Objective: We report a rare case of amyotrophic lateral sclerosis (ALS) / progressive supranuclear palsy (PSP) phenotype.

Background: Increasing evidence supports a common pathophysiology between ALS, frontotemporal lobar degeneration (FTLD) and PSP.1 Mutations in the MAPT, TARDBP, PRGN genes and abnormal c9orf72 hexanucleotide repeat expansion (HRE) have been reported in these overlapping presentations.1.

Methods: A 77-year-old Chinese man presented with a seven-month history of cognitive and behavioural disturbance (apathy, emotional lability and forgetfulness). This was followed three months later by progressive gait instability leading to recurrent falls, and asymmetrical limb weakness associated with muscle twitching, which later progressed to involve other muscles. There was no relevant family history. Muscle wasting and fasciculations were noted in the tongue and all limbs. Muscle power was MRC grade 3 in the upper limbs and grade 4 in the lower limbs. Sensation was intact. Tendon reflexes were brisk with downgoing plantar responses. He had supranuclear vertical gaze palsy, predominant axial rigidity, bradykinesia and postural instability. Montreal Cognitive Assessment and frontal assessment battery scores were 20/26 and 12/18, respectively. Brain MRI showed midbrain atrophy. Nerve conduction studies were consistent with a motor neuronopathy. Electromyography revealed denervation and reinnervation changes in genioglossus, and upper and lower limb muscles. A diagnosis of clinically-definite ALS overlapping with probable PSP was made. He died from respiratory failure nine months after disease onset.

Results: Genetic screening for mutations in PSP- and ALS-related genes including MAPT, TARDP, PRGN and C9orf72 HRE was negative. Next-generation sequencing studies have commenced in an attempt to identify the possible causative gene(s) in this patient.

Conclusions: An overlap syndrome of ALS-PSP is described in a single patient that further extends the clinical spectrum of atypical parkinsonism. Future studies incorporating clinical, pathological and genetic analyses are necessary to gain a better understanding of the underlying pathophysiology in these syndromes.

References: 1. Ticozzi N, Tiloca C, Calini D, Gagliardi S, Altieri A, Colombrita C, Cereda C, Ratti A, Pezzoli G, Borroni B, Goldwurm S, Padovani A, Silani V. C9orf72 repeat expansions are restricted to the ALS-FTD spectrum. Neurobiol Aging. 2014 Apr;35(4):936.e13-7. 2. Wilke C, Pomper JK, Biskup S, Puska’s C, Berg D, Synofzik M. Atypical parkinsonism in C9orf72 expansions: a case report and systematic review of 45 cases from the literature. J. Neurol. 2016 Mar;263(3):558-74. doi: 10.1007/s00415-016-8021-7. Epub 2016 Jan 25.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/amyotrophic-lateral-sclerosis-progressive-supranuclear-palsy-phenotype-with-negative-c9orf72-mutation/