Phenotypic Variability in ATP13A2 Mutations: The First Report of SPG78 From India

Lakshmi Priya Lalitha; Asish Vijayaraghavan; Syam Krishnan

doi:10.14802/jmd.25100

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Letter to the editor Phenotypic Variability in ATP13A2 Mutations: The First Report of SPG78 From India: Lakshmi Priya Lalitha¹, Asish Vijayaraghavan², Syam Krishnan²; Journal of Movement Disorders 2025;18(4):369-371.
DOI: https://doi.org/10.14802/jmd.25100
Published online: June 29, 2025

¹Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, India

²Comprehensive Care Center for Movement Disorders, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, India

Corresponding author: Asish Vijayaraghavan, MD, DM Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Jai Nagar W Rd, Chalakkuzhi, Thiruvananthapuram, Kerala 695011, India / Tel: +91-471-2524262 / E-mail: asish.vijayaraghavan@gmail.com

• Received: April 15, 2025 • Revised: May 7, 2025 • Accepted: June 29, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Supplementary Materials
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REFERENCES

Dear Editor,

Hereditary spastic paraplegia (HSP) is a heterogeneous group of genetic neurodegenerative disorders. HSP presents at any age with progressive spasticity (pure) and with/without a combination of various other neurological features (complex) based on the specific gene affected, thereby causing length-dependent corticospinal tract and dorsal column degeneration [1]. The genetic classification is based on the sequential numbering of chromosomal loci or specific genes in order of being identified, using the Spastic Paraplegia Gene (SPG) designation [1]. To date, more than 80 causative genes have been reported for HSP [2]. ATP13A2 (OMIM 610513) was initially implicated in Kufor–Rakeb syndrome (OMIM 606693), which is characterized by early onset parkinsonism, pyramidal tract degeneration, supranuclear vertical gaze palsy, facial-faucial-finger myoclonus, and cognitive dysfunction [2]. Subsequently, ATP13A2 variants were also reported in neuronal ceroid lipofuscinosis, amyotrophic lateral sclerosis, and ataxia-myoclonus syndrome in addition to HSP [3]. Here, we report the first case of a pure HSP-SPG78 (OMIM 617225) mutation in the ATP13A2 gene in India.

A 41-year-old female who was born of nonconsanguinity reported a negative family history and normal birth and development presented with a 4-year history of gradually progressive gait difficulty due to stiffness in both lower limbs and imbalance, followed by recent onset dexterity issues in both upper limbs, slurring speech and urinary urgency without any sensory, extrapyramidal, autonomic or cognitive impairment. On examination, she had normal higher functions, a normal ophthalmic fundus, mild spastic dysarthria, normal eye movements, bilateral symmetrical spasticity (lower limbs>upper limbs), mild bilateral upper limb incoordination, and wide-based ataxic gait (Supplementary Video in the online-only Data Supplement). Her routine blood parameters, including vitamin B12 levels, were under normal limits. Magnetic resonance imaging (MRI) of the brain was normal. A nerve conduction study revealed no evidence of neuropathy. The cause for this late-onset progressive symmetrical spastic ataxic syndrome was considered to be genetic. Clinical exome sequencing revealed a homozygous missense variation in exon 13 of the ATP13A2 gene that resulted in the amino acid substitution of methionine for threonine at codon 402 (c.1205C>T; p.Thr402Met; OMIM617225), which is classified as “likely pathogenic” according to the American College of Genetics and Genomics. The observed mutation hotspot lies in the E1-E2 adenosine triphosphatase (ATPase) domain of the ATP13A2 protein (PM1). The p.Thr402Met variant has not been reported in the 1000 Genomes Project and Genome Aggregation Database and has a minor allele frequency of 0.01% (PM2). The in silico predictions of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by Sorting Intolerant From Tolerant, likelihood ratio test, and MutationTaster2 (PP3). This variant has been classified as likely pathogenic in the ClinVar database (PP5). She was initiated symptomatic treatment (baclofen for spasticity), speech therapy, and structured intensive physiotherapy along with genetic counseling. Her symptoms worsened significantly at the 2-year follow-up. Her Mini-Mental State Examination score was 30, her Adverse Childhood Experiences score was 98, and her eye movements were normal. Her spasticity in both lower limbs worsened significantly. She required minimal or one-person support for ambulation (Supplementary Video in the online-only Data Supplement).

The age of onset is usually in the late 30s, and HSP typically takes approximately 5–20 years for presentation, similar to our case. The majority of patients present with gait difficulty and varying degrees of cognitive impairment. Pyramidal tract, spinocerebellar, and oculomotor involvement were consistent in most of the patients (Supplementary Table 1 in the online-only Data Supplement). Sensorimotor neuropathy, typically demyelinating, and bladder involvement were noted in some patients. MRI findings revealed cerebellar more than cerebral atrophy, and few patients presented with the “ear of lynx” sign (T2 hyperintensity in the anterior forceps of the corpus callosum). Few patients have abnormal visually evoked potentials, without any clinical manifestations [4]. However, none of these features were observed in our patient, even after 2 years of follow-up. Therefore, early identification of this syndrome may be challenging, as it can be indistinguishable from common genes causing pure HSP.

Certain genes associated with HSP are also implicated in other neurological conditions where spasticity is not a primary symptom. For example, mutations in FA2H (OMIM 611026) and KIAA1840 (OMIM 610844) have been linked to neurodegeneration with brain iron accumulation and Charcot–Marie–Tooth disease [2,5]. Similarly, genes that play a role in other neurological disorders, such as ALS2 (OMIM 205100), POLR3A (OMIM 614258), DNMT1 (OMIM 614116), and ATP13A2, are also involved in HSP [2,6]. We describe the clinical features and follow-up of a patient with HSP due to a pathogenic mutation in the ATP13A2 gene. There are only a few case reports of ATP13A2 reported worldwide, and to the best of our knowledge, this is the first case from India. All previously reported case reports were identified using the keywords “ATP13A2,” “spasticity,” and “HSP” and were included without specific exclusion criteria. These are summarized in Supplementary Table 1 (in the online-only Data Supplement. HSP associated with ATP13A2 tends to present with psychiatric symptoms, cognitive dysfunction, eye movement abnormalities, and extrapyramidal features [2]. However, no such association was found in our patient. De Michele et al. [7] reported a patient with the same genetic variant as our patient who presented with adult-onset progressive ataxia, action myoclonus, brisk knee reflexes, and executive dysfunction without extrapyramidal involvement.

ATP13A2 is a lysosomal P5-type ATPase that is predicted to be an energy-driven transporter of various substrates, such as cations, heavy metals, lipids, zinc, and manganese [8]. Its activity is driven by the binding of lysosomal signaling lipids at its N-terminus, causing autophosphorylation, which confers its neuroprotective activity during oxidative stress, alpha-synuclein-mediated toxicity and metal exposure by facilitating the recruitment of histone deacetylase 6 to the lysosomal membrane to promote autophagosome‒lysosome fusion [8]. Loss of ATP13A2 function leads to abnormal accumulation of intracellular storage material, aggregation of alpha-synuclein and impaired lysosomal and mitochondrial function.

The suspicion of ATP13A2-associated HSP 78 is primarily based on clinical features such as eye movement abnormalities, cognitive decline, and extrapyramidal signs in patients with HSP. Genetic studies are key to confirming the diagnosis. No biomarkers such as serum or cerebrospinal fluid tests are available for diagnosing or prognosticating the disease, and further research into this field is needed.

Supplementary Materials

The online-only Data Supplement is available with this article at https://doi.org/10.14802/jmd.25100.

Video 1.

Segment 1A: Mild spastic dysarthria, bilateral upper limb incoordination, spastic gait with a wide base. Segment 1B: Follow-up after 2 years (worsening of spastic gait).

Supplementary Table 1.

Characteristics of HSP patients harbouring ATP13A2 gene mutation

jmd-25100-Supplementary-Table-1.pdf

Notes

Ethics Statement

Written informed consent was taken from the patient.

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

None

Acknowledgments

Authors are thankful for Ms. Geetha R’s contribution in acquisition of patient’s video. Authors are also grateful to the patient who consented to the publication of his clinical details.

Author Contributions

Conceptualization: Asish Vijayaraghavan. Data curation: Asish Vijayaraghavan, Lakshmi Priya Lalitha. Formal analysis: Asish Vijayaraghavan, Syam Krishnan. Investigation: Asish Vijayaraghavan, Syam Krishnan. Methodology: all authors. Project administration: all authors. Resources: all authors. Supervision: Syam Krishnan. Validation: all authors. Visualization: Asish Vijayaraghavan. Writing—original draft: Lakshmi Priya Lalitha. Writing—review & editing: Asish Vijayaraghavan, Syam Krishnan.

REFERENCES

1. Shribman S, Reid E, Crosby AH, Houlden H, Warner TT. Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches. Lancet Neurol 2019;18:1136–1146.Article PubMed
2. Estiar MA, Leveille E, Spiegelman D, Dupre N, Trempe JF, Rouleau GA, et al. Clinical and genetic analysis of ATP13A2 in hereditary spastic paraplegia expands the phenotype. Mol Genet Genomic Med 2020;8:e1052. Article PubMed PMC PDF
3. Manrique L, Sánchez-Rodríguez A, Pelayo-Negro AL, Corral-Juan M, Matilla-Dueñas A, Infante J. Ataxia and action myoclonus related to novel mutations in ATP13A2 gene. Mov Disord Clin Pract 2021;8:969–971.Article PubMed PMC
4. Estrada-Cuzcano A, Martin S, Chamova T, Synofzik M, Timmann D, Holemans T, et al. Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78). Brain 2017;140:287–305.Article PubMed PMC
5. Kruer MC, Paisán-Ruiz C, Boddaert N, Yoon MY, Hama H, Gregory A, et al. Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA). Ann Neurol 2010;68:611–618.Article PubMed PMC
6. Gauquelin L, Tétreault M, Thiffault I, Farrow E, Miller N, Yoo B, et al. POLR3A variants in hereditary spastic paraplegia and ataxia. Brain 2018;141:e1. Article PubMed PMC
7. De Michele G, Galatolo D, Lieto M, Fico T, Saccà F, Santorelli FM, et al. Ataxia-myoclonus syndrome due to a novel homozygous ATP13A2 mutation. Parkinsonism Relat Disord 2020;76:42–43.Article PubMed
8. Butz ES, Chandrachud U, Mole SE, Cotman SL. Moving towards a new era of genomics in the neuronal ceroid lipofuscinoses. Biochim Biophys Acta Mol Basis Dis 2020;1866:165571.Article PubMed