Respiratory failure as main presentation sign of MAPT-related disorder.

Introduction: The MAPT gene encodes Tau, a protein mainly expressed by neurons. Tau protein plays an important role in cerebral microtubule polymerization and stabilization, in axonal transport and synaptic plasticity. Heterozygous pathogenic variation in MAPT are involved in a spectrum of autosomal dominant neurodegenerative diseases known as taupathies, including Alzheimer's disease, Pick's disease, fronto-temporal dementia, cortico-basal degeneration and progressive supranuclear palsy. Taupathies are characterized by the constant presence of neuronal and/or glial aberrant Tau inclusions leading to atrophy and subsequent neuronal loss resulting in central nervous system degeneration. We report here two unrelated families in which segregates a MAPT-related neurodegenerative disorder marked by respiratory failure in the foreground.

Results: Nine individuals from two unrelated families were affected by a neurodegenerative disorder. Respiratory features were progressively worsening dyspnea-orthopnea with episodes of acute respiratory decompensation leading to hypercapnic coma or sudden death. A diaphragmatic paralysis was shown in three cases. Associated neurological signs were gait disturbances, bulbar signs including swallowing disorders and dysarthria, pyramidal signs, cognitive and behavioral disorders. ENMG inconstantly found signs of mild denervation. Post-mortem brain immuno-histochemical analysis in one patient revealed unusual composite neuronal Tau inclusions, significant neuronal loss and reactive gliosis, in cortical and subcortical regions, cranial nerves and anterior horn of spinal cord. The heterozygous missense variant c.2041C > T, p. (Pro681Ser) in MAPT was identified in both families by gene panel or exome sequencing.

Discussion: In the literature, four additional related patients carrying the same MAPT variant, in heterozygous state, also presented rapidly progressive respiratory failure and unusual composite neuronal Tau inclusions in anterior horn of spinal cord.

Conclusion: Our observation allows to extend the phenotypic spectrum associated with MAPT variants describing a rapidly progressive respiratory failure, with episodes of exacerbations and premature death.