Objective: Describing two patients from an Italian family carrying the DCTN1 p.(Gly59Ser) and their phenotypes.

Background: Mutations in Dynactin 1 (DCTN1) gene are responsible for a spectrum of autosomal dominant neurodegenerative disorders, including Perry syndrome, distal hereditary motor neuropathy type 7B (HMN7B), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neuropathological findings include TDP-43 deposition in all cases, with prominent neuronal loss in the substantia nigra, striatum and brainstem as distinctive features of Perry syndrome [1]. The first pathogenic mutation discovered in DCTN1, p.(Gly59Ser), was initially reported in a family with HMN7B [2] and in three additional families worldwide affected by the same disease [3,4].

Method: Clinical evaluation, Ioflupane[123I]-FP-CIT-SPECT, neurophysiology tests.

Results: A 71-year-old woman born to non-consanguineous Italian healthy parents presented at age 63 with respiratory failure, leading to a diagnosis of bulbar ALS requiring PEG and tracheostomy placement. At age 69, she developed extrapyramidal signs (rest and postural tremor, moderate bradykinesia at upper limbs, shuffling gait) with limitation of upward vertical gaze and generalized myoclonic jerks more prominent in the left hemibody. Motor neuron signs were also present (muscle atrophy, diffuse muscle fasciculations, brisk reflexes, bilateral Hoffman sign). [123]I-FP-CIT-SPECT showed absent tracer uptake bilaterally. Laryngoscopy revealed left vocal cord paralysis.

Her daughter, aged 48, developed progressive dyspnoea and subsequently dysphonia and dysphagia in her 30s.  Clinical examination revealed upper motor neuron signs (brisk reflexes, Hoffman sign) and tongue fasciculations, without parkinsonism. [123]I-FP-CIT-SPECT was normal and EMG/NCS were within normal limits. A restrictive ventilatory deficit was observed together with vocal cords hyperadduction on videofluoroscopy.

Genetic analysis revealed the DCTN1 gene mutation c.175G>A p.(Gly59Ser), ACMG-AMP class V in both patients.

Conclusion: This family highlights the intra-familial phenotypic heterogeneity of DCTN1-related disease, encompassing motor neuron signs, parkinsonism, respiratory symptoms and myoclonus.

References: [1] Armen J. et Al, Dynactin is required for transport initiation from distal axon, Neuron. 2012 April 26; 74(2): 331–343. doi: 10.1016/j.neuron.2012.02.025
[2] Plus et al, Mutant dynactin in motor neuron disease, Nature Genetics, 2003 March 10, doi:10.1038/ng1123
[3] Hwang SH, Kim EJ, Hong YB, Joo J, Kim SM, Nam SM et al, (2016) Distal hereditary motor neuropathy type 7B with dynactin 1 mutation, Mol Med Rep 14:3362-3368
[4] Nath Pasutharnchat et al, Clinical and neurophysiological characterization of p.Gly59Ser mutation in DCTN1: a study in a Thai family and a brief review, Neurological Sciences (2025) 46:935-941

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MDS Abstracts - https://www.mdsabstracts.org/abstract/dctn1-gene-a-p-gly59ser-family-report/