Dystonia and Optic Neuropathy: Expanded Phenotype of Dynactin 1 Related Neurodegeneration

Axonal transport is essential to provide nutrients to axons and nerve terminals and to clear up misfolded proteins to avoid the accumulation of toxic aggregates. There is emerging evidence about the relationship between axonal transport defects and neurodegenerative diseases.1 Dynactin is a multi-subunit protein complex which binds dynein and plays a crucial role in retrograde axonal transport.2 Mutations in dynactin 1 result in a rare neurodegenerative autosomal dominant parkinsonism called as Perry Syndrome also characterized by psychiatric symptoms, weight loss and central hypoventilation.3 Dynactin 1 mutations have also been linked with amyotrophic lateral sclerosis, progressive supranuclear palsy, frontotemporal dementia like syndromes and more recently with hereditary motor neuropathy type 7B.4-6 We report a patient with Dynactin 1 mutation who had dystonia and vision loss as the presenting and predominant manifestation with anterior horn cell and frontal lobe involvement developing late in the disease course. A 45-year-old male product of non-consanguineous marriage with normal birth and developmental history presented with 5-year history of visual disturbances followed by weakness and abnormal posturing of all four limbs of 4-year duration. His illness started in 2015 when he noticed painless progressive blurring of vision in his right eye followed by involvement of left eye over 15 days. His peripheral field of vision was affected with sparing of central vision and the visual disturbances remained static since then. In 2017, patient developed abnormal posturing of left foot while walking with spread to face and perioral area in 2018 and involvement of neck and hands in 2020. Simultaneously in 2017 he developed weakness of left lower limb followed by right lower limb with difficulty in getting up from squatting position in a span of 6 months. In 2018, he started walking with the assistance of a stick along with development of weakness of left upper limb (distal followed by proximal) followed by right upper limb in 4 months. He also noticed a strained and dystonic quality to his speech. Family history was non-contributory. His Mini Mental Status Examination (MMSE) was 19/25. Detailed lobar functions revealed frontal predominant cognitive decline. Frontal release signs (snout, grasp reflex) were present. Visual acuity was 20/20 Snellen equivalent. His color vision was impaired bilaterally. Fundus examination and optical coherence tomography of the retinal nerve fiber layer analysis showed bilateral primary optic atrophy with a few chorio-retinal scars and no evidence suggestive of retinitis pigmentosa (Fig. 1). Visual field examination showed field loss in the periphery of no specific pattern with macular sparing bilaterally. Fundus Fluorescein angiography revealed normal disc perfusion with staining of the chorio-retinal scars suggestive of healed choroiditis (Fig. 2). He also exhibited vertical supranuclear gaze palsy (Video 1). Rest of the cranial nerves were normal. On motor system examination, generalized wasting with fasciculations were observed and fasciculatory tremor was present in bilateral hands. Power was 3/5 in upper limbs and 1/5 in lower limbs with hand grip of 10%. Deep tendon reflexes were brisk in upper limbs with absent knee and ankle reflexes. His plantar response was extensor on the right side and mute on the left side. He also exhibited cervical dystonia in the form of laterocollis to right side with ipsilateral shoulder elevation with perioral movements and dystonic posturing of bilateral hands (Video 2). In view of presence of frontal predominant cognitive decline, vertical supranuclear gaze palsy, multifocal dystonia, optic neuropathy, pyramidal and anterior horn cell involvement, various differential diagnosis was considered like Niemann Pick type C, Whipple Disease, Kufor Rakeb Disease, mitochondrial gene mutation or some inherited form of Motor Neuron disease. His MRI brain revealed diffuse cerebral atrophy with no evidence of iron deposition (Fig. 3). Nerve conduction studies showed pure motor axonopathy with neurogenic pattern in cervical and lumbar segments. Patient was also investigated to delineate the cause of optic neuropathy. CSF analysis including HSV PCR, TB PCR, measles antibody, autoimmune and paraneoplastic panel was negative. FDG PET did not reveal any significant abnormal hypermetabolism anywhere in the body. Mitochondrial gene mutation panel was negative. However, whole exome sequencing revealed a heterozygous variant of uncertain significance (c. 3046 A > G p. Met1016 Val) in Exon 26 of DCTN1 gene which was confirmed on Sanger sequencing (Fig. 4). This variant has not been reported previously and is indicated to be novel in gnomAD and 1000G (PM2 according to ACMG guidelines). In silico prediction tools (SIFT and Polyphen-2) found this variant to be damaging and the residue is conserved across species (PP3 according to ACMG guidelines). Familial segregation studies were not undertaken as the family did not consent for the same. A final diagnosis of Dynactin 1 related neurodegeneration was made. Dynactin 1 as a causative gene for Perry syndrome was first discovered in 2009.7 It encodes dynactin subunit p150Glued on chromosome 2p. Pathologically, Perry Syndrome is a TDP-43 proteinopathy characterized by TDP-43 positive neuronal cytoplasmic inclusions in the substantia nigra and globus pallidus with very sparse to absent Lewy bodies.8 Atypical phenotypes of the Perry syndrome include PSP like and FTD like syndromes. In 2003, Puls and colleagues first linked mutation in dynactin 1 gene causing single base pair change with distal spinal and bulbar muscular atrophy and showed familial segregation. Since then, several dynactin 1 variants have been described in both sporadic and familial cases of ALS.4, 9 Like our case, Cady et al. also described a variant on Exon 26 (R1049Q) in a patient with sporadic ALS but our variant is 33 amino acids away from this published variant.10 Moreover, complete segregation in families has not been demonstrated in majority of the cases. Ikenaka et al. hypothesized that quantitative loss of dynactin 1 disrupts the transport of autophagosomes and induces the degeneration of motor neurons.11 To the best of our knowledge, dystonia as a prominent manifestation has not been elaborated in detail with Dynactin 1 mutation. The involvement of globus pallidus in previous pathological studies serve as a good clinicopathological correlate to dystonia in these mutations. Another atypical finding in our patient was presence of vision loss and optic atrophy. This can also be explained by accelerated loss of retinal ganglion cells and their axons because of impaired axonal transport. The presence of bilateral chorioretinal scars in our patient are unlikely to be associated with degenerative optic neuropathy and was most probably an incidental finding due to an endemic disease like tuberculosis in India.12 To conclude, Dynactin 1 related neurodegeneration not only present as classical Perry syndrome but with atypical features and should be considered in the differential diagnosis of parkinsonism, PSP, ALS or FTD phenotype. Dystonia and vision loss add to the phenotypic spectrum of these rare mutations. SM: 1A, 1B, 1C, 2A, 2B AG: 1B, 1C, 2B DS: 1B, 1C SR: 1C, 2B BT: 1C, 2B AT: 1C, 2B VL: 1A, 2B Ethical Compliance Statement: The authors confirm that the Ethics board clearance was not required for this work. The subject has provided written video consent. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflicts of Interest: No specific funding was received for this work and the authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for the Previous 12 Months: Authors have no financial disclosures.