X-linked adrenoleukodystrophy as an etiological cause of progressive spastic paraplegia: A case report

Abstract

X-linked adrenoleukodystrophy is a rare peroxisomal disorder caused by mutations in ABCD1, thereby resulting in impaired β-oxidation of very long-chain fatty acids. Its adult-onset form, adrenomyeloneuropathy, typically presents as progressive spastic paraparesis that mimics hereditary spastic paraplegia. Brain and spinal magnetic resonance imaging findings are often unremarkable, contributing to diagnostic delays and misdiagnosis. Herein, we report the case of a 60-year-old woman who presented with a 10-year history of progressive lower limb stiffness, weakness, and gait disturbance. She was initially diagnosed with hereditary spastic paraplegia and sought a second opinion. Her family history was remarkable for her father, who experienced a chronic gait disturbance of unknown etiology but never received a formal diagnosis. Neurological examination revealed mild weakness and spasticity in the bilateral lower extremities accompanied by bladder dysfunction, whereas magnetic resonance imaging of the brain and spine was normal. Given the relevant family history and presence of urinary symptoms, metabolic testing was performed. Elevated plasma very long-chain fatty acid levels and a pathogenic variant in ABCD1 confirmed the diagnosis of X-linked adrenoleukodystrophy presenting as adrenomyeloneuropathy. This case underscores the need to consider X-linked adrenoleukodystrophy in patients with progressive spastic paraparesis, even in the absence of imaging abnormalities.

Introduction

In clinical practice, patients often present with progressive lower limb weakness, spasticity, and gait disturbance. These symptoms are typically attributed to upper motor neuron lesions. Among chronic progressive disorders, hereditary spastic paraplegia (HSP) is a common cause of such presentations. ¹ However, similar neurological features can develop in metabolic or demyelinating disorders involving the central nervous system, ² resulting in a misdiagnosis as HSP. ³

X-linked adrenoleukodystrophy (X-ALD) is a rare peroxisomal disorder caused by pathogenic variants in ABCD1, resulting in impaired β-oxidation of very long-chain fatty acid (VLCFA). ⁴ As a result, VLCFAs accumulate, causing demyelination and axonopathy in the white matter of the nervous system and affecting the adrenal glands. ⁴ X-ALD exhibits a broad clinical spectrum, including childhood cerebral ALD, adrenomyeloneuropathy (AMN) in adults, and isolated adrenal insufficiency. ⁵ Adult-onset forms of X-ALD can mimic HSP because of their slowly progressive spastic paraparesis and the absence of overt cerebral demyelination in the early disease course. ³ In this report, we describe a case of adult-onset X-ALD initially misdiagnosed as HSP.

Case presentation

A 60-year-old woman presented to the outpatient clinic of the Department of Physical Medicine and Rehabilitation at Yeungnam University Hospital in Daegu, South Korea, in May 2024 for evaluation of a previously diagnosed HSP at another hospital and for a second opinion. She reported a 10-year history of slowly progressive weakness and stiffness in both lower extremities, which began at approximately 50 years of age and resulted in increasing gait disturbance. She also reported increased urinary frequency but did not experience sensory loss, cognitive decline, or visual changes. The patient showed no additional features, including autonomic dysfunction, skin or mucosal hyperpigmentation, psychiatric symptoms, or cerebellar ataxia. Her family history was remarkable for her father, who experienced a chronic gait disturbance of unknown etiology but never received a formal diagnosis. No other family members reported a history of gait disturbance or related disorders.

Neurological examination revealed that her muscle strength (Medical Research Council grade 4) in the bilateral hip flexors, knee extensors, and ankle dorsiflexors and plantarflexors was mildly weakened In contrast, upper limb strength and tone were preserved. She exhibited marked spasticity and increased muscle tone in both lower extremities. Ankle clonus was noted bilaterally (15 beats on both sides), and bilateral deep tendon reflexes, including those of the patella and Achilles, were exaggerated. However, bilateral deep tendon reflexes in the upper extremities, including the biceps, triceps, and brachioradialis, were normoactive. Babinski signs were positive on both sides.

Routine laboratory findings, including electrolytes and thyroid and liver function test results, were unremarkable. Nerve conduction studies and electromyography of the lower extremities showed no evidence of peripheral neuropathy. Magnetic resonance imaging (MRI) of the brain and spine revealed no abnormal signal intensity or structural lesions.

Considering the slowly progressive spastic paraparesis that began at age 50 and the normal MRI findings, HSP was suspected. However, given the possibility of metabolic or peroxisomal disorders that can mimic HSP, plasma VLCFAs were measured. The results demonstrated an elevated hexacosanoic acid (C26:0 = 2.21 µmol/L) levels and an increased C26:0/C22:0 ratio (0.044), suggesting impaired peroxisomal β-oxidation.

We performed genetic analysis using a targeted next-generation sequencing panel for HSP and related disorders by extracting genomic deoxyribonucleic acid from peripheral blood leukocytes. We achieved target enrichment through hybridization-based capture (NextSeq-GVI v3.0) and sequenced the enriched libraries on an Illumina NextSeq platform. Bioinformatic analysis employed the NextSeq_BI-GVI pipeline (v1.1.0), aligned to the human reference genome hg19/GRCh37. This analysis identified a heterozygous missense variant in the ABCD1 gene (NM_000033.3:c.1628C>T, p.Pro543Leu) on chromosome X. According to the 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines, this variant is classified as pathogenic. ⁶ The inheritance pattern was consistent with an X-linked recessive disease. Although we could not perform formal segregation analysis because family members were unavailable for testing, the patient’s father reportedly exhibited a similar gait disturbance, supporting the clinical relevance of this variant.

On the basis of these findings, a final diagnosis of adult-onset X-ALD presenting as AMN was established. The patient was treated with 2.5 mL/kg/day of Lorenzo’s oil (a 4:1 mixture of glyceryl trioleate and glyceryl trierucate) to reduce plasma VLCFA levels.

This study was approved by the local Institutional Review Board of Yeungnam University Hospital, Yeungnam University, Daegu, South Korea (Approval Number: 2025-05-025; Approval Date: 23 May 2025). Written informed consent for treatment and publication of this case report was obtained from the patient. The case report adheres to the Case Report (CARE) guidelines. ⁷

Discussion

X-ALD is a rare peroxisomal disorder that exhibits remarkable phenotypic variability, even among individuals carrying the same ABCD1 mutation. ⁴ Its adult-onset form, AMN, is characterized by slowly progressive spastic paraparesis, sphincter dysfunction, and, in some cases, peripheral neuropathy or adrenal insufficiency. ⁸ Brain and spinal MRI findings are often unremarkable in AMN, particularly during the early stages, contributing to frequent misdiagnosis.^9–11 Because of the slowly progressive symptoms involving the spinal cord and the absence of cerebral involvement in approximately half of patients with AMN, the condition is often misdiagnosed as HSP, especially in female carriers.

Traditionally, women carrying pathogenic variants in ABCD1 were considered asymptomatic carriers. However, accumulating evidence suggests that up to 80% of heterozygous females develop neurological symptoms during adulthood, most commonly in their 40s to 50s. ¹² These symptoms often include spastic paraparesis and gait disturbance, which closely resemble the symptoms of HSP.

In our case, the 60-year-old female patient presented with slowly progressive spastic paraparesis beginning at approximately the age of 50, which is consistent with the known age range of symptom onset in symptomatic female carriers. Although her MRI findings were unremarkable, the presence of bladder symptoms and a family history suggestive of similar neurological problems raised suspicion of an underlying metabolic or genetic disorder. Biochemical testing revealed elevated plasma VLCFAs levels, and genetic analysis identified a pathogenic variant in ABCD1, confirming the diagnosis of X-ALD. Differentiating X-ALD from HSP can be clinically challenging because of overlapping neurological features. Currently, no curative therapy for AMN exists. Lorenzo’s oil, a 4:1 mixture of glyceryl trioleate and glyceryl trierucate, can normalize plasma VLCFA levels and may delay disease progression, particularly when used early in the disease course. ¹³

Recent reports show that ABCD1 mutations can produce a phenotype closely resembling HSP, suggesting an overlapping clinical spectrum between X-ALD and HSP.^3,8,14 Hsu et al. ¹⁴ further emphasized that ABCD1 mutations can underlie HSP-like presentations and recommended ABCD1 gene analysis in patients with clinically suspected HSP of unknown genetic origin.

Some previously reported cases of adult-onset X-ALD presenting with spastic paraparesis share key clinical features with our patient, including slowly progressive lower limb spasticity, normal or nonspecific brain and spinal MRI findings, and an initial misdiagnosis of HSP.^3,8,14 Similar to our patient, these cases often lacked early cerebral involvement and received a diagnosis only after biochemical evaluation revealed elevated VLCFAs followed by identification of pathogenic ABCD1 variants. Notably, most earlier reports involved male patients with earlier symptom onset and more frequent signs of adrenal insufficiency, such as alopecia and skin or mucosal hyperpigmentation.

Regarding genotype–phenotype correlation, previous studies show that ABCD1 mutations occur throughout the gene without a consistent relationship between mutation location and clinical phenotype. ¹⁵ Pathogenic variants associated with AMN, cerebral ALD, or HSP-like phenotypes have been identified across multiple functional domains of the ABCD1 protein.^3,8,14 Reports of HSP-like presentations linked to diverse ABCD1 variants suggest that this phenotype does not result from a specific mutation site but rather reflects the broad clinical spectrum of ABCD1-related disorders. Current evidence, therefore, does not support a precise genotype–phenotype correlation based solely on the location of the mutation.

This case emphasizes the need to consider X-ALD in patients with progressive spastic paraparesis, even when imaging findings are normal. Through early recognition, appropriate metabolic testing, genetic confirmation, and family screening can be performed, ultimately allowing timely management. It also helps clinicians recognize the risk of potentially life-threatening adrenal insufficiency early in male patients with X-ALD.