Variants in the ganglioside induced differentiation associated protein 2 (GDAP2) gene cause a rare subtype of autosomal recessive cerebellar ataxia (1; Online Mendelian Inheritance in Man 618369). Here we report an individual with a unique phenotype, initially presenting as isolated dystonia with much later progression to cerebellar ataxia.
A 22‐year‐old right‐handed man of Jewish Ashkenazi descent initially presented to our clinic with a 3‐ to 4‐year history of neck tension and progressive forward tilt of his entire body associated with violent neck flexion movements. He also had mild cognitive impairment, depression, personality changes (aggressive behavior and emotional lability), and infrequent visual and auditory hallucinations. His birth was complicated by eclampsia, and his developmental milestones were delayed, especially regarding learning. Family history included a maternal grandfather with gait impairment and a sister with mild intellectual disability.
Examination revealed isolated trunk and cervical dystonia (Video 1) and mild cognitive dysfunction. Genetic testing was negative for torsion dystonia 1 (DYT‐1), Wilson's disease, Huntington's disease, and spinocerebellar ataxias 2, 3, and 6. Brain magnetic resonance imaging (MRI), electroencephalogram, and plasma ceruloplasmin and urine copper levels were normal. Trihexyphenidyl up to 30 mg daily provided minimal benefit, whereas tetrabenazine 37.5 mg twice daily resulted in a clear and sustained improvement in his dystonia over years (see Video 1, segment 2).
Video 1.
The initial segment demonstrates the individual at the age of 22 with isolated cervical and trunk dystonia. Segment 2 was recorded 17 years later. The individual's dystonia remains much less severe than on the initial assessment and continues to benefit from tetrabenazine; there are new additional features of cerebellar ataxia and mild lower limb spasticity.
He remained stable for the next 5 years, when he then began to report mild gait difficulties. Examination demonstrated a wide‐based gait, mild lower extremity spasticity, and clumsiness on rapid finger tapping. During the following 4 years, his features of cerebellar ataxia progressed, including wide‐based gait, saccadic pursuit, and upper and lower limb dysmetria (Video 1). He had no significant deterioration in cognition and mood.
At the age of 39, his MRI demonstrated subtle gliosis in the subcortical white matter of occipital lobes and mild cerebellar atrophy (Figure 1). He also complained of paresthesia on both hands and was subsequently found to have bilateral cubital syndrome with ulnar neuropathy, atrophy, and denervation of intrinsic muscles on a nerve conduction study and electroneuromyography. Neurophysiological testing was otherwise unremarkable.
FIG. 1.
(A, B) Axial and sagittal brain magnetic resonance imaging showing mild cerebellar atrophy and suble gliosis in the subcortical white matter of the occipital lobes.
A chromosomal microarray was normal and male, and mitochondrial genome analysis was negative. Trio whole‐exome sequencing revealed a homozygous pathogenic variant in GDAP2 (c.946C>T, p.Gln316*; heterozygous in both parents). In addition, he also had a paternally inherited heterozygous pathogenic variant in plakophiulin‐2 gene (PKP2) (c.148_151del, p.Thr50Serfs*61), described in autosomal dominant arrhythmogenic right ventricular dysplasia type 9.
The biological function of the GDAP2 gene is unclear, although it has been shown to be highly expressed in the brain, particularly in the cerebellum during development. 1 Studies point to the role of GDAP2 in motor function and lifespan. Variants in the GDAP2 gene are associated with autosomal recessive spinocerebellar ataxia 27, with only 4 cases described in the literature to date. 2 , 3 , 4 Clinically, all 4 described individuals who experienced a slowly progressive course, initially characterized by gait ataxia and dysarthria, followed by cognitive difficulties, with an age of onset ranging from 30 to 38 years. Imaging findings included cerebellar atrophy in all reported patients in the first few years of presentation. Mild behavioral changes have also been described. To our knowledge, only 1 individual was reported to have mild dystonia (cervical dystonia characterized as mild leftward torticollis) presenting at a later stage. Interestingly, this individual had the same variant as our patient (c.946C>T, p.Gln316*). 5
Our report highlights a novel and unique phenotype consisting of isolated cervical and truncal dystonia with a delayed progression to cerebellar ataxia and spasticity. This report adds GDAP2 to the list of genes that can present as isolated dystonia, expands the phenotype of the rare GDAP2‐related disorder, and further exemplifies the importance of recognizing dystonia‐ataxia syndromes.
Author Roles
(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.
D.G.D.: 1A, 1B, 1C, 2A, 2B
D.W.: 1A, 1B, 2B
V.M.: 1B, 2B
A.E.L.: 1A, 1B, 2B
Disclosures
Ethical Compliance Statement: The authors confirm that the approval of an institutional review board consent was not required for this work. Informed consent was obtained from the patient. 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: The authors report no conflict of interest or funding sources relevant to this work.
Financial Disclosures for the Previous 12 Months: Dr. Lang has served as an advisor for AbbVie, AFFiRis, Alector, Amylyx, Biogen, BioAdvance, BlueRock, Bristol Myers Squibb (BMS), CoA Therapeutics, Denali, Janssen, Jazz, Lilly, Novartis, Paladin, Retrophin, Roche, Sun Pharma, and UCB; received honoraria from Sun Pharma, AbbVie, and Sunovion; received grants from Brain Canada, Canadian Institutes of Health Research, Edmond J. Safra Philanthropic Foundation, The Michael J. Fox Foundation, the Ontario Brain Institute, Parkinson Foundation, Parkinson Canada, and W. Garfield Weston Foundation; and received publishing royalties from Elsevier, Saunders, Wiley‐Blackwell, Johns Hopkins Press, and Cambridge University Press.
Acknowledgments
We acknowledge the individual presented here as well as his family. We also thank Genome Sequencing Ontario for their assistance in the diagnostic workup.
Relevant disclosures and conflicts of interest are listed at the end of this article.
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