Background: Progressive ataxia and palatal tremor (PAPT) can be observed in both acquired brainstem or cerebellar lesions and genetic disorders.
Phenomenology shown: PAPT due to mutation in POLG, the gene encoding the mitochondrial DNA polymerase.
Educational value: POLG mutation should be considered in patients with PAPT, particularly when additional clues such as a sensory neuronopathy or an ophthalmoplegia are present.
We show a 43-year-old Finnish patient with a 2-year history of progressive ataxia and palatal tremor (PAPT). In addition to the palatal tremor, examination found a cerebellar syndrome with mild gait ataxia, ataxic dysarthria and limb dysmetria (Video 1). The patient had no nystagmus. She had a slight limitation of movements of both eyes in all directions. Ankle jerks were absent and vibration sense was reduced in the lower limbs. Electrophysiological assessment was consistent with a sensory neuronopathy. Brain magnetic resonance imaging showed mild cerebellar atrophy and bilateral hypertrophy of the inferior olivary nuclei with hyperintensity on T2-weighted images. There was no signal change in the cerebellum or the basal ganglia.
Molecular analysis found a homozygous W748S mutation in POLG, the gene encoding the mitochondrial DNA polymerase. This pathogenic mutation has a high carrier frequency in Finland, and all chromosomes with this mutation are likely to originate from a single common ancient founder in populations of European descent.1
PAPT is a rare syndrome characterized by the combination of a low-frequency palatal tremor and a cerebellar disorder that gradually worsens. Although its cause remains undetermined in most patients, PAPT has been linked to both acquired brainstem or cerebellar lesions and genetic disorders, including Alexander’s disease and mitochondrial disorders.2 In our patient, PAPT was the initial manifestation of the disorder, as recently reported in another patient with POLG mutation.3
POLG mutation is a highly pleomorphic disease. The most frequent manifestations are ptosis, ophthalmoplegia, limb muscle weakness, features of sensory neuropathy, cerebellar syndrome, hyperkinetic movement disorders (dystonia, myoclonus, tremor, or chorea), epilepsy, cognitive and psychiatric disturbances, and hypoacusia. The combination of muscle involvement and multiple neurological disorders is a good clue to the diagnosis.4 When present, sensory neuronopathy is strongly suggestive of POLG mutation in this setting.
Our observation further illustrates that a wide range of phenotypes can reveal POLG mutations and provides a demonstrative video of this rare clinical picture. POLG mutation should be considered in patients with PAPT, particularly when additional clues such as a sensory neuronopathy or an ophthalmoplegia are present.
1 Funding: Dr Mongin received a research grant from the FRM (Fondation pour la Recherche Médicale), and received travel funding from ANAINF, JNLF. Dr Delorme received a research grant from ARS, and travel funding from JNLF, Movement Disorders Society and Dystonia Europe. Dr Roze received research support from CNRS, INSERM (COSSEC), AP-HP (DRC-PHRC), Fondation pour la Recherche sur le Cerveau (FRC), the Dystonia Coalition (Pilot project), Merz-Pharma, Orkyn, IP santé, Ultragenix. Dr Roze received travel funding from Teva, Genzyme, the Dystonia Coalition, the Movement Disorders Society, the World Federation of Neurology Association of Parkinsonism and Related Disorders, International Federation of Clinical Neurophysiology.
2 Financial Disclosures: Dr Lenglet is consulting for LFB biomedicaments. Dr Roze served on scientific advisory boards for Orkyn, Ipsen, Ultragenix and Merz-pharma and received speech honorarium from Orkyn Merz-Pharma and Ultragenix.
3 Conflicts of Interest: The authors report no conflict of interest.
4 Ethics Statements: All patients that appear on video have provided written informed consent; authorization for the videotaping and for publication of the videotape was provided.
We thank Marta Ruiz and Arlette Welaratne for their help in preparing the manuscript.
Hakonen, AH Heiskanen, S Juvonen, V et al. (2005). Mitochondrial DNA polymerase W748S mutation: a common cause of autosomal recessive ataxia with ancient European origin. Am J Hum Genet 77: 430–441. doi: 10.1086/444548. [PubMed]
Samuel, M, Torun, N, Tuite, PJ, Sharpe, JA and Lang, AE (2004). Progressive ataxia and palatal tremor (PAPT): clinical and MRI assessment with review of palatal tremors. Brain 127: 1252–1268. doi: 10.1093/brain/awh137. [PubMed]
Tchikviladzé, M Gilleron, M Maisonobe, T et al. (2015). A diagnostic flow chart for POLG-related diseases based on signs sensitivity and specificity. J Neurol Neurosurg Psychiatry 86: 646–654. doi: 10.1136/jnnp-2013-306799. [PubMed]