Tremor‐Dominant Pantothenate Kinase‐associated Neurodegeneration

Abstract

Neurodegeneration with brain iron accumulation (NBIA) includes a rare and heterogeneous group of disorders characterized by iron deposition in the basal ganglia. Pantothenate kinase‐associated neurodegeneration (PKAN) is the most common NBIA and has 2 main presentations: typical and atypical, the latter rarely presents with tremor. Our reported patients underwent full neurologic examination, standard brain magnetic imaging, and genetic testing for PKAN. Three patients who had “tremor‐dominant” PKAN with a relatively benign course were reported, including 1 with dystonic tremor and 2 with parkinsonian tremor. All 3 patients had homozygous mutations in the PANK2 gene and typical eye of the tiger sign on brain imaging. PKAN (and NBIA in general) may be a potential cause of tremor, thus emphasizing the need to consider this diagnosis even in patients with a clinical diagnosis of essential, dystonic, or parkinsonian tremor.

The term neurodegeneration with brain iron accumulation (NBIA) encompasses a heterogeneous group of disorders characterized by iron deposition in the brain, particularly in the basal ganglia. Pantothenate kinase‐associated neurodegeneration (PKAN), formerly known as Hallervorden‐Spatz disease, is the most common NBIA and has 2 main presentations. The typical form usually starts in the first decade of life with severe dystonia, dysarthria, parkinsonism, pyramidal signs, and cognitive and visual disturbances with an aggressive course, leading to death by the second decade of life. The “atypical” form is more heterogeneous, with different presentations, a slower progression, and a more benign course.1 There are few case series of atypical PKAN with tremor, either at rest or during action. Here, we report three cases of PKAN in patients who presented with relatively benign conditions, mainly characterized by tremor.

Case Series

Case 1

A 38‐year‐old woman came to our attention with a 26‐year history of arm and leg tremor and dysarthria. The presenting symptom was right hand action tremor, which then spread to the rest of the body. Different medications (including amantadine, gabapentin, clozapine, biperiden, clonazepam, and propranolol) were tried without significant improvement. On neurologic examination, she had a mild and very slow resting tremor and a severe and irregular postural tremor with higher frequency; tremor affected both hands, greater on the right. Dystonic posturing of the hands was also visible (Video S1). There was no kinetic tremor or dysmetria, and she was without hypokinesia, rigidity, or pyramidal signs. Cognitive function was normal, and no retinal or visual problems were detected. Her cousin was also diagnosed with PKAN, which presented with generalized dystonia and severe dysarthria. A brain magnetic resonance image (MRI) revealed the typical eye of the tiger sign (Fig. 1A), and the genetic analysis detected a homozygous disease causing mutation in the PANK2 gene (c.1208A>T, p.Asp403Val).

Figure 1.

A, B, and C show axial brain magnetic resonance images with typical eye of the tiger sign in Patients 1, 2, and 3, respectively.

Case 2

A 30‐year‐old man was referred to our clinic because of resting tremor of the right hand that had started 6 years earlier. Gradually, the tremor increased in severity, partially responded to levodopa (l‐dopa), and was followed by slowing of movements and dysarthria. On neurologic examination, he also had monotonic and hypophonic speech, hypokinesia, and limb rigidity, which was greater on the right (Video S2). There were no pyramidal or cerebellar signs. Right arm swing was decreased while walking. Brain MRI disclosed the typical eye of the tiger sign (Fig. 1B), and a genetic study detected a pathogenic homozygous mutation in the PANK2 gene (c.G833T, p.Arg278Leu).

Case 3

A 25‐year‐old man came to our attention with a 3‐year history of resting tremor that exclusively affected his legs. At onset, tremor was only present on the right, and it gradually spread to the other leg. There was no tremor in the upper limbs or other symptoms. The patient's younger brother had a similar problem. On neurologic examination, there was tremor at rest in both legs without rigidity or hypokinesia (Video S3). Deep tendon reflexes were brisk in his lower limbs, with bilateral flexor plantar responses. His brain MRI showed the typical eye of the tiger sign (Fig. 1C), and the genetic analysis detected a homozygous disease causing mutation in the PANK2 gene (c.1583C>T, p.Thr528Met).

Discussion

We have presented 3 cases of “tremor‐dominant” PKAN, which were classifiable from a phenomenological standpoint as dystonic tremor in 1 patient (Case 1) and as parkinsonian tremor at rest in the remaining 2 patients (Cases 2 and 3). Lee et al., in a small case series from an Asian population, demonstrated that tremor was more prevalent in atypical forms of PKAN compared with classic cases (10 out of 12 patients with atypical PKAN had tremor compared with 2 of 9 patients who had classic PKAN).2

This is in contrast to the case series reported by Thomas and colleagues, who indicated that there was no difference in the prevalence of tremor between typical and atypical cases of PKAN (2 out of 6 and 2 out of 4 patients had tremor, respectively).3

In keeping with what we observed in our Case 1, some of these patients presented with an action tremor that initially were misdiagnosed as essential tremor (ET) but subsequently had features of dystonic tremor (jerky in nature and associated with dystonia).4 Yamashita and colleagues described a 24‐year‐old woman with PKAN whose first symptom was postural tremor of the right hand that was initially diagnosed as ET. Later on, she developed left hand tremor, spasticity, and mild ataxia; the eye of the tiger sign on brain MRI resulted in a diagnosis of PKAN, which was genetically confirmed.4 Liang et al. described a 53‐year‐old man with PANK2 mutations who had presented 28 years earlier with action “ET‐like” tremor affecting both hands.5 Aggarwal and coworkers reported a genetically proven case of PKAN in a patient who presented at age 37 years with unilateral, jerky action tremor of the right arm and dystonic posture.6

In other cases, the combination of a dystonic tremor with parkinsonian features that partly responded to l‐dopa was reported. Yoon et al. reported a 55‐year‐old Korean man with a 15‐year history of postural and kinetic tremor of the right hand who had a partial response to l‐dopa.7 In another report, Seo and colleagues described a 45‐year‐old patient who had PKAN with a 10‐year history of postural tremor, which affected both hands and his tongue, and with parkinsonian symptoms that did not respond to l‐dopa, although his tremor improved with dopamine agonists.8 Finally, Zhang and colleagues reported a 27‐year‐old patient with PKAN whose problem started at age 17 years with writing tremor, followed by overt dystonia and parkinsonian resting tremor of both hands with hypokinesia and rigidity9 (Table S1).

Our Cases 2 and 3 are characterized by a more pure form of parkinsonian tremor without dystonia or other signs, such as ataxia or spasticity. To our knowledge, this mild form, resembling “tremor‐dominant Parkinson's disease,” has never been reported in patients with PKAN. However, this phenotype has been reported in 2 patients who had NBIA with unilateral resting tremor and parkinsonian features but did not carry PANK2 mutations.6 Table S1 summarizes the reported tremor cases in patients with PKAN as well as our patients’ clinical features.

In conclusion, we have presented 3 cases of PKAN mainly characterized by different types of tremor. Despite the variable prevalence of tremor in typical and atypical forms of PKAN in different nations, clinicians should be aware that PKAN (and NBIA in general) may be a potential cause of tremor; this is especially the case in younger patients, although a broad range of onset is possible, emphasizing the need to consider the diagnosis even in older patients, in whom ET and other causes of parkinsonism are more likely. Clinical red flags for the form with dystonic tremor are a diagnosis of “asymmetric or unilateral ET” associated with dystonia, ataxia, or spasticity. In contrast, it may be more difficult to differentiate some of these cases from tremor‐dominant Parkinson's disease, especially at onset. This further emphasizes the need to obtain a brain MRI in patients with tremor, especially gradient‐echo or T2* sequences, because the occurrence of iron deposition, with or without the eye of the tiger sign, might guide clinicians toward a diagnosis of NBIA and prompt the execution of appropriate genetic testing.

Author Roles

1. Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript preparation: A. Writing the First Draft, B. Review and Critique.

M.R.: 1A, 1C, 3A

G.S.: 3B

A.A.: 1C, 3B

A.E.L.: 3B

N.Y.: 1C

S.R.: 1C

A.F.: 1A, 2A, 3A, 3B

Disclosures

Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflict of Interest: The authors report no sources of funding and no conflicts of interest.

Financial Disclosures for the previous 12 months: The authors report no sources of funding and no conflicts of interest.

Supporting information

A video accompanying this article is available in the supporting information here.

Table S1. Clinical features and genetic analysis of some reported PKAN patients with tremor

Video S1. The video shows a mild and slow resting tremor and a prominent and irregular postural tremor with higher frequency in both hands that is greater on the right side. There is also obvious posturing of the hands.

Video S2. The video shows tremor at rest of the right hand, hypokinesia of both upper limbs, and masked face.

Video S3. The video shows tremor at rest of the legs, which is greater on the left side.