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Palatal tremor and cognitive decline in neuroferritinopathy
  1. A J Wills1,
  2. G V Sawle1,
  3. P R Guilbert2,
  4. A R J Curtis3
  1. 1Department of Neurology, Queen's Medical Centre, Nottingham, UK
  2. 2Department of Clinical Genetics, Nottingham City Hospital
  3. 3Institute of Human Genetics, The International Centre for Life, Central Parkway, Newcastle upon Tyne, UK
  1. Correspondence to:
 Dr Wills;
 ade{at}wills99.swinternet.co.uk

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Neuroferritinopathy is a recently described autosomal dominant, adult onset, neurodegenerative disorder associated with iron accumulation, particularly in the basal ganglia.1 All patients found to date have a single adenine insertion between nucleotides 460 and 461 in exon 4 of the ferritin light chain gene. This results in a frame shift and is predicted to cause structural alteration of the polypeptide carboxy terminus. Magnetic resonance imaging of the brain shows iron accumulation, and this has been confirmed pathologically with the detection of numerous iron positive inclusions particularly in the globus pallidus. In spite of this, serum ferritin levels are found to be abnormally low or at the low end of the normal range. Patients tend to present in mid-life with a movement disorder, characterised by chorea, dystonia, and rigidity. In contrast with Hallervorden-Spatz syndrome, which is also associated with accumulation of brain iron, visual and cognitive function is preserved.

Here, we report a patient with genetically proven neuroferritinopathy in which the clinical features included cognitive decline and palatal tremor. These features extend the phenotype of this condition from those previously reported.

The patient was a 49 year old man who developed lingual and oral dyskinetic movements and a slurring dysarthria at the age of 37. Initially, the movement disorder was partially controlled with high dose anticholinergics but then progressed to involve his limbs. Over the next 10 years, he developed dysphagia, unsteadiness, and cognitive decline, particularly of frontal lobe function. His father, paternal uncle, and paternal grandmother had all developed a movement disorder in middle age. A diagnosis of Huntingdon's disease was made at that time and was assumed in the patient until disproved by a negative genetic test result. The family continued to seek diagnostic clarification to enable life planning for the patient's children.

On examination, he was alert and orientated. He scored 7/10 on a mini mental state examination. Detailed cognitive testing showed particular impairment of non-verbal abstract reasoning, with some word retrieval difficulties. He tended to perseverate, and his cognitive estimates were poor. He exhibited pout, palmomental, and grasp reflexes. He manifested appreciable oral, lingual, and facial dyskinesias. Eye movements were abnormal, with saccadic intrusion into pursuit and use of head thrust to initiate saccades. He had apraxia of eyelid opening. There was no evidence of a pigmentary retinopathy or Kayser-Fleischer rings, and the optic discs were normal. There was a palatal tremor at a frequency of 1 Hz. Examination of the limbs showed pronounced choreiform movements and dystonic posturing. There was no evidence of a peripheral neuropathy or myoclonus.

The following blood tests were normal or negative; full blood count and film, copper studies, creatine kinase levels, ferritin levels (60 μg/l, normal range 25–350 μg/l), liver function tests, and genetic tests for Huntington's disease (HD), dentatorubral pallidoluysian atrophy, and spinocerebellar ataxia 1–3, 6, and 7. Nerve conduction studies were normal. A muscle biopsy was normal. Cerebrospinal fluid analysis was normal, with no evidence of xanthochromia. Magnetic resonance imaging of the brain (fig 1) showed considerable hyperintensity, with a band of surrounding hypointensity on T2 weighting involving the putamen, pallidum, thalamus, substantia nigra, and dentate nucleus. The cerebral cortex was atrophic. A computed tomography scan showed no evidence of cerebral calcification.

Mindful of the clinical features, ferritin deposits, dominant inheritance, and family origin reported in neuroferritinopathy,1 further genetic testing confirmed the presence of the same A insertion at position 460–461 of the ferritin light chain gene. Investigation of genotypes at six polymorphic microsatellite markers close to the gene location on chromosome 19 showed sharing of one allele at each marker. Thus, it is likely that the patient potentially shares the disease associated haplotype with all affected individuals of the originally described families and is another example of inheritance of an initial founder event. Additional evidence comes from the northwest geographical origin of his family.

The differential diagnosis in this case initially included HD, neuroacanthocytosis, and Wilson's disease, but these conditions were excluded by appropriate investigations. Atypical Hallervorden-Spatz syndrome was also considered, particularly in the light of the appearances on brain imaging, but this condition is recessively inherited and associated with a defective pantothenate kinase gene (PANK2).2 Interestingly, our patient had significant cognitive impairment and palatal tremor in addition to the movement disorders so far described in patients with neuroferritinopathy. In other neurodegenerative disorders, particularly HD, the causative proteins may be involved in iron metabolism.3 Thus, cognitive impairment may be predicted to occur in neuroferritinopathy, especially in the presence of a pre-existing hyperkinetic movement disorder.4

The development of palatal tremor in our patient deserves further explanation. Palatal tremor (previously known as palatal myoclonus) may be classified as essential or symptomatic.5 It is thought that palatal tremor arises because of functional disruption in “Mollaret's triangle”, which consists of the inferior olivary nucleus, red and dentate nuclei. The symptomatic form is usually associated with hypertrophy of the inferior olivary nucleus and may arise from vascular lesions, particularly in the cerebellum.6 Further evidence for this hypothesis comes from a positron emission tomography study, which showed hypermetabolism in the inferior olivary nucleus.7 Most patients also have cerebellar ataxia. However, palatal tremor may also occur in other conditions including multiple system atrophy, progressive supranuclear palsy, and Alexander's disease.5 As in our case, symptomatic palatal tremor is not usually associated with ear clicking. Presumably, in our patient, iron deposition in the dentate nuclei was responsible for disruption of rubral and olivary pathways.

Ferritin is an iron storage protein and alteration in structure of the carboxy terminus could lead to the release of free iron and excessive oxidative stress.8 In other conditions, such as haemosiderosis, the use of iron chelators has been advocated as a potentially useful treatment. Results, in the main, have been disappointing. Whether free radical scavengers, such as idebenone,9 have useful therapeutic value in neuroferritinopathy remains to be seen.

Neuroferritinopathy should be considered in all patients with a hyperkinetic movement disorder, imaging evidence of iron deposition within the brain, and an autosomal dominant family history.

Figure 1

Magnetic resonance image of the brain showing hyperintensity with surrounding hypointensity on T2 weighting affecting the putamen, pallidum, and thalamus.

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