The tau hypothesis of nodding syndrome in Africa

Nodding syndrome (NS) was first described in the Mahenge mountains in Tanzania, where it exists in an endemic form of epilepsy [1].In her pioneering work in Tanzania, Louise Jilak-Aall described NS as a pediatric seizure disorder and later observed parkinsonian-likeAU : Pleasenoteth manifestations in some adult survivors with NS [1].NS later emerged in an epidemic form in both South Sudan and northern Uganda.In South Sudan, Spencer and colleagues [2] reported an association of NS with onchocerciasis but later attributed this to a coincidental opportunistic infection.In Uganda, the NS epidemic coincided with regional insurgency by the Lord's Resistance Army and displacement of families into refugee camps with the occurrence of new cases of NS peaking in the mid-2000s [3].NS usually begins with spells of head bobbing [4-7], which have now been determined to represent atonic seizures.Clinical presentation with nodding is typically at 5 to 15 years of age with the progression to grand mal seizures within months or years of the initial presentation.Many children with NS have a clinical course dominated by grand mal seizures.However, some children also develop marked neurocognitive and motor decline.Some individuals with NS develop marked impairment of speech with mutism, and other can develop frontal lobe disinhibition (e.g., coprophagia) [8].It is unknown if NS is invariably fatal, but when death occurs, it is often related to accidental drowning during seizures, status epilepticus, or neurologic decline with malnutrition and pressure ulcers [8].The brain in NS shows varying degrees of brain atrophy, cerebellar degeneration, white matter degeneration, and microglial activation (neuroinflammation) [9].The brain also has intraneuronal deposition of an abnormally phosphorylated protein: the microtubular associated protein tau [8].In fatal cases of NS, tau pathology is variably abundant in the brain with preferential involvement of the frontal neocortex. Potential multifactorial pathogenesisEpidemiological studies on NS in Uganda have disclosed correlation between parasitic infection [10], malnutrition [11], environment (insurgency and civilian displacement) [3], and young age.These associations suggest potential multifactorial pathogenesis for NS.The exclusive occurrence of NS in the young likely relates to a selective vulnerability present at a certain stage of neurodevelopment in early childhood, but the precise details are unclear.Furthermore, NS often affects more than one sibling in a family, but not the parents.This suggests that common environmental factor(s) could be responsible for NS, rather than a mendelian disorderAU : PleasenotethatasperPLOSstyle; eponymicderivativesshouldbelowercase:Hence; }Mendelia .

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