A Case of HSP Carrying c.1537-11A > G Mutation of the SPAST Gene Presented as Stiff-Person Syndrome
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.325344
Source of Support: None, Conflict of Interest: None
Hereditary spastic paraplegia (HSP) is a genetic neurodegenerative disease characterized by progressive muscle weakness and spasticity of the lower limbs and it is sometimes associated with seizures, extrapyramidal symptoms, cerebellar signs, and cognitive problems.,, The genetic analysis of spastic paraplegia (SPG) genes is the most reliable test to confirm the diagnosis of HSP. Among those genes, SPG4 encoding the protein spastin is the most common genetic abnormality in patients with HSP, and has been also referred to as SPAST.,,,, Here, we will describe a man with HSP carrying a c.1537-11A > G mutation of SPAST presented as stiff-person syndrome (SPS) with anti- glutamic acid decarboxylase antibody (GAD) antibodies.
A 47-year-old man presented with progressive gait disturbance, limb weakness, and continuous muscle spasms with episodic attacks of pain involving the upper and lower limbs and axial musculature over the course of 5 years. Neurological examinations revealed mildly slurred speech, spastic gait disturbance, painful muscle spasm, lumbar hyperlordosis, and muscle weakness with Medical Resource Council (MRC) grade 4/5 in overall limbs. The deep tendon reflexes of all limbs revealed mildly increased responses. However, there were no pathological reflexes such as Babinski's and Hoffman's signs. Other neurological evaluations involving cognition, cranial nerve function, sensory system, and swallowing revealed no abnormalities. Laboratory investigations revealed that his hemogram, serum electrolytes, thyroid hormone, liver, and renal functions were normal. Spinal magnetic resonance imaging showed lumbar hyperlordosis with multilevel central canal stenosis and spondylosis with cervical spinal straightening without myelopathy. Electromyography of the vastus lateralis, tibialis anterior, peroneus longus, and paraspinal muscles revealed continuous motor unit activity with normal morphology. Laboratory investigations showed a marked elevation of his serum anti-GAD antibody level (>300 IU/L, normal range; 0–0.99); however, the other paraneoplastic or autoimmune antibodies including rheumatoid factor, lupus anticoagulant, anti-SSA/SSB, anti-Hu, anti-Yo, anti-CV2/CRMP5, anti-Ri, anti-Ma2, anti-amphiphysin and ligand-gated ion channels (N-methyl-D-aspartic acid, AMPA, and GABA-B receptor channels) antibodies were all normal, therefore only anti-GAD antibodies were detected in this patient.
Collectively, based on a suspicion of SPS, the patient was treated with diazepam, baclofen, prednisolone, mycophenolate mofetil, and intravenous immunoglobulin, and he showed mild improvements of painful muscle spasms, axial muscle stiffness, and gait disturbance. However, after continuous symptomatic and immunologic treatment, the patient's spastic gait and increased deep tendon reflex of limbs became dominant instead of his previous neurological manifestations. So after obtaining informed consent for genetic examination, we sequenced the SPAST, spinal bulbar muscular atrophy, superoxide dismutase 1, and spinal muscular atrophy genes as well as the levels of hexosaminidase in serum.
From these examinations, a heterozygous c.1537-11A > G mutation of SPAST was identified [Figure 1], and additionally, his younger brother showed the same gene mutation. Previously, only one patient with HSP carrying a c.1537-11A > G mutation of SPAST was reported. Therefore, our patient and his younger brother are the second and third reported cases with HSP carrying a c.1537-11A > G mutation of SPAST.
Furthermore, our patient showed presented manifestations indicating SPS including painful muscle spasms in the paraspinal and skeletal muscles, hyperlordosis, continuous motor unit activity on electromyography, and a high serum titer of antibodies against GAD., Unlike HSP, SPS is an immune-associated disease characterized by specific antibodies to GAD which is an excellent diagnostic marker in SPS and have been linked to its pathogenesis and it is often improved with immunotherapy and muscle relaxants.,, Therefore, our case revealed the clinical implication that our patient showed two different diseases; HSP carrying a c.1537-11A > G mutation of SPAST and SPS of an auto-immune cause which has not been reported to our knowledge.
In conclusion, this case suggests that if the clinical manifestations of the patients with HSP are not compatible with HSP, or if immune treatments are not effective in the patients with SPS, further biochemical assessments or genetic analysis should be considered before confirming a diagnosis of HSP or SPS.
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This research was supported by Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (NRF-2016R1D1A1B03936287).
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There are no conflicts of interest.