Clinico-Pathological Correlation in Progressive Ataxia and Palatal Tremor: A Novel Tauopathy

Abstract

Palatal tremor (PT) is an uncommon movement disorder that has been subdivided into essential and symptomatic forms. A distinct subgroup of the symptomatic form presents with progressive ataxia and PT. The histopathology of progressive ataxia and PT has not been previously determined. This study consisted of a clinical review, histopathology, and electron microscopy of the brain of a man with progressive ataxia and PT. The inferior olivary hypertrophy was symmetrical and homogenous, and no focal pathologic lesions could be identified in the brainstem. Insoluble tau deposits were found in neurons, exclusively infratentorially. We present the clinical and pathological evaluation of a case of progressive ataxia and PT that provide evidence for a unique form of 4R tauopathy.Keywords: neurodegenerative disorders, neuropathology, ataxia, tremor.Symptomatic palatal tremor (SPT) may develop as a result of brainstem or cerebellar pathology involving the pathway between the dentate nucleus and inferior olive (IO), two sides of the "Guillain-Mollaret triangle."1,2 The dentato-(rubro)-olivary pathway (DROP) originates from the dentate on one side, passes within the superior cerebellar peduncle, crosses over to the contralateral side, circles around the red nucleus (without rubral synaptic relay), and then joins the central tegmental tract to the IO. Associated with injuries in these pathways, inferior olivary hypertrophy (IOH) can develop as a result of trans-synaptic degeneration. Etiology of PAPT has not been determined and no pathological evaluation of cases has been reported in the literature.We report here on the first case of PAPT with histologically proven, unique 4R tau pathology. Patient and Methods Case ReportA Caucasian right-handed man first developed dysarthria and falls at the age of 63. In addition to the imbalance, his gait was noted to be wide based. He also had abnormal limb coordination and hand tremor. After years of relatively slow progression, his symptoms seemed to plateau. He had mouth angle twitching, which was later confirmed to correlate with his palatal tremor (PT). On specific request by physicians, the patient's wife observed that the facial twitching continued in sleep. His first neurological exam, approximately 1 year after symptom onset, was conducted by a community neurologist and was incomplete, but was significant for dysarthric speech, postural hand tremor, titubation, PT without ear clicks, dyssynergia on finger-to-nose testing, and an ataxic respiratory pattern. There was neither nystagmus nor gaze palsy. His initial workup

A clinicopathological study of ALS with L126S mutation in the SOD1 gene presenting with isolated inferior olivary hypertrophy

“…Moreover, intra‐neuronal vacuoles were not visible, and both the dentate nucleus and central tegmental tract were not involved, just like in our case. These observations suggest that the abnormal neuronal accumulation of proteins, such as pNF or Tau, might be associated with isolated hypertrophy of the inferior olive nucleus.…”

“…Mari et al . reported an autopsy case with progressive ataxia and palatal tremor, showing symmetrical inferior olivary hypertrophy with filamentous bundled cytoplasmic inclusions . Moreover, intra‐neuronal vacuoles were not visible, and both the dentate nucleus and central tegmental tract were not involved, just like in our case.…”

“…reported an autopsy case with progressive ataxia and palatal tremor, showing symmetrical inferior olivary hypertrophy with filamentous bundled cytoplasmic inclusions . Moreover, intra‐neuronal vacuoles were not visible, and both the dentate nucleus and central tegmental tract were not involved, just like in our case. These observations suggest that the abnormal neuronal accumulation of proteins, such as pNF or Tau, might be associated with isolated hypertrophy of the inferior olive nucleus.…”

Palatal Tremor – Pathophysiology, Clinical Features, Investigations, Management and Future Challenges

“…The inflammation of the GMT was postulated in PAPT [25,33]. Recently, Mari et al found an insoluble four-repeat (4R) tau deposition in the inferior olive of the medulla [34]. The authors hypothesised that this tau deposition could trigger the retrograde degeneration of the dentato-olivary fibers.…”

Some New and Unexpected Tauopathies in Movement Disorders

“…Its distribution differed, but generally comprised somatodendritic inclusions in the inferior olives, nigra, locus coeruleus, red nucleus, and thalami alongside cortical and/or hippocampal tau pathology that was interpreted as an incidental finding related to aging. 26,27 Globular Glial Tauopathies (GGT)…”