Novel genetic variant in hereditary spastic paraparesis

Abstract

A man in his 30s was referred to neurology with right-sided paraesthesia, tremors, chest pain and lower urinary tract and erectile dysfunction. He had a medical history of left acetabular dysplasia, and subjective memory impairment, the latter being in the context of depression and chronic pain with opioid use. There was no notable family history. On examination, he had a spastic paraparesis. Imaging revealed atrophy of the thoracic spine. Lumbar puncture demonstrated a raised protein but other constituents were normal, including no presence of oligoclonal bands. Genetic testing revealed a novel heterozygous likely pathogenic SPAST variant c. 1643A>T p.(Asp548Val), confirming the diagnosis of hereditary spastic paraparesis. Symptomatic treatment with physiotherapy and antispasmodic therapy was initiated. This is the first study reporting a patient with this SPAST variant. Ensembl variant effect predictor was used, with the application of computational variant prediction tools providing support that the variant we have identified is likely deleterious and damaging. Our variant CADD score was high, indicating that our identified variant was a highly deleterious substitution.

Background

The hereditary spastic paraplegias (HSPs), also known as Strumpell-Lorrain syndrome, are a group of clinically and genetically heterogeneous neurodegenerative disorders characterised by bilateral lower limb spasticity and weakness. The prevalence of HSP has been estimated to be between 1 and 10 per 100 000 and affects both males and females with no evidence there is an ethnic predilection.^{1 2} The presentation of HSP, the symptoms, severity and age of onset varies considerably, ranging from infancy to 70 years of age.³ The management is symptomatic. The diagnosis can have considerable impact on families as it an inherited condition.

Our patient presented with paraesthesia, lower urinary tract and erectile dysfunction. He had a spastic paraparesis and was ultimately diagnosed with HSP. The case demonstrates the importance of considering this diagnosis in patients without a family history of spasticity and the role of genetic testing.

Case presentation

A man in his 30s presented with a 6-month history of right-sided paraesthesia along with lower urinary tract and sexual dysfunction. He had frequency and urgency of micturition, increased tone of the bladder neck and erectile dysfunction. In addition, he had lower limb paraesthesia and stiffness. He was able to walk independently, without apparent issues.

He had a background of left acetabular dysplasia with chronic pain and depression.

His regular medications were sertraline for depression, paracetamol and tramadol for pain affecting the right hip and zopiclone.

The patient was a smoker of 10 cigarettes a day and did not drink any alcohol. Of note one of his four children has a spastic diplegia diagnosed as cerebral palsy. There was no known family history of spasticity otherwise. The only other family history was of ischaemic stroke in his father when he was in his 50s.

On examination, he had a mild spastic gait. Cranial nerves were normal. There was spasticity in the upper limbs (Ashworth grade 1/4) with normal preservation of power and brisk reflexes (+++). There was a subjective altered sensation throughout the rest of the right upper limb. Coordination was normal.

There was more marked spasticity in both lower limbs (Ashworth scale 3/4) with sustained clonus. Power was normal throughout. Despite his complaint of paraesthesia, sensory examination was normal. There was no incoordination. Reflexes were brisk (++++) and both plantar responses were extensor.

Investigations

The following blood tests were either normal or negative; these included a full blood count, urea and electrolytes, glucose, cortisol and liver function. Plasma viscosity was 1.63 mPa.s. (1.5–1.72) and C reactive protein less than 4. Bone profile (corrected calcium and albumin), thyroid function tests and folate did not demonstrate any abnormalities. Vitamin B₁₂ was 955 ng/L (200–940 ng/L). Serum tests for causes of neuroinflammation included serum ACE, immunoglobulins, complement, connective tissues disease screen and aquaporin 4 antibodies; these did not demonstrate any abnormal findings. Infectious screening, including serum syphilis, Borrelia and HIV, was negative.

MRI thoracic spine demonstrated atrophy, as shown in figure 1A. MRI brain was considered to be within normal limits, with a normal corpus callosum, as demonstrated in figure 1B,C. MRI cervical spine demonstrated mild degenerative changes only, and lumbar sacral imaging was normal.

Figure 1.

MRI scans. (A) Sagittal T2-weighted MRI thoracic spine demonstrating thoracic cord atrophy. (B) Sagittal Fluid Attenuated Inversion Recovery (FLAIR) MRI brain sequence demonstrating a normal corpus callosum. (C) Axial FLAIR MRI brain sequence with non-specific high signal change thought to be within normal limits.

Cerebrospinal fluid (CSF) protein was raised at 679 mg/L (150–450 mg/L). Other CSF constituencies, including white cell count, gram stain, culture and oligoclonal bands, were normal.

The thoracic cord atrophy and suggestive family history in the patient’s child, along with the absence of any definite neuroinflammatory or compressive aetiology, led to genetic testing for HSP. This identified a heterozygous SPAST variant c. 1643A>T p.(Asp548Val) and consequently the patient was diagnosed with HSP. This was identified as a novel variant and not previously reported in the literature or on the gnomAD database. It is predicted to disrupt the highly conserved ATPase domain where most reported pathogenic missense variants are located. The initial analysis reported the variant to be likely pathogenic, therefore, we felt this result was consistent with the phenotype seen in this patient.

Differential diagnosis

Neuroinflammatory conditions, such as multiple sclerosis, neuromyelitis optica spectrum disorder, neurosarcoidosis and cerebral vasculitis, were considered, however, negative or non-confirmatory tests ruled these out. Spinal compression was considered as a cause of a similar presentation, however, imaging did not demonstrate changes consistent with this. Infections and vitamin deficiencies were also considered as differential diagnoses, but normal tests also ruled these out.

Treatment

The patient was commenced on baclofen 10 mg once daily, uptitrated to three times per day, for symptomatic treatment of spasticity with modest effect.

Outcome and follow-up

There has been some alleviation of spasticity with baclofen. Genetic counselling and consideration of testing of offspring, particularly the one with a current diagnosis of cerebral palsy, and parental testing is ongoing. In retrospect, we think that the chest pains the patient had been experiencing may have been secondary to chest wall muscle spasticity. His lower urinary tract dysfunction and erectile impairment are thought to be related to his spinal cord disorder aggravated by depression and medication.

Discussion

HSP can be classified based on the mode of inheritance, chromosomal locus, clinical phenotype and, if known, the causative mutation, along with other pathophysiological mechanisms.

The number of known HSP genes continues to expand and, to date, more than 80 chromosomal locations (‘loci’) designated as SPGs (from SPastic parapleGia) have been identified. These are numbered sequentially in order of discovery from SPG1.^{4 5} These affected genes encode proteins that have a diverse effect on intracellular and axonal transport, synapse formation and myelin maintenance.

This case describes a missense mutation on the SPAST gene. This is the most commonly mutated gene in autosomal-dominant HSP and sporadic HSP, resulting in SPG type 4 (SPG4) or SPAST-HSP.^{6 7} The SPAST gene is located on chromosome 2p22.2 and encodes spastin, a protein found throughout the body, but particularly in neurones. Spastin is a member of the AAA protein family (ATP-ases Associated with diverse cellular Activities) and hydrolyses ATP to sever microtubules, thus controlling aspects of microtubule dynamics, directly affecting axonal transport.^{8 9} The AAA domain and microtubule interacting and trafficking (MIT) domain play key functional roles. Over 300 mutations have been reported along the SPAST gene including missense, nonsense, splice and frameshift mutations, and single or multiple exon deletions and insertions, which subsequently result in axonal dysfunction.

We used ensembl variant effect predictor.¹⁰ The application of computational variant prediction tools provided support that the variant we have identified is likely deleterious. The variation we describe has a Sorting Intolerant From Tolerant (SIFT) score of 0.00, which is most deleterious on a scale from 0 to 1.¹¹ The aspartate to valine substitution in our patient has a PolyPhen-2 score of 0.996, where 0 is likely benign and 1 is likely deleterious.¹² Therefore, this score predicts our variant to be probably damaging. Our variant Combined Annotation Dependent Depletion (CADD) score was 29.6. Variants with scores greater than 20 are predicted to be in the top 1% of the most deleterious substitutions in the genome and scores greater than 30 are in the top 0.1%.¹³

Most pathogenic mutations occur at the AAA cassette or the MIT domains; this SPAST variant occurs at the former. The mechanism of disease causation is most commonly understood to be due to a loss of function (haploinsufficiency), where the disease occurs once the level of functional spastin falls below a critical level.¹⁴ Alternate theories have been proposed, such as the dominant-negative theory where spastin is proposed to constitutively bind to microtubules leading to impairments in organelle transport and resulting in corticospinal axon degeneration.¹⁵ Accordingly, HSPs are characterised by a gradual distal degeneration of the long axons of the lateral corticospinal tract, causing the upper motor neuron syndrome. Postmortem neuropathological studies show axonal degeneration in the fasciculus gracilis fibres.¹

Marked atrophy of the upper spinal cord has been documented in patients with HSP of various genetic variants.^{16 17} One study found that SPG6 and SPG8 variants display early and more severe spinal cord atrophy. Conversely, SPG4 variants showed less marked atrophy in the cross-sectional spinal cord area, however, there was a reduced anteroposterior diameter.¹⁶ As demonstrated in figure 1A, our patient had atrophy of the thoracic spine but relative sparing of the cervical spine.

HSPs can be inherited in an autosomal dominant, autosomal recessive, X-linked and mitochondrial manner or can occur sporadically. SPAST-HSP is inherited in an autosomal dominant fashion, thus meaning individuals usually have a symptomatic parent. More rarely, as in this case, they can present as sporadic. It is important to recognise that seemingly sporadic cases of HSP are not always true de novo SPAST mutations; they might be due to reduced penetrance, early death of parent before onset of symptoms, non-paternity or failure to recognise the disorder in family members among other reasons. True de novo mutations are confirmed when neither parent possesses the mutation. In our case, as of yet other family members have not been tested. It is unknown whether our patient’s son with a spastic diplegia is affected.

For many HSP genetic mutations, there remains no clear genotype–phenotype correlation, where the same genetic mutations can be associated with both pure and complicated phenotypes.¹ However, as SPAST-HSP is the most common variant, there have been several cross-sectional cohort studies aiming to find consistencies. There is now a known bimodal age of onset with the first peak occurring before the first decade of life, and the second lower peak between the third and fifth decades.^{9 18} It is estimated that 6% of patients with an SPAST mutation will remain asymptomatic. This is likely due to incomplete penetrance, reported to be more likely in women.¹⁸ The phenotype of our case is one of initial lower urinary tract dysfunction with subsequent subacute spasticity and paraesthesia.

HSP does not usually affect life expectancy but can lead to significant morbidity. Although individual disease progression and prognosis are difficult to predict exactly, a cross-sectional cohort study found that after 40 years of disease duration, around 25% of HSP patients walk unaided and less than one-third are wheelchair dependent in their daily life.¹ While some patients may experience no clinical progression, it is important to note that the degree of spasticity may increase if adequate range of motion is not maintained through muscle spasticity reduction, stretching and physiotherapy.

There are some fundamental considerations to explore with a patient with suspected HSP, outlined in figure 2.

Figure 2.

A summary of important considerations when assessing a patient with suspected HSP. HSP, hereditary spastic paraplegias.

Management is multidisciplinary, and at present, there are no disease-modifying therapies available for HSP. Oral antispasmodics such as baclofen and tizanidine slowly uptitrated have proven symptomatically beneficial to patients with spasticity regardless of the underlying disease process or severity, to decrease tone, disability and pain.¹⁹ When oral drugs are ineffective or not tolerated, intrathecal baclofen or botulinum toxin injections can be trialled for further symptomatic management.²⁰ Bladder training together with pharmacological management can be trialled for urinary dysfunction. Physiotherapy and stretching is encouraged to develop and maintain strength in the lower limbs to improve range of motion, reduce spasticity and improve balance. Depending on the degree of impairment, some patients might benefit from orthoses, walking-aids or wheelchairs.

Learning points.

• In patients presenting with spastic paraplegia with urinary symptoms in the absence of acquired causes, hereditary spastic paraplegia (HSP) must be considered in the differential diagnosis.

• In a patient with a family history of spasticity, even when not diagnosed with HSP, this should be considered as a possible cause and genetic testing is an important investigation to consider.

• The number of pathogenic HSP genes continues to expand; this particular SPAST mutation supports the heterogeneity of the HSPs. The addition of novel variants of genetic diseases to the database is important as it contributes to the understanding of the genetic landscape, with benefits to research and clinical applications.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).