This case displays a complex early‐onset neurological phenotype with cognitive decline, supranuclear ophthalmoplegia, anarthria associated with risus sardonicus, progressive parkinsonism‐dystonia, and spasticity.1 Whilst acquired (hypoxic, infectious, toxic, neoplastic) causes should be considered, the positive family history of a similarly (but more mildly) affected sibling and relatives with parkinsonism strongly suggests a genetic etiology with possible autosomal recessive or mitochondrial inheritance. Although the phenomenology is suggestive of Wilson's disease, there is no corroborative evidence of copper accumulation in serum, urine, or neuroimaging studies. Juvenile Huntington's and GCH1‐related disease should also be considered, as well as other rare genetic causes of juvenile parkinsonism‐dystonia such as PRKN, DNAJC6, ATP1A3, ATP13A2, and FBXO7. Disorders of Neurodegeneration with Brain Iron Accumulation (NBIA), manganese transportopathies, and mitochondrial disorders are also potential differential diagnoses here.
Video 1.
Full video from the 2020 Video Challenge discussion of this case.
For this case, a major diagnostic clue is provided by neuroimaging studies; bilateral posterior putaminal hyperintensities on T2‐weighted MRI images are highly suggestive of a metabolic etiology such as GM1 gangliosidosis type III or glutaric aciduria type 1.2 Although not undertaken for this patient, iron‐sensitive neuroradiological sequences would also be of interest, to look for a “wish bone sign”.3
Exome sequencing confirmed GM1 gangliosidosis type III; whilst the proband has many classical disease features (typical age of onset, progressive movement disorder, cognitive decline, T2‐weighted neuroradiology findings), the presence of prominent parkinsonism and supranuclear ophthalmoplegia, and lack of skeletal abnormalities and generalized dystonia are somewhat atypical.
In conclusion, this informative case demonstrates (1) the phenotypic variability of GM1 gangliosidosis type III; (2) that this condition should be considered in the differential diagnosis of juvenile‐onset parkinsonism‐dystonia, even without a skeletal phenotype; and (3) how awareness of the distinct MRI signs associated with a condition can accelerate clinical diagnosis.
Author Roles
(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique.
M.A.K.: 1A, 1B, 3B
R.K.: 1A, 1B, 1C, 3A
P.A.: 1C, 3B
U.G.: 1C, 3B
S.G: 1C, 3B
K.S.: 1C, 3B
A.M.: 1C, 3B
M.P.F.: 1C, 3B
H.H.: 1C, 3B
F.C.: 1A, 1B, 3B
Disclosures
Ethical Compliance Statement
The authors confirm that neither informed patient consent nor the approval of an institutional review board was necessary for this work. 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 declare that there are no conflicts of interest relevant to this work.
Financial Disclosures for the Previous 12 Months
The authors declare that there are no disclosures to report.
Relevant disclosures and conflicts of interest are listed at the end of this article.
References
- 1.Kaiyrzhanov R, Guliyeva U, Gulieva S, et al. GM1‐gangliosidosis type III associated parkinsonism. Mov Disord Clin Pract 2021;8(S1):S21–S23. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Muthane U, Chickabasaviah Y, Kaneski C, Shankar SK, Narayanappa G, Christopher R, Govindappa SS. Clinical features of adult GM1 gangliosidosis: report of three Indian patients and review of 40 cases. Mov Disord 2004;19(11):1334–1341. [DOI] [PubMed] [Google Scholar]
- 3.Prasad S, Sahoo LK, Saini J, Pal PK. Wishbone pattern of iron accumulation: a pathognomonic sign of type III GM1 gangliosidosis. Ann Mov Disord 2019;2:134–135. [Google Scholar]