Fampridine in Hereditary Spastic Paraplegia Type 4 With SPAST Variant c.683-2A>C: A Case Report

Introduction

Hereditary spastic paraplegia (HSP), also called familial spastic paraparesis, is a group of inherited neurological disorders that primarily affect the spinal cord and are clinically characterized by progressive spasticity and weakness of the leg muscles [1–4]. At onset, affected patients may have difficulty walking and feel somewhat stiff. Over time, these symptoms usually worsen. Many people with HSP eventually require the use of a cane, other walking aid, or a wheelchair [1–3]. The gene most commonly mutated in HSP is SPAST [4,5]. Approximately 40% of patients with pure HSP carry a SPAST mutation [4,5]. More than 50% of patients carrying a SPAST mutation have leg weakness and impaired sensation in their lower legs. Sphincter disorders are very common. Cerebral and spinal MRI may show reduced thalamic volume, structural lesions of the cerebrospinal or thalamocortical pathways, cerebellar atrophy, vermal atrophy, thin corpus callosum, subtle white-matter lesions (WMLs), and myeloid atrophy [6]. Three-fourths of the SPAST mutations are located in the AAA cassette of the spastin protein and impair its microtubule-severing activity [7,8]. Treatment of HSP4 is usually symptomatic. Fampridine has been successfully used to treat gait disturbances in some patients with HSP [9–11]. A beneficial effect of fampridine in HSP4 due to the c.683-2A>C variant in SPAST has not been reported to date. These new findings will expand knowledge on how spasticity can be effectively treated in patients with certain SPAST mutations.

Case Report

Our patient was a 63-year-old woman, 171 cm tall and 67 kg in weight. She had been experiencing hypogeusia and hyposomia for several years prior to the onset of pollakiuria since the age of 34, being triggered by flatulence or intestinal peristalsis. Since the age of 53, she developed mild foot drop and a scissor stance, resulting in gait disturbance. Since the age of 58, she noticed a decrease in walking speed. Since the age of 59, she occasionally experienced dysphagia and delayed defecation. Since the age of 59, she occasionally noted memory deficits. Since the age of 60, she had hypoacusis on the right side. Since the age of 62, she noticed myalgia and muscle cramps triggered by exercise. All these symptoms persisted to the present.

Her family history was positive for HSP in her 69-year-old sister, who had also had pollakiuria since her youth (Figure 1). Since the age of 50, the sister experienced frequent stumbling, unsteadiness, spasticity, and positional vertigo. A neurological examination at the age of 60 revealed severe paraspasticity of the lower extremities, hyperreflexia, positive pyramidal signs, and pallhypoesthesia. Somatosensory evoked potentials (SSEPs) of the tibialis showed prolonged latencies of the P40 response and reduced P25-N33 amplitude. Nerve conduction studies (NCS), EEG, VEPs, cerebrospinal fluid examination, and MRI of the brain and spine were inconclusive. She had required a walking aid since the age of 62. The mother of the 2 sisters died at the age of 76 as a result of diabetes, but she also had an unsteady gait, which is why she required use of a wheelchair. The maternal grandmother died of heart failure at the age of 65, but needed a cane to walk. At the ages of 60 and 53, respectively, the 2 sisters underwent genetic testing for HSP, which revealed the heterozygous variant c.683-2A>C in SPAST. This particular mutation has rarely been reported as a cause of autosomal dominant HSP.

The clinical neurological examination of our patient revealed painful neck muscles, hyposmia, hypogeusia, mild weakness of hip flexion (M5−), and minimal weakness of foot extension (M5−). The patellar tendon reflexes were pronounced, while the Achilles tendon reflexes were diminished. She had pallhypoesthesia in the lower legs. Her walking was characterized by a scissor gait, walking in a straight line was unsteady, and there was a tendency to fall when walking with eyes closed. Compared to 7 years earlier [12], she had newly-developed mild cognitive impairment, unilateral hearing loss, mild proximal weakness of the lower extremities, decreased Achilles tendon reflexes, and pallhypoesthesia. NCSs were unremarkable. Differential diagnoses considered included spinocerebellar ataxia, multiple sclerosis, spinal cord compression, vitamin deficiencies, leukodystrophies, vascular abnormalities, and mitochondrial disorders. They were thoroughly ruled out by appropriate clinical, laboratory, electrophysiological, and imaging examinations. Since the age of 62, she had been receiving fampridine (4-aminopyridine), which led to improvement in spasticity, gait disorders, and walking speed, as documented by the 6-meter walk test (6MWT) (from 559 m to 661 m), spastic paraplegia rating scale (SPRS) (from 22 to 14), and multidimensional self-esteem scale (MSWS). Within 1 year, the 6MWT improved from 11.5 seconds to 9.5 seconds, the SPRS improved from 22 to 14, and the MSWS improved from 9 to 14. A positive effect of fampridine on autosomal dominant HSP due to the variant c.683-2A>C in SPAST has not been previously reported. Her muscle cramps and myalgia responded well to magnesium and TENS.

Discussion

The present case is interesting because it is the first case carrying the SPAST variant c.683-2A>C that reacted positively to fampridine, because the disease progressed slowly over a period of 7 years, because of new key features of HSP4 such as hearing loss, diffuse paraparesis of the lower-extremity muscles, sensory disturbances, and muscle cramps developed, and because the disease progressed much more rapidly and occurred earlier in her affected sister.

Fampridine has previously been described as beneficial for at least some types of HSP. In a triple-blind, randomized, placebo-controlled pilot study, the effect of dalfampridine (20 mg/day) on walking speed, muscle length, spasticity, functional strength, and functional mobility was investigated in 4 patients with HSP [9]. The primary endpoint was the Timed 25-Foot Walk Test (T25FWT) at the end of the 8-week treatment, and the secondary endpoints were functional mobility, functional muscle strength, muscle length, and spasticity [9]. An improvement in the T25FWT was observed, but functional mobility, functional muscle strength, muscle length, and spasticity also improved [9]. No adverse events were observed. It was concluded that dalfampridine in combination with physical therapy improves muscle parameters and increases walking speed in HSP patients [9]. Treatment with fampridine in a patient with HSP due to the pathogenic variant c.1635+3G>T in PNPLA6 resulted in a significant improvement in symptoms [10]. In a proof-of-concept study involving 12 HSP patients, patients receiving dalfampridine (20 mg/day) showed significant improvement on the SPRS and the MSWS [11]. No serious adverse effects were observed.

Fampridine, or 4-aminopyridine, is a chemical compound from the aminopyridine group. Pharmacologically, it acts as a reversible potassium channel blocker, which is why it is used, among other things, as a drug to improve walking ability in adult patients with multiple sclerosis and severe walking disabilities [10]. It acts on damaged nerves and prevents potassium ions from escaping from the nerve cells. It is believed that this allows electrical impulses to travel further along the nerves and stimulate the muscles, making walking easier [11].

There is currently no cure for HSP4, and treatment focuses on alleviating the various symptoms [13]. Spasticity can be treated with baclofen, tizanidine, or botulinum toxin. Gait disorders can be alleviated through physical therapy, orthotics, and aids such as canes or walkers. Anticholinergics and alpha blockers can help treat urinary urgency and frequent bladder emptying. If HSP4 is accompanied by fatigue, pain, and cognitive changes, specific treatment is required. Some individuals have difficulty swallowing, which sometimes requires a feeding tube. Cognitive impairment is not usually a prominent feature, but some patients have changes in executive function and social cognition. In rare cases, patients with HSP4 develop psychosis, which requires the support of a psychiatrist. Many HSP4 patients require a use of a wheelchair due to progressive gait disturbances.

The limitations of the study are that the therapeutic effect of fampridine was documented in only 1 case, the effect was not systematically and prospectively evaluated, the assessment of the therapeutic effect was partially based on subjective impressions and may have been partly a placebo effect, natural fluctuations in symptoms could explain the treatment effect, and no continuous monitoring of the drug’s effect was performed. Magnesium and TENS had no confounding effect, as they were started before fampridine and did not improve spasticity.

Conclusions

Our report shows that HSP4 can progress slowly over a period of 7 years, HSP4 may present with typical phenotypic characteristics of the disease as it progresses, the rate of progression can vary between affected family members, and HSP4 patients can still work even in old age, and do not necessarily need antispastic drugs. This case also provides preliminary evidence that fampridine may be a viable symptomatic treatment option for patients with HSP4, including those with the mutation c.683-2A>C. It justifies further prospective, controlled studies in a larger SPAST-HSP population.