Poretti et al. provide a detailed clinical characterization of head titubation in 12 out of 13 young children with Joubert syndrome. Head titubation has only once been previously reported in a child with Joubert syndrome and neuroepithelial cysts. It appears characteristically at around 2 months of age, consists of a horizontal head tremor with high frequency and small amplitude, and gradually decreases over time with early spontaneous resolution within the first months of life. This last point is probably the reason why its frequency has until now been underestimated.
Head titubation should be easily differentiated from head thrusts, also seen in Joubert syndrome. Head thrusts are not rhythmical and they are not exacerbated by fatigue, emotion, or stress and appear later, at around 6 months of age, after the child has acquired head and neck control in the context of oculomotor apraxia. The detection of head titubation may lead to early diagnosis of Joubert syndrome, avoiding unnecessary investigations and prompting the search for the pathognomonic molar tooth sign by neuroimaging.
Interestingly, about 85% of patients with rhomboencephalosynapsis also develop head-shaking movements, but compared to head titubation in Joubert syndrome, their frequency is lower and the amplitude is larger. Head titubation has been reported in other midline cerebellar defects such as pontine tegmental cap dysplasia, Dandy-Walker syndrome, and in partial midline fusion of cerebellar hemispheres with vertical folia. Head titubation occurs in 28% of patients affected with ataxia and isolated vitamin E deficiency, while it is rarely found in Friedreich ataxia. It is also commonly found in spinocerebellar ataxia (SCA) type 2 and has been occasionally reported in SCA13 and in neurodevelopmental disorders such as Angelman syndrome, ‘Epilespy, ataxia, sensorineural deafness, tubulopathy’ (EAST) syndrome due to KCNJ10 mutations, and in a male carrying an MECP2 mutation. Head titubation was found in 11 out of 47 children with cerebellar malformations.
The pathogenesis of head titubation is unclear. Head titubation can occur in isolation or combined with a postural tremor, especially in the upper limbs or oculomotor deficits such as pursuit initation and the suppression of the vestibulo-ocular reflex (VOR). It has been shown that there is a strong correlation between the oculomotor impairment and the intensity of the tremor, and this may indicate an impairment of the caudal vermis. A close interplay of pathophysiology relating nystagmus, oscilloscopia, the VOR, and head titubation to the cerebellar vermis has therefore been postulated.
Unfortunately, in the patients with Joubert syndrome analysed by Poretti et al. the oculomotor and vestibular testing could not be performed. Increased awareness of the spectrum of head tremor phenotypes and their correlation with the underlying molecular mechanisms should shed light on the pathogenesis of head titubation in Joubert syndrome and other (midline) cerebellar disorders.