Pantothenate Kinase-Associated Neurodegeneration Caused by PANK2 Mutations (NBIA type 1)

The most common among the NBIA disorders is pantothenate kinase-associated neurodegeneration (PKAN), due to mutations in the PANK2 gene. The worldwide prevalence has been estimated at 1 in 1,000,000. The classic presentation is relatively homogeneous, with onset usually before age 6 years of a gait disorder due to dystonia and rigidity of legs [2, 3]. Oromandibular dystonia is often prominent. Pigmentary retinal degeneration, often detected by electroretinography, is almost invariably present in classic PKAN [4]. There is a well-known correlation between the age of onset and the rate of disease progression. Onset may, however, also occur late, i.e. in early adulthood, as atypical late-onset PKAN. Here, cognitive decline and psychiatric features are often the leading symptoms whereas motor involvement tends to be less severe. Movement disorders often present as unilateral dystonic tremor or focal arm dystonia [2, 5–11].

PLA2G6-Associated Neurodegeneration Caused by PLA2G6 Mutations (NBIA Type 2)

The second core NBIA syndrome is PLA2G6-associated neurodegeneration (PLAN) due to PLA2G6 gene mutations (NBIA type 2). The classic form begins early, between 6 months and 2 years of age as infantile neuroaxonal dystrophy (INAD). Progressive motor deterioration often leads to spastic or hypotonic tetraparesis with marked truncal hypotonia. Optic atrophy causes vision impairment. Seizures may occur at later stages of the disease, and dystonia has been reported in patients with long disease duration [12]. Denervation on EMG and fast rhythms on EEG are the typical electrophysiological findings that may facilitate early diagnosis [13]. In patients with later disease onset the phenotype may be atypical (atypical neuroaxonal dystrophy) and includes dystonia–parkinsonism combined with pyramidal signs, cerebellar ataxia, eye movement abnormalities, cognitive decline, and psychiatric features. Parkinsonism is characterized by the presence of tremor, i.e. a typical pill-rolling resting tremor, rigidity, and severe bradykinesia with a good response to levodopa. The latter may be in line with the finding of Lewy body pathology [14–16]. Early development of dyskinesias occurs. Development of Parkinson disease in siblings with heterozygous PLA2G6 mutations has been reported.

Beta-Propeller Protein-Associated Neurodegeneration Caused by WDR45 Mutations

Mutations in WDR45 cause beta-propeller protein-associated neurodegeneration (BPAN). The clinical presentation was initially summarized under the term “static encephalopathy (of childhood) with neurodegeneration in adulthood” (SENDA syndrome) [17–19]. Onset is in early childhood, with developmental delay and intellectual disability, which remain relatively static until adulthood. In early adulthood, affected individuals usually develop sudden-onset progressive dystonia–parkinsonism and dementia. The clinical spectrum further includes seizures, ataxia, and behavioral problems that are often similar to autism spectrum disorder. Seizure types are diverse and include focal and generalized seizures (absence, tonic, atonic, tonic–clonic, and myoclonic), infantile spasms, and epileptic encephalopathies consistent with Lennox Gastaut syndrome. Overall, seizures tend to resolve or become less prominent with age, whereas cognitive decline and movement disorders (progressive parkinsonism and dystonia) emerge as characteristic findings. Additional features include eye movement abnormalities, sleep disorders, frontal release signs, and dysautonomia.

Mitochondrial Membrane Protein-Associated Neurodegeneration Caused by C19orf12 Mutations

Mutations in C19orf12 at chromosome 19q12 cause mitochondrial membrane protein-associated neurodegeneration (MPAN) [20]. Due to a founder effect, MPAN is more common in the Polish community. Onset is in childhood to early adulthood (age range 4–30 years), with a mean of 11 years. Spastic para- or tetraparesis with muscle atrophy are typical for MPAN. Dysarthria, parkinsonism, and dystonia are very common but not present in all cases. Optic atrophy, cognitive decline, and psychiatric symptoms may occur [20–27]. Notably, a mild phenotype resembling idiopathic Parkinson disease has been reported.

Other NBIA Genes (FA2H, ATP13A2, COASY, FTL1, CP, DCAF17, SCP2, and GTPBP2)

FA2H mutations were recently identified as another cause of NBIA, FAHN [28]. The clinical spectrum overlaps with leukodystrophies and the hereditary spastic paraplegias. The clinical phenotype of FAHN is characterized by childhood-onset gait impairment, spastic quadriparesis, severe ataxia, and dystonia. Seizures and divergent strabismus may also be present and overlap with the clinical features of PLAN.

Mutations in ATP13A2 located on chromosome 1p cause Kufor–Rakeb syndrome. The clinical phenotype comprises levodopa-sensitive parkinsonism, pyramidal-tract signs, eye movement abnormalities with incomplete supranuclear upgaze palsy, facial-faucial (i.e. tonsillar)-finger mini-myoclonus, autonomic dysfunction, psychiatric features, and dementia. Disease onset is usually in adolescence [29–31].

COASY-associated neurodegeneration (CoPAN) due to mutations in the coenzyme A (CoA) synthase (COASY) gene is a form of NBIA metabolically closely related to PKAN [32]. It also presents with early-onset gait difficulty and learning disabilities, followed in puberty by bradykinesia, generalized dystonia, and spastic–dystonic tetraparesis with distal areflexia due to motor axonal neuropathy. Notably, there is no retinopathy, in contrast to PKAN and some of the other NBIA syndromes.

Neuroferritinopathy due to FTL1 gene mutations is often thought of as one of the Huntington-like disorders because of adult-onset chorea, psychiatric features, and cognitive decline. Inheritance is autosomal-dominant. However, other features such as orolingual–mandibular dyskinesia, blepharospasm, cerebellar ataxia, and parkinsonism (even at onset) may be present. As in Huntington disease, pyramidal involvement is usually absent.

Aceruloplasminemia also presents in adulthood. Core neurological features are cognitive impairment, cerebellar ataxia, and craniofacial dyskinesia. Notably, a recent case series involving 55 cases revealed that diabetes was the first symptom in almost 70% of patients, manifesting at a median age of 38 years, often accompanied by microcytic or normocytic anemia. The combination preceded neurological symptoms in almost 90% of the neurologically symptomatic patients by more than ten years [33]. Ophthalmological examination often reveals peripheral retinal degeneration secondary to iron accumulation and photoreceptor cell loss. Systemic iron accumulation also leads to increased liver iron content (without cirrhosis).

Mutations in the DCAF17 gene cause Woodhouse–Sakati syndrome, a rare autosomal-recessive multisystem neuroendocrine disorder characterized by hypogonadism, childhood-onset hair thinning that often progresses to alopecia totalis, diabetes mellitus, deafness, cognitive decline, and extrapyramidal features. Seizures, polyneuropathy, thyroid dysfunction, keratoconus, and syndactyly of hands or feet may also be present [34]. Some 30 families have been described, mostly from Middle Eastern countries. Insulin-like growth factor 1 is usually low; ECG may be abnormal, albeit patients are usually asymptomatic.

Bi-allelic mutations in SCP2, encoding the peroxisomal enzyme sterol carrier protein x (SCPx), have recently been described to cause NBIA in two unrelated patients [35, 36] The first patient presented with torticollis and dystonic head tremor, mild cerebellar signs, hyposmia, and azoospermia with motor neuropathy, with onset in late childhood. The other presented with adult-onset spinocerebellar ataxia and deafness, with brain MRI characteristic of NBIA, in the absence of movement disorders or myopathy. Abnormal pristanic acid and phytanic acid levels may be a clue. Dietary therapy, similar to the diet recommended for Refsum disease, led to improvement.

Finally, there is a recent report of GTPBP2 mutations associated with NBIA [37] in a consanguineous family with three affected children. All had delayed early developmental milestones with moderate intellectual disability. Upon presentation at ages 34, 30, and 29 years, respectively, there was dystonia, mild to moderate ataxia, and autonomic dysfunction including skin thickening, mottling, and loss of hair on the legs. Investigations demonstrated chronic motor neuronopathy and abnormal electroretinography.

Imaging Findings in PKAN

MRI [42, 43] with appropriate iron sensitive T2*-weighted or SWI sequences detects the characteristic “eye of the tiger” sign, corresponding to a hyperintensity surrounded by an hypointense rim. The latter is produced by iron accumulation in the anterior-medial part of the globus pallidus, sometimes extending into the knee of the internal capsule, subthalamic nucleus, and substantia nigra [41, 44]. Additional calcifications in the basal ganglia have been described in some cases. As mentioned above, the development of the MRI alterations may be dynamic, in some preceding the development of clinical signs, or it may rarely be absent despite clinical signs in others [6, 41, 45, 46].

Using diffusion tensor imaging, increased fractional anisotropy along with abnormal mean diffusivity was demonstrated in the globus pallidus and substantia nigra of PKAN patients, probably due to iron deposits disturbing the local magnetic field [41, 47]. Proton MRS is not consistent but sometimes shows markedly decreased N-acetylaspartate in the globus pallidus, reflecting neuronal damage. Dopamine transporter single-photon emission CT imaging, a measure of striatal dopamine function, is generally normal in PKAN, although abnormal findings have been reported in line with the clinical experience that PKAN may manifest as parkinsonism. Cardiac ¹²³I-meta-iodobenzylguanidine imaging, which is used to assess postganglionic neuronal function of the sympathetic nervous system, was also normal in PKAN, in contrast to Parkinson disease and other Lewy body disorders, where uptake is typically reduced. Transcranial sonography demonstrates bilateral hyperechogenicity in the substantia nigra and lenticular nucleus. It was thus suggested that transcranial sonography may be used as an inexpensive and simple screening method for the diagnosis of NBIA disorders.

Imaging Findings in PLAN

Neuroimaging in the PLA2G6-associated form (PLAN, NBIA2) shows cerebellar atrophy occurring in the early stages of INAD, but this was absent in late-onset disease. Although half of INAD patients may lack signs of iron accumulation early in the disease course [13], they usually develop globus pallidus hypointensities reflecting iron as the disease progresses [12]. Notably, in contrast to the pattern seen in PKAN there is no central hyperintensity. Additional iron deposits in the substantia nigra may be present [14]. Contrary to PKAN, iron accumulation is not a universal feature of PLAN. Late-onset cases may lack signs of iron accumulation and MRI may even be completely normal. Others may show cortical atrophy or white matter changes. Thus, not all forms of PLA2G6-related neurodegeneration fall into the group of NBIA disorders but there is neuroradiological variability.

Imaging Findings in BPAN (WDR45-Associated NBIA)

Imaging features highly characteristic of BPAN are (a) iron deposition is more marked in the substantia nigra than in the globus pallidus in T2-weighted images, and (b) the hypointensity of the substantia nigra is surrounded by a halo of hyperintensity in T1-weighted images [17, 48]. Furthermore, cerebral and milder cerebellar atrophy may be seen.

Imaging Findings in MPAN (C19orf12-Associated NBIA)

In MPAN, iron deposition extends beyond the pallidal region involving the substantia nigra. Hyperintense streaking of the medial medullary lamina between the globus pallidus interna and externa (which may resemble the eye of the tiger sign) may be present in 20% of patients. Generalized brain atrophy or cerebellar atrophy may be present. Transcranial sonography in MPAN patients demonstrates bilateral hyperechogenicity of the lenticular nucleus in the absence of nigral abnormalities.

Imaging Findings in Other NBIA forms (FA2H, ATP13A2, COASY, FTL1, CP, and DCAF17)

In FAHN, MRI features include progressive leukoencephalopathy with cortical, cerebellar, and brainstem atrophy – in addition to pallidal iron accumulation. Not all patients with FAHN, however, show iron accumulation. Corpus callosum thinning may be a diagnostic clue.

Brain imaging in patients with Kufor–Rakeb syndrome may show diffuse moderate generalized atrophy, with iron accumulation affecting the putamen and sometimes the caudate.

Brain imaging in CoPAN revealed bilateral hyperintensity and swelling of the caudate nucleus, putamen, and thalamus. In addition, a thin corpus callosum and frontotemporal and parietal white matter changes have been described.

Hypointensities are more widespread in neuroferritinopathy. Here, iron deposition extends from the globus pallidus to the nigra, cortex, and other nuclei of the basal ganglia. In addition, cavitations depicted as low T1 and high T2 signals, sometimes surrounded by a rim of T2 hypointensity, are found. Scans may also show generalized cortical and, in some cases, cerebellar atrophy. Furthermore, pencil lining, reflecting pathological iron deposition in the periphery of the cortex and other gray matter structures may be a clue toward the diagnosis of neuroferritinopathy. Finally, imaging changes may also be present in asymptomatic gene mutation carriers.

Iron also accumulates widely in aceruloplasminemia, affecting the caudate nucleus, putamen and pallidum, and thalamus, as well as the red nucleus and dentate. Cerebellar atrophy may also be seen.

In Woodhouse–Sakati syndrome, MRI reveals variable abnormalities in periventricular white matter. In addition, iron deposition in the globus pallidus may, rarely, be present.

In SCP2-associated neurodegeneration, MRI brain showed bilateral hyperintense signals in the thalamus, butterfly-like lesions in the pons, and lesions in the occipital region, without gadolinium enhancement, in one patient. There was no iron in this case. However, the second patient showed mineral deposition in the basal ganglia on SWI sequences [35, 36].

In GTPBP2–associated neurodegeneration, brain MRI shows atrophy of the cerebellar vermis. SWI demonstrates abnormal signal (hypointensity) in the globus pallidus and substantia nigra suggestive of abnormal iron deposition [37].