Throat‐Clearing Vocalizations in Primary Brain Calcification Syndromes

Abstract

Primary brain calcification syndromes are heterogeneous disorders characterized by pathological peri-microvascular calcium deposition in the basal ganglia, subcortical white matter, thalamus and cerebellum. Most are inherited in an autosomal dominant fashion (SLC20A2, XPR1, PDGFRB, PDGFB), though recently, biallelic variants in the MYORG and JAM2 genes have been identified as autosomal recessive causes of the syndrome. Clinical manifestations are protean. Some affected individuals remain asymptomatic despite demonstrable brain calcinosis, though most experience progressive neurological decline. Psychiatric symptoms (depression, anxiety, psychosis), movement disorders and cognitive impairment are typical. Herein, we report two patients who displayed grunting/ throat-clearing vocalizations as an early manifestation of primary brain calcification (Fig. 1). The case histories are summarized in Table 1, and further elaborated in the Supplementary Material S1. The vocalizations and other clinical features are illustrated in the accompanying videos (Videos 1 and 2). Involuntary vocalizations are a primitive form of emotiondriven communication. For many mammals, they are the primary means of conveying anger, fear, satisfaction and mating desire. In humans, they form part of normal early development, prior to the development of language, but may become pathological either through their occurrence beyond specific developmental stages and/or their performance outside of appropriate social contexts. Generation of vocalizations is critically dependent on the periaqueductal gray matter (PAG) and its efferent projections to the lower brainstem reticular formation. In turn, the PAG receives rostral afferent inputs from limbic and basal ganglia regions, modulating and controlling vocalization behaviors. In movement disorder practice, the most commonly encountered vocalizations are vocal tics. These peak in incidence in late childhood/early adolescence, particularly in males, and can be self-limiting (transient/provisional tic disorder, lasting<12 months) or persistent, either as chronic tics (which generally ease with age) or Tourette’s syndrome. In these groups, psychiatric comorbidity-attention deficit hyperactivity disorder, obsessive compulsive disorder or impulse control disorderis common. New onset vocalizations in adulthood are unusual, and require close attention. In some, they may represent reemergence of a childhood tic disorder which had initially dissipated and remained dormant, only to re-emerge in later life. In this setting, a history of childhood tics is extremely helpful. In adults without a past history of tic disorder, or in the presence of other abnormal features on neurological examination, tic-like vocalizations should raise concern for underlying neurodegenerative disorders. Indeed, ‘secondary’ vocal tics have been described in numerous disorders including Huntington’s disease, neuroacanthocytosis, progressive supranuclear palsy, neurodegeneration with brain iron accumulation and others. Autoimmune, structural and importantly drug-induced (particularly stimulants, e.g., cocaine/amphetamines) are other important differential diagnoses to consider for new adult-onset vocalizations. Involuntary vocalizations have not hitherto been highlighted as a major feature of brain calcification syndromes. Palilalia and echolalia are occasionally reported, while guttural vocalizations have only been described once previously. Altered limbic-PAG connectivity associated with pathological intracranial calcification may be the driver of abnormal utterances in these cases, and one may surmise that the similar throat-clearing qualities in all cases(Table 1) reflects