De novo mutations in SPG3A: a challenge in differential diagnosis and genetic counselling
Hereditary spastic paraplegias (HSPs) are genetically determined neurodegenerative disorders presenting with spasticity and progressive weakness predominantly affecting the lower limbs due to a length-dependent, retrograde axonopathy of corticospinal motor neurons. Traditionally, HSPs can be divided into pure (uncomplicated) and complicated forms, depending on the presence of additional neurological and non-neurological features . To date, about 70 HSPs gene loci have been mapped and all patterns of inheritance have been described . Mutations in SPG3A/ATL1, encoding atlastin-1, cause both pure and complicated forms and represent the most common autosomal dominant (AD) HSP with onset before age 10 years . The rate of progression is usually slow; wheelchair dependency or need for a support to walk is relatively rare . Herein, we describe three patients with infantile onset HSP harbouring de novo mutations, including a new variant, in SPG3A/ATL1.
Patient 1 is a 50-year-old man, born to healthy non-consanguineous parents, with a clinically pure slowly progressive form of HSP diagnosed in his early childhood as “infantile cerebral palsy”. Subsequently, he fathered a similarly affected daughter, now aged 17. Both patients sought expert neurological evaluation and counselling last year. At examination, Patient 1 showed moderate to marked spastic scissor gait, brisk lower limb reflexes, bilateral foot clonus and Babinski sign. He was still able to walk unsupported. He complained also of urinary urgency. His ‘Spastic Paraplegia Rating Scale’ (SPRS) score was 17/52. Both his parents were examined and their neurological condition was unremarkable. His daughter developed walking difficulties after age 3 years. At neurological examination, she had mild spastic gait, brisk lower limb reflexes and bilateral Babinski sign. She has no urinary complaints. Her SPRS score was 9/52. Brain and spinal cord MRI showed no relevant abnormalities in both Patient 1 and his daughter. Both patients harboured the heterozygous c.859C>T/p.R239C in SPG3A/ATL1 mutation. In contrast both Patient 1’s parents did not harbour any SPG3A/ATL1 mutation.
Patient 2 is a 3-year-old boy, born to healthy non-consanguineous parents, who presented with delay of motor milestones acquisition in childhood. He was able to stand at 15 months and walk unsupported at 23 months of age. He was the product of full-term, uncomplicated gestation, labour and delivery. At examination, he showed moderate lower limb spasticity, brisk lower limb reflexes and bilateral Babinski sign. His SPRS score was 7/52. Brain and spinal cord MRI as well as EMG and nerve conduction velocities (NCV) were normal. SPG3A/ATL1 analyses disclosed a novel heterozygous c.1308T>A/p.N436K mutation that was absent in his healthy parents. The p.N436K mutation was absent in 400 healthy control chromosomes and predicted to be deleterious in silico (Polyphen2, genetics.bwh.harvard.edu/pph2/).
Patient 3 is a 15-year-old boy with a moderately severe form of HSP since his early childhood. His neurological examination showed moderate stiffness while walking, mild spasticity and brisk tendon reflexes over his lower limbs and bilateral foot clonus (SPRS score 9/52). EMG and NCV studies showed mild axonal motor and sensory neuropathy. Mutation analyses disclosed a heterozygous c.1040T>C/p.M347T mutation in SPG3A/ATL1 in the patient but not in his neurologically healthy parents. SPG3A/ATL1 mutations represent the most frequent cause of early onset HSP, accounting for 32.8 % of the AD-HSP kindreds with onset before 10 and 14 % after 20 years . De novo occurrence of SPG3A/ATL1 mutations in isolated cases, both pure and complicated, poses a particularly difficult challenge [4, 5]. The aim of this letter is to promote the awareness, among clinicians and especially child neurologists, of AD-HSPs in the differential of infantile or early childhood onset spastic paraplegia, even in the face of healthy parents and no significant family history for similar neurological manifestations. Children with early onset SPG3A are easily misdiagnosed as diplegic infantile cerebral palsy, even though there is no clear history of gestation, labour or delivery complications and neuroimaging is unremarkable. The course of the disease is usually very slow and can be misinterpreted as non-progressive. Furthermore, de novo mutations can be transmitted to offspring. Relevant to this aspect, Patient 1 fathered a similarly affected daughter because he had been informed of the non-hereditary nature of his neurological condition by a previous genetic counselling.
Conflict of interest
All authors of the paper De novo mutations in SPG3A: a challenge in differential diagnosis and genetic counselling declare no conflict of interest.