who are no longer weight-bearing and may be osteopenic. The treatment of dystonic storm is very challenging; no controlled studies have been published but treatment strategies have been reviewed in two publications [16,17].

The contribution of iron accumulation to the core pathophysiology of the disease remains in question [18], but until that question is answered, iron chelation remains under investigation as a disease-modifying approach. A preliminary study of deferiprone, an iron chelator that readily crosses the blood-brain barrier, showed robust reduction of brain iron on brain MRI in PKAN patients, but no measurable benefit in clinical disease outcomes [19]. A double-blind, placebo-controlled international multicenter clinical trial is underway to more rigorously investigate the drug’s benefit (https://clinicaltrials.gov/ct2/show/NCT01741532?term=deferiprone+PKAN&rank=1). A rational therapeutic approach aimed at bypassing the enzymatic defect with a novel compound is also under investigation.

Imaging findings in PLAN

Cerebellar atrophy is the most common neuroimaging finding in both INAD and aNAD. It is present in the majority of patients even when imaged early in disease, and in virtually 100% of well-established INAD cases. It is an important clue to the diagnosis in a child undergoing workup for psychomotor regression. Additional features seen on MRI include diffuse T2 white matter hyperintensities, and thinning of the corpus callosum and optic chiasma. The imaging of late-onset PLAN is more variable in its features: cerebellar atrophy is inconsistently present though cerebral volume loss may be evident, especially later in the disease. In all forms of PLAN, iron accumulation, manifesting as T2 hypointensity, may be absent or subtle early in the disease course and may never become evident in INAD and aNAD; susceptibility weighted imaging (SWI) may reveal iron not apparent on standard T2 sequences. Iron is generally evident in the globus pallidus on MRI imaging in late-onset patients presenting with clear-cut motor signs of dystonia and parkinsonism (Figure 2).

Pathology of PLAN

Pathologic studies are limited to case reports and small case series. Consistent with the MRI findings during life, cerebellar and cortical atrophy may be observed on gross pathology, with widespread neuronal loss and gliosis evident microscopically. Dystrophic axonal spheroids, historically the hallmark diagnostic finding, are seen as eosinophilc swellings in peripheral nerves, spinal cord, brainstem and basal ganglia. A more recently recognized pathologic feature of PLAN is the prominent Lewy body pathology involving the basal ganglia and neocortex, particularly striking in disease of later onset and longer duration. Tau pathology may also be observed with hyperphosphorylated neurofibrillary tangles and neuropil threads [23,24].

Treatment considerations in PLAN

Like other forms of NBIA, treatment of PLAN is geared towards relief of symptoms and prevention of complications. Standard medications to treat seizures, spasticity, dystonia, and parkinsonism are employed, though treatment with levodopa of adult-onset dystonia-parkinsonism is complicated by early motor fluctuations and exacerbation of neuropsychiatric symptoms. Physiotherapy early in INAD/aNAD may delay or prevent contractures. Gastrostomy tube placement supports nutritional status as the disease advances.

Prospects for treatment are perhaps more immediate in PLAN than in some other forms of NBIA, in part because mouse models recapitulate important aspects of the disease, providing a mechanism to test rational therapeutics. Although no clinical trials are yet underway, mouse studies have revealed reduced incorporation of docosahexanoic acid into the mutant mouse brain using novel imaging techniques [25–27], as well as derangements in calcium signaling [28], suggesting future directions for both imaging biomarker development and therapeutics. Perhaps most encouraging, a “proof of concept” study testing a gene therapy approach is underway in the mouse model [29].

Clinical findings in MPAN

Mitochondrial membrane protein-associated neurodegeneration typically presents in the first decade of life, but may also have its onset in early adulthood. In childhood, development of a spastic gait with extensor plantar responses is typically the earliest sign, commonly accompanied by optic atrophy, learning difficulties, dysarthria, and sometimes behavioral and psychiatric features. Dystonia, when present, tends to be limited to the feet and hands. The initial presentation in adulthood is more variable, but typically manifests with cognitive and behavioral changes, parkinsonism and mixed gait disorders [30,31].

Generally, the disease progresses slowly, and most individuals with childhood onset survive into their 20s or beyond. However, some individuals may exhibit rapid and terminal progression, either immediately following the onset of disease or after a period of slow decline. Interestingly, the literature and our own experience suggest that this occurs primarily in adult-onset patients [31,32]. This is in contrast to PKAN and PLAN, where rapid progression is associated with childhood-onset disease.

As the disease progresses, lower motor neuron signs may emerge, particularly in childhood-onset patients. Clinically, this manifests as loss of deep tendon reflexes, muscle weakness and sometimes atrophy; electrophysiologically, as a motor neuronopathy/axonopathy [31,33–35]. The combination of upper and lower motor neuron findings may raise the question of amyotrophic lateral sclerosis [35,36]. Cognitive decline appears to be universal in MPAN, sometimes accompanied by disabling psychiatric features; most patients are overtly demented by mid-stage disease. Bowel and bladder incontinence are common; it is not clear whether this is due to an autonomic neuronopathy or simply a non-specific feature associated with progressive dementia. Dysphagia is also common later in disease; this may lead to aspiration pneumonia.

Imaging findings in MPAN

Pallidal and nigral iron accumulation is evident on brain MRI on T2 and GRE sequences, variably accompanied in some patients by hyperintense streaking of the globus pallidus in the region of the medial medullary lamina (Figure 2). This may be interpreted as an “eye of the tiger” leading to an erroneous radiologic diagnosis of PKAN. Cortical and cerebellar atrophy may be seen in more advanced disease, and T1 hyperintensity in the caudate and putamen has been reported [31,35,37].

Pathology of MPAN

Pathologically, MPAN is a synucleinopathy, exhibiting a remarkable burden of Lewy bodies and Lewy neurites not only in the basal ganglia but also in the neocortex [31]. Cortical Lewy body pathology in MPAN exceeds that seen in sporadic Parkinson disease by 40-fold. Even Lewy body dementia, the archetypal cortical Lewy body disease, does not rival MPAN in this regard. Axonal spheroids, thought to represent dying neurons, are seen both peripherally and centrally. Iron deposits are seen in the globus pallidus and to a lesser extent in the substantia nigra; little or no iron is seen in the cortex. Neuronal loss and gliosis are especially prominent in the substantia nigra.

Treatment considerations in MPAN

Like all NBIAs, treatment is symptomatic. Anti-spasticity agents such as baclofen may be helpful and allow patients to maintain ambulation for a longer period. Trihexyphenidyl may provide relief when dystonia is problematic. Even when parkinsonism dominates the motor dysfunction, dopaminergic compounds seem to offer only modest relief at best, and may precipitate adverse neuropsychiatric effects; dopamine agonists in particular should be used with caution. There are no reports of deep brain stimulation in MPAN, but the prominent cognitive decline in the disease would strongly argue against its use. Treatment of bladder incontinence ideally should be guided by urodynamic studies and may need to be reassessed as the disease progresses, particularly if patients develop prominent lower motor neuron signs when urinary retention and overflow incontinence may replace a hyperactive detrusor. Standard bowel regimens may lessen the risks of impaction and fecal incontinence. A gastrostomy tube may maintain nutritional status and prolong life as dysphagia progresses.

When present, psychiatric features such as emotional lability, agitation, hallucinations, and compulsive behaviors can be particularly challenging for families. The close involvement of a psychiatrist familiar with treating cognitively-impaired patients is ideal. For patients with neuropsychiatric complications and prominent parkinsonism in particular, the choice of antipsychotic agent must be made with care and dosed cautiously.

Clinical features of BPAN

The child with BPAN may initially appear normal, but it quickly becomes apparent that developmental milestones are not being attained on schedule. Motor milestones are delayed: the child may exhibit toe walking or a broad-based, ataxic gait. Intellectual disability is marked: little expressive language is acquired, with most children attaining only a few spoken words. Seizures are common, and may represent a major source of morbidity for the child with BPAN. On one end of the spectrum is the child who has only one or two seizures during childhood, none at all, or only febrile seizures; these children may require no treatment with anti-epileptic drugs. Other children, however, exhibit a picture of a severe syndromic epilepsy, with multiple seizure types present (partial complex, generalized tonic-clonic, atonic and/or myoclonic) that may be refractory to therapy. Some children exhibit sleep disorders, including hypersomnolence, hyposomnolence, shortened sleep latency, and abnormal rapid eye movement sleep. The presence of hand stereotypies in some children with BPAN, along with marked abnormalities in language development, disordered sleep, and seizures may have earned them a diagnosis of “atypical Rett syndrome” before mutations in WDR45 are found.

Children with BPAN make slow developmental gains in childhood, though remaining far behind their developmentally-normal peers. During the teenage years or early adulthood, signs of parkinsonism emerge, sometimes fairly precipitously. The posture becomes stooped, movements slow, and the gait changes, with shortened step length and freezing. While these symptoms are responsive to dopaminergic medications, sometimes robustly so, the benefit tends to be short-lived, with brittle levodopa-induced dyskinesias or dystonia quickly complicating management. In addition to the motor signs, a progressive decline in cognitive function becomes evident and previously-learned skills are lost. Challenging new behaviors may appear, often exacerbated by dopaminergic drugs. Though the decline may be gradual, eventually all patients lose ambulatory ability and become profoundly demented.

Imaging of BPAN

Imaging in early childhood is typically unremarkable. Later in the course, particularly as parkinsonism becomes evident on exam and prompts further diagnostic studies, a characteristic pattern appears on MR imaging. On T2 sequences, the globus pallidus, substantia nigra and cerebral peduncles become hypointense consistent with iron accumulation in these structures; these findings are more apparent and seen earlier in the disease with the use of iron-sensitive sequences such as T2* and susceptibility-weighted imaging. The hypointensity is most pronounced in the substantia nigra where it appears as a discrete linear streak. This same area on T1 sequences is surrounded by a hyperintense “halo” extending to the cerebral peduncles, thought to represent neuromelanin release from degenerating neurons (Figure 2) [38,43,44]. Derangements in white matter architecture and impaired pallidal and nigral metabolism have been demonstrated in a single adult BPAN case using diffusion tensor imaging and MR spectroscopy [44]. Other findings that may be seen on MRI include thinning of the corpus callosum, cerebellar atrophy and more global atrophy as the disease advances [38,40].

Pathology of BPAN

Grossly, cerebellar atrophy and thinning of the cerebral penduncles is apparent [38]. The iron accumulation can be seen in the unstained brain as a rusty discoloration in the substantia nigra. The iron is much less prominent in the unstained globus pallidus, but both structures show strong reaction when treated with iron-specific stains such as Prussian blue. Despite the prominent parkinsonism seen clinically, BPAN does not demonstrate the α-synuclein pathology seen in idiopathic Parkinson disease; rather, tau positive neurofibrillary tangles are seen in the cortex, putamen, hippocampus and hypothalamus. Axonal spheroids, a pathologic feature representing dying neurons and common to many forms of NBIA, are readily seen in the substantia nigra and globus pallidus, as well as in the medulla, pons and thalamus.

Treatment considerations in BPAN

As the most recent form of NBIA to be characterized, we are only just starting to understand the phenotypic spectrum of BPAN and define optimal approaches to management. In childhood, the most challenging problem is refractory seizures. Although only present in a minority, these BPAN patients should have the close involvement of a pediatric specialist experienced in the management of severe syndromic epilepsies. In adulthood, the parkinsonism can be treated successfully with dopaminergic medications, although as mentioned, motor fluctuations and dyskinesias pose problems and the drug benefit is not durable. Dopamine agonists might be predicted to have adverse neuropsychiatric effects in BPAN where cognitive impairment is a prominent part of the phenotype [45]; however, we have not seen that in our own clinic.

Preliminary work to create a mouse model of BPAN is yielding promising results [46]. As we begin to understand the role of autophagy in the disorder, we anticipate the development of rational therapeutics targeting the underlying defect.

Our own observations of the phenotype in BPAN to date are based on a highly homogeneous cohort selected specifically for gene discovery efforts. As more patients are found earlier in childhood through whole exome sequencing, we expect to see greater phenotypic variability, particularly since timing of somatic mutation and X-inactivation patterns likely influence the phenotype.

Fatty acid hydroxylase-associated neurodegeneration (FAHN)

The FA2H gene product is responsible for hydroxylating fatty acids and plays a key role in myelin production in the central nervous system and possibly in cell cycle regulation [47]. Mutations in the gene were originally described as causing leukodystrophy and a complicated form of hereditary spastic paraplegia (HSP35) [48–50]. Subsequent investigations revealed the presence of pallidal T2 hypointensities in some patients harboring FA2H mutations and led to fatty acid hydroxylase-associated neurodegeneration’s (FAHN’s) designation as a subtype of NBIA [51]. The disease usually presents in the first decade of life with gait difficulties and falling. Progressive spasticity, dystonia and cerebellar dysfunction contribute to disability, leading to loss of ambulation in many cases, along with dysarthria and dysphagia. Optic atrophy is frequently present on exam, with variable degrees of accompanying visual impairment. Most children exhibit progressive cognitive decline; seizures are less consistently a feature. An axonal neuropathy has been described in one family [52]; further study is needed to see if this is a consistent part of the phenotype. In addition to evidence of iron accumulation in the globus pallidus (which is not always present), MR imaging of the brain reveals T2-bright white matter lesions, thinning of the corpus callosum, and progressive atrophy of cerebellum, pons, medulla and cord [53].

Many of FAHN’s clinical features mirror those of INAD/aNAD; thus, a child suspected of having PLAN but without mutations in PLA2G6 should be tested for FAHN. Like other forms of NBIA, the phenotypic spectrum of the disease is expected to broaden as more patients are discovered through whole exome sequencing.

COASY protein-associated neurodegeneration (CoPAN)

COASY protein-associated neurodegeneration (CoPAN) joins PKAN as the second inborn error of coenzyme A metabolism. CoPAN manifests in the first decade of life with gait difficulties and mild cognitive impairment. Oromandibular dystonia, dysarthria, and progressive spasticity follow, along with the appearance of an axonal neuropathy. The emergence of parkinsonism further adds to the disability. MRI demonstrates non-homogenous T2 pallidal hypointensity with a region of medial hyperintensity that is reminiscent of the “eye of the tiger” sign seen in PKAN. Although only two families with CoPAN have been reported thus far [54], the discovery that mutations in the gene encoding Coenzyme A synthase (COASY) could cause a form of NBIA confirms the importance of the CoA pathway in neuronal health.

Neuroferritinopathy

Mutations in the gene encoding ferritin light chain protein cause neuroferritinopathy, a dominantly-inherited syndrome of chorea, dystonia, parkinsonism, cognitive decline and low serum ferritin that typically presents in mid-life. A majority of the cases described in the literature are clustered geographically in the Cumbrian region of Britain and have a common 460insA mutation [55], suggesting a founder effect. Single families with private mutations and slightly different phenotypes have been described in Europe, North America, and Japan. Neuroferritinopathy can be distinguished from Huntington disease by its prominent action-induced orofacial dystonia, asymmetric presentation, late cognitive decline and by the presence of abnormal iron accumulation on brain MRI in the caudate, putamen, thalamus, globus pallidus, substantia nigra and red nucleus. Cystic change of the caudate and putamen occurs late in the disease [56,57]. Neuroferritinopathy differs from other forms of NBIA by its dominant inheritance pattern, uncommon presentation in childhood, and distinctive pattern of iron accumulation. Like aceruloplasminemia but distinct from most forms of NBIA, the pathophysiology of neuroferritinopathy explains the brain iron accumulation: the mutant protein disrupts the structure and iron-carrying capacity of ferritin, resulting in abnormal iron deposition in the brain.

Aceruloplasminemia

Aceruloplasminemia presents in adulthood and is characterized by microcytic anemia, diabetes, retinal disease, and a movement disorder consisting of facial dystonia, chorea, tremor, parkinsonism, ataxia, and cognitive decline [58,59]. In addition to anemia, laboratory investigations reveal low or absent serum ceruloplasmin, elevated ferritin, low iron, and low serum copper but normal urinary copper. Like neuroferritinopathy, it is a disorder of iron metabolism: mutations in the CP gene cause an absence of or reduction in the copper-carrying ceruloplasmin protein. This results in abnormal iron trafficking and deposition throughout the body, including the central nervous system. Iron chelation is routinely employed as a rational therapeutic, but while changes in iron deposition in peripheral organs and the brain can be demonstrated after several years of treatment, it is not clear whether this is accompanied by significant clinical improvement [60,61].

Woodhouse-Sakati syndrome

DCAF17 encodes a nucleolar protein thought to be involved in transcriptional regulation, and mutations in the gene result in an unusual syndrome of endocrine and neurologic abnormalities [62]. Affected individuals exhibit hypogonadism, diabetes mellitus, alopecia, abnormalities on electrocardiogram, extrapyramidal movement disorders, intellectual disability, and sensorineural healing loss [63,64]. MRI imaging reveals basal ganglia T2 hypointensities as well as white matter disease. Most of the described cases arise from a founder in the Saudi Arabian population, though affecteds of other ethnicities have been described [65].

Kufor-Rakeb syndrome

Kufor-Rakeb syndrome is a syndrome of juvenile-onset parkinsonism, spasticity, and cognitive decline originally described in a Jordanian family [66] and now described in multiple other ethnicities [67–71]. Variable clinical features include supranuclear gaze palsy, facial-finger-faucial mini myoclonus, and tremor. Generalized atrophy is a universal finding on brain MRI as the disease advances; basal ganglia iron may not be evident, especially early in disease. The parkinsonism is levodopa-responsive but, like MPAN and BPAN, management is complicated by the early development of motor fluctuations and dyskinesias. The disease is caused by mutations in the APT13A2 gene [72 encoding a lysosomal ATPase and is also known as PARK9.