Dilated Cardiomyopathy in a Woman With SPG4-Associated Hereditary Spastic Paraplegia

Abstract

Background

Hereditary spastic paraplegia (HSP) is primarily an inherited neurodegenerative disorder, although reports suggest possible systemic involvement. Cardiac manifestations in SPG4-HSP remain poorly understood, and dilated cardiomyopathy (DCM) has not previously been documented.

Case Summary

A 54-year-old woman with genetically confirmed SPG4-HSP presented with progressive dyspnea and a new left bundle branch block. Echocardiography and cardiac magnetic resonance revealed nonischemic DCM with reduced ejection fraction and dyssynchrony. Alternative causes were excluded, and extended cardiomyopathy gene testing was negative. Guideline-directed medical therapy was initiated with symptomatic improvement at outpatient follow up, and she subsequently received cardiac resynchronization therapy with defibrillator given persistent low ejection fraction and dyssynchrony.

Discussion/Novelty

To the best of our knowledge, this is the first reported experience of coexisting SPG4-HSP and idiopathic DCM. While causality remains uncertain, the case highlights a potential cardiac phenotype in SPG4 and underscores the importance of targeted cardiac evaluation in HSP patients presenting with exertional symptoms.

Take-Home Messages

Cardiac symptoms in SPG4-HSP warrant structured cardiac assessment. Standard heart-failure therapy and device management remain applicable.

Visual Summary

Hereditary spastic paraplegia (HSP) comprises a heterogeneous group of inherited neurodegenerative disorders characterized primarily by progressive lower limb spasticity and weakness. The SPAST gene (SPG4 subtype), encoding the microtubule-severing protein spastin, represents the most common genetic cause of autosomal-dominant HSP.^1,2 Although SPG4 mutations predominantly affect the corticospinal tracts, emerging evidence suggests a broader phenotypic spectrum that may include nonmotor manifestations.³ Although rare, cardiac involvement in HSP has been suggested in isolated reports.^4,5 However, none of these described cases had SPG4 mutations.

Take-Home Messages

• •Clinicians managing patients with hereditary spastic paraplegia should be alert to non-neurological symptoms such as dyspnea or exercise intolerance. Early cardiac evaluation may be warranted, particularly in those with a family history of heart disease.
• •Standard guideline-directed medical therapy for heart failure and subsequent device implantation can be safely initiated and adapted in patients with this underlying neurogenetic condition.

Here, we present the case of a woman with a heterozygous pathogenic SPG4 mutation and newly diagnosed dilated cardiomyopathy (DCM).

History of Presentation

A 54-year-old Caucasian woman with HSP due to a heterozygous pathogenic SPAST variant (NM_014946.4:c.1685G>A) presented with gradually increasing dyspnea and intermittent chest discomfort over the preceding weeks. She did not report chest pain on arrival, and she denied palpitations or syncope. However, she reported intermittent lower extremity swelling at home. She had no orthopnea.

On admission, she was in a satisfactory general state of health, hemodynamically stable with normal heart rate of 71 beats/min and blood pressure of 134/82 mm Hg. She had a normal respiratory rate of 12 breaths/min. Clinical examination revealed that she was warm and well perfused, with no crackles on lung auscultation, no cardiac murmurs, and no peripheral edema. No new or focal neurological symptoms were reported, and therefore a neurological examination was not conducted. The on-call neurologist was consulted and determined that no further examination was warranted.

Past Medical History

The patient's medical history included genetically confirmed SPG4-associated HSP, celiac disease, and surgery for perforated gastric ulcer in 2015. She had smoked from youth until age 41 years. Her family history was notable for HSP in both her mother and maternal grandfather (Figure 1). The medical records of her mother are not available, but according to the index patient, she was diagnosed with heart failure in her late 50s, and she also had coronary artery disease toward the end of life. The patient's father had a history of myocardial infarction.

Figure 1.

Pedigree Illustrating the Inheritance Pattern of the SPG4-Associated Mutation

The index patient (arrow) carries both the mutation and developed heart failure, as did her mother. Circles indicate females and squares males; filled symbols denote individuals with HSP, while unfilled symbols represent unaffected individuals. HSP = hereditary spastic paraplegia.

Her medication at presentation included the serotonin-norepinephrine reuptake inhibitor duloxetine for depression and chronic pain, tapentadol extended-release and oxycodone/naloxone prolonged-release for chronic pain, as well as acetaminophen and as-needed oxycodone. She was also taking pantoprazole for a history of gastric ulcer, medroxyprogesterone and transdermal estradiol as hormone therapy, zopiclone as a hypnotic agent, and macrogol as a laxative. She did not use any immunotherapy or immunosuppressive agents.

Differential Diagnosis

Several systemic and organ-specific conditions may present with intermittent chest discomfort and gradually progressive functional dyspnea. Cardiac differential diagnoses include ischemic cardiomyopathy, myocarditis of viral or autoimmune etiology, drug-induced cardiomyopathy, and genetic cardiomyopathy. Consideration of autonomic dysfunction related to the patient's underlying HSP was also plausible.

Investigations

Suspicion of heart disease arose quickly after early investigations. Electrocardiogram revealed sinus rhythm and a newly developed left bundle branch block (QRS duration: 138 ms) (Figure 2). N-terminal pro–B-type natriuretic peptide was markedly elevated at 4,924 pg/mL. Her total cholesterol levels were 6.9 mmol/L, with a low-density lipoprotein level of 4.4 mmol/L. Her body mass index was 27.0 kg/m².

Figure 2.

The Patient's ECG on Admission

The index patient's ECG on admission demonstrated sinus rhythm at 75 beats/min with a left bundle branch block and a prolonged QRS interval of 138 ms. ECG = electrocardiogram.

Transthoracic echocardiography showed mild dilation of the left ventricle (end-diastolic dimension: 5.3 cm, end-systolic dimension: 4.8 cm), global hypokinesis with reduced left ventricular ejection fraction (25%), and normal myocardial thickness with a septal diameter of 9 mm. There was mild mitral regurgitation and borderline elevated pulmonary pressures. There was no pericardial or pleural effusion.

Computed tomography coronary angiography performed during hospitalization showed no significant disease except for a minor eccentric calcified plaque present in the proximal left anterior descending artery just before the origin of the first diagonal branch.

Management

The patient was started on standard heart failure therapy with an angiotensin receptor blocker, mineralocorticoid receptor antagonist, sodium-glucose transport protein 2 inhibitor, and beta-blocker. During admission, the angiotensin receptor blocker was replaced by sacubitril/valsartan (angiotensin receptor neprilysin inhibitor).

Continuous heart monitoring during hospitalization showed persistent sinus rhythm, stable left bundle branch block morphology, and only occasional isolated ventricular extrasystoles.

Outcome and Follow-Up

After discharge, the patient was evaluated at a heart failure outpatient clinic. She reported symptomatic improvement. Orthostatic hypotension prompted reduction in metoprolol dosage. As noted, the patient had been prescribed duloxetine, which inhibits CYP2D6 and may raise metoprolol levels—a factor considered during dose adjustments.

Outpatient cardiac magnetic resonance confirmed left ventricular dilatation with dyssynchronous contraction and global hypokinesis. Left ventricular end-diastolic volume was 180 mL (indexed 104 mL/m²), end-systolic volume 123 mL (indexed 71 mL/m²), and ejection fraction was 32%. No hypertrophy was present (septum: 1.0 cm, lateral wall: 0.6 cm). A small subepicardial signal on late gadolinium enhancement indicated possible fibrosis, though artifact could not be excluded. No other signs of fibrosis or scarring were present. Extracellular volume was 28%, in the upper normal range. No significant valvular abnormalities were detected. Right ventricular volumes and function were normal. Extended genetic testing using a next-generation sequencing gene panel (see list in Supplemental Material) did not identify additional pathogenic variants associated with cardiomyopathy. In accordance with European Society of Cardiology guidelines for sinus rhythm, QRS >130 ms, low ejection fraction <35%, persistent dyssynchrony, and symptoms after guideline-directed medical therapy, she received cardiac resynchronization therapy with defibrillator (CRT-D) (Figure 3).

Figure 3.

Timeline of the Patient's Clinical Course From Preadmission to Outpatient Follow-Up

The timeline illustrates the clinical course of the index patient, beginning several months before admission and concluding with outpatient follow-up. CAD = coronary artery disease; CMR = cardiac magnetic resonance; CRT-D = cardiac resynchronization therapy with defibrillator; CT = computed tomography; DCM = dilated cardiomyopathy; GDMT = guideline-directed medical therapy; LBBB = left bundle branch block; LV = left ventricular; NT-proBNP = N-terminal pro–B-type natriuretic peptide.

Discussion

Cardiac manifestations in HSP are sporadically reported, and to our knowledge no previous cases have described pathogenic SPG4 mutations. Gdynia et al⁴ described cardiomyopathy in 2 patients with spastin mutation–negative HSP, and Corona et al⁵ reported a family with a non-SPG–associated HSP and heterogeneous clinical presentation, including cardiomyopathy. González-Salazar et al⁶ found preserved cardiovascular autonomic function in SPG4 patients. Although mitochondrial dysfunction in muscle tissue has been implicated in other HSP subtypes, particularly SPG7,^2,7, 8, 9, 10 no such alterations have been observed in SPG4, and no mechanistic evidence links SPAST mutations to cardiomyopathy.

Causality cannot be established; however, the occurrence of heart failure in a first-degree relative carrying a SPG4 mutation raises the possibility of a shared pathophysiological mechanism. The patient reported that her mother also had heart failure in her late 50s, although she had coronary artery disease toward the end of her life, and her medical records are unavailable.

Cardiac magnetic resonance confirmed the diagnosis of nonischemic DCM, demonstrating a dilated left ventricle with dyssynchronous contraction and global hypokinesis. Late gadolinium enhancement showed only a subtle, uncertain area of possible subepicardial fibrosis in the basal inferolateral wall, without widespread scarring or hypertrophy, supporting a primary cardiomyopathic process, which further supported the idiopathic nature of the patient's DCM.

Novelty of the submission

To the best of our knowledge, this case represents the first coexistence of idiopathic DCM and SPG4-HSP. This observation expands the phenotypic spectrum associated with SPAST-related disease and raises the possibility that autonomic dysfunction or other systemic mechanisms may contribute to cardiac manifestations in this subtype.

Future Directions

Clinicians should consider early cardiac evaluation in SPG4-HSP patients presenting with unexplained dyspnea, even in the absence of other cardiovascular risk factors. Standard management of heart failure with guideline-directed medical therapy, followed by cardiac resynchronization therapy when indicated, appears to be safe in this patient population.

Conclusions

Although a direct causal relationship remains unproven, this case highlights a potential association between SPG4 mutations and cardiomyopathy and expands the known phenotypic spectrum of SPG4-HSP.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.