Late-Onset Hereditary Spastic Paraplegia: A Rare Case Report of  ATL1-Associated Disease

Snega, V; Divya, V

doi:10.65188/nurexus.1097

Snega V et al | DOI: 10.65188/nurexus.1097

Page 8

Journal of MedVerse Research & Practice

ISSN: 3107-4278

Late-Onset Hereditary Spastic Paraplegia: A Rare Case Report of

ATL1-Associated Disease

V Snega

1

, V Divya

2

Postgraduate, Professor

Department of General Medicine, PSP Medical College Hospital & Research Institute, Chennai

Email ID: sneganegavikram@gmail.Com

Submission Date: 09.07.2026

Accepted Date:16.08.2026

Published Date: 31.08.2026

DOI: 10.65188/nurexus.1097

article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted

use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

Abstract

Background

Hereditary spastic paraplegia (HSP) comprises a heterogeneous group of inherited neurological disorders

characterized primarily by progressive lower-limb spasticity and weakness. Autosomal dominant HSP associated

with ATL1 (SPG3A) mutations usually presents during childhood, whereas late-onset presentations are uncommon

and may be difficult to distinguish from acquired causes of spastic paraparesis.

Case Presentation

A 61-year-old male presented with progressively worsening gait difficulty and lower-limb stiffness. He reported mild

difficulty in walking since childhood, with marked deterioration over the preceding year. Neurological examination

revealed lower-limb spasticity, clonus, hyperreflexia, and bilateral extensor plantar responses, with no sensory,

cerebellar, cognitive, or bladder involvement. Two siblings were similarly affected, suggesting an autosomal

dominant pattern of inheritance.

Investigations and Diagnosis

Metabolic, nutritional, autoimmune, and infectious investigations were unremarkable. Electrophysiological studies

demonstrated preserved peripheral nerve function. MRI of the spine showed advanced multilevel degenerative disc

and facet changes, while brain MRI demonstrated frontal periventricular hyperintensities suggestive of the “ears of

the lynx” sign. Whole-exome sequencing identified a likely pathogenic ATL1 missense variant, c.1376A>G

(p.Tyr459Cys), supporting the diagnosis of late-onset ATL1-associated HSP.

Management and Outcome

The patient was treated with oral baclofen and structured physiotherapy. At six-month follow-up, there was modest

improvement in gait stability and lower-limb spasticity, with preserved upper-limb strength and no development of

new neurological deficits.

Conclusion

Late-onset ATL1-associated HSP is an uncommon presentation that may be overlooked because of its clinical

similarity to acquired neurological disorders. A history of subtle lifelong symptoms and a positive family history

should prompt consideration of a hereditary etiology. Genetic testing is valuable for confirming the diagnosis and

facilitating appropriate management and genetic counseling.

Keywords: Hereditary spastic paraplegia; ATL1 mutation; SPG3A; Late-onset HSP; Spastic paraparesis; Genetic

testing; Whole-exome sequencing; Neurodegenerative disorder.

Introduction

Hereditary spastic paraplegia (HSP) is a rare and genetically heterogeneous group of familial

neurodegenerative disorders characterized predominantly by slowly progressive spasticity and weakness of

the lower limbs. The reported prevalence of HSP ranges from 1.2 to 9.6 per 100,000 population [1,2].

Clinically, HSP is broadly classified into pure and complicated forms. Pure HSP is primarily characterized

by lower-limb pyramidal involvement and may be associated with mild urinary dysfunction or impaired

CASE REPORT

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distal vibration sensation, whereas complicated HSP may present with additional manifestations such as

cognitive impairment, ataxia, peripheral neuropathy, seizures, and muscle atrophy [1,3].

HSP demonstrates considerable genetic heterogeneity and may follow autosomal dominant, autosomal

recessive, or X-linked patterns of inheritance [3,4]. Autosomal dominant forms constitute an important

proportion of HSP. While several autosomal recessive forms, including SPG11 and SPG15, generally

manifest during childhood or early adolescence, some autosomal dominant forms, particularly SPG4

associated with SPAST, may present later in adulthood [3,5].

ATL1-associated HSP (SPG3A) is classically considered an early-onset form; however, late-onset

presentations can occur and may create considerable diagnostic difficulty [3,6]. Progressive gait impairment

and lower-limb spasticity in older adults may be attributed to degenerative spinal disease or other acquired

neurological conditions, potentially delaying recognition of an underlying hereditary disorder [7,8].

The present case describes a rare late-onset presentation of ATL1-associated hereditary spastic paraplegia

in an adult patient. It highlights the importance of recognizing subtle lifelong motor symptoms and

obtaining a detailed family history when evaluating progressive spastic paraparesis. Accurate identification

of the hereditary etiology is important for appropriate diagnosis, management, genetic counseling, and

assessment of potentially affected family members [5,6].

Case Presentation

Patient Presentation

A 61-year-old man presented with progressively worsening difficulty in walking. He reported mild gait

difficulty since childhood, characterized by occasional tripping on uneven surfaces, with significant

worsening of lower-limb stiffness during the preceding year. There was no history of upper-limb weakness

or stiffness, cranial or bulbar symptoms, seizures, cognitive decline, or bladder and bowel involvement. His

medical history included controlled diabetes mellitus and hypertension for four years.

Neurological Examination

Cognitive function was normal. Bilateral lower-limb power was 4/5, while upper-limb power was

preserved. Increased lower-limb spasticity was present, with patellar and ankle clonus and bilateral extensor

plantar responses. Sensory and cerebellar examinations were normal, and the Romberg test was negative.

Family History

A strong family history suggestive of autosomal dominant inheritance was noted. His father and brother

had similar gait difficulties. His father also developed visual and hearing impairment in later life, while his

brother had toe walking and hearing impairment.

Laboratory Investigations

Complete hemogram, renal, hepatic, and thyroid function tests were within normal limits. Serum vitamin

B12 and homocysteine levels were normal. HIV and syphilis serology were negative. Cerebrospinal fluid

analysis was normal. Nerve conduction studies showed preserved peripheral nerve function.

Magnetic Resonance Imaging Findings

MRI of the spine demonstrated multilevel degenerative disc and facet changes with canal stenosis at C5–

C6 and C6–C7. Fusion of the T4 and T5 vertebral bodies and a posterior disc-osteophyte complex at T7–

T8 were also noted.

Brain MRI demonstrated hyperintense signals at the tips of the frontal horns of the lateral ventricles on

T2/FLAIR images, corresponding to the characteristic “ears of the lynx” sign.

Genetic Evaluation

In view of the slowly progressive lower-limb spasticity, subtle lifelong gait symptoms, and strong family

history, genetic testing was performed. Whole-exome sequencing identified a missense variant in exon 12

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of the ATL1 gene, c.1376A>G (p.Tyr459Cys). The variant was classified as likely pathogenic according to

ACMG criteria based on PM1, PP2, PM2, PP3, and PP5.

Differential Diagnosis

Primary lateral sclerosis, spinocerebellar ataxia, and chronic myelopathy were considered as differential

diagnoses. The absence of cerebellar involvement, normal electrophysiological studies, preserved

sensation, and slowly progressive symmetric lower-limb spasticity favored hereditary spastic paraplegia.

Treatment and Follow-up

The patient was treated with oral baclofen 10 mg three times daily, targeted physiotherapy, and

rehabilitative gait training. At six-month follow-up, modest improvement in gait stability and lower-limb

spasticity was observed. Upper-limb strength remained preserved, with no new neurological deficits.

Discussion

Hereditary spastic paraplegia (HSP) comprises a heterogeneous group of inherited neurodegenerative

disorders characterized by progressive lower-limb spasticity and weakness due to corticospinal tract

involvement. ATL1-associated HSP (SPG3A) is an important form of autosomal dominant HSP and

typically presents during childhood or adolescence. The present case is unusual because the patient

presented with significant progression of symptoms in the seventh decade, despite having subtle gait

difficulty since childhood, highlighting the marked phenotypic variability of ATL1-associated disease

[7,8].

Diagnostic Challenges in Late-Onset HSP

Late-onset HSP can be difficult to diagnose because its clinical manifestations overlap with several

acquired neurological disorders, including primary lateral sclerosis, adult-onset leukodystrophies,

cervical spondylotic myelopathy, and metabolic myelopathies [9,10]. In older patients, age-related

spinal degenerative changes may further complicate interpretation of imaging findings. In the present

case, although MRI demonstrated multilevel degenerative changes and canal stenosis, the absence of

sensory deficits, preserved cognition, normal nerve conduction studies, and lack of cerebellar

involvement supported a hereditary rather than an acquired cause of spastic paraparesis [9,10].

Role of Neuroimaging

Neuroimaging has a supportive role in the evaluation of HSP but is not diagnostic by itself. The “ears

of the lynx” sign identified on brain MRI is classically associated with SPG11 and reflects abnormalities

involving the anterior forceps of the corpus callosum. However, this radiological feature may also occur

in other forms of upper motor neuron degeneration and should therefore be interpreted in conjunction

with clinical and genetic findings [11]. The spinal degenerative changes observed in this patient also

emphasize the importance of correlating imaging findings with the clinical phenotype rather than

attributing progressive gait impairment solely to structural abnormalities [7,11].

Genetic Confirmation

Genetic analysis remains an important component in establishing the diagnosis of atypical HSP. In the

present case, whole-exome sequencing identified the ATL1 missense variant c.1376A>G;

p.(Tyr459Cys), which was classified as likely pathogenic according to ACMG criteria. Previous reports

have demonstrated that ATL1 mutations may exhibit considerable phenotypic variability, including

differences in age at onset and disease severity [12,13]. The identification of an ATL1 variant in this

patient therefore provides molecular support for the diagnosis and demonstrates that ATL1-associated

HSP can occasionally manifest with a much later clinical presentation than traditionally expected

[12,13].

Pathophysiological Considerations

ATL1 encodes atlastin-1, a GTPase involved in maintaining the endoplasmic reticulum network and

neuronal axonal integrity. Alterations in ATL1 may interfere with these cellular processes and contribute

to progressive corticospinal tract degeneration [14]. The slow, symmetrical progression of lower-limb

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spasticity in the present patient is consistent with the neurological phenotype associated with hereditary

spastic paraplegia.

Management and Clinical Implications

Management of HSP is primarily supportive and aims to reduce spasticity, maintain mobility, and

improve functional independence. The patient was treated with oral baclofen, targeted physiotherapy,

and rehabilitative gait training, resulting in modest improvement in gait stability and spasticity at six-

month follow-up. Early recognition and genetic confirmation are clinically valuable because they

facilitate appropriate symptomatic management, genetic counseling, prognostic assessment, and

screening of potentially affected family members [12–14].

Summary

This case highlights a rare late-onset presentation of ATL1-associated hereditary spastic paraplegia in a

61-year-old man with subtle gait difficulty since childhood and progressive lower-limb spasticity. The

strong family history, characteristic neurological findings, exclusion of metabolic and acquired causes,

supportive MRI findings, and identification of a likely pathogenic ATL1 variant established the

diagnosis. The case emphasizes that hereditary spastic paraplegia should be considered even in older

adults presenting with progressive spastic paraparesis, particularly when there are lifelong symptoms

and a positive family history. Early genetic confirmation is important for appropriate management,

rehabilitation, prognostic assessment, and family counseling.

Conclusion

Mucocutaneous manifestations are very common in HIV patients. The usual lesions can present with

unusual and atypical manifestations in HIV patients. The non-infectious lesions were more common than

infectious lesions. Among infectious lesions, fungal infections were more common and papulopruritic

eruption was more common among non-infectious lesions. Neoplastic lesions were seen in only 1.8% of

patients. There was a significant correlation between the CD4 count and the mucocutaneous lesions. In our

study, the mean CD4 count was found to be low (< 350 cells/cumm) in patients with infectious lesions,

whereas non infectious lesion was associated with CD4 count of >350 cells/cumm. No significant

correlation was seen between viral load and mucocutaneous lesions in our study.

Declaration

Conflict of Interest: The authors declare that they have no competing interests or conflicts of interest

related to this work.

Funding: Nil

Ethical Permission: Ethical approval was obtained from the Institutional Ethics Committee of the

concerned institution prior to the conduct of the study. Written informed consent was obtained from the

patient for publication of the case and relevant clinical information. Patient confidentiality was maintained

throughout, and no personally identifiable information was disclosed.

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