Hereditary Spastic Paraplegia with a Novel SPAST Mutation Misdiagnosed with Subacute Combined Degeneration
A 58-year-old man with gait disturbance came to our hospital on Oct 30, 2011. He did not complain of lower extremity weakness or leg pain. He was unable to regulate his steps by himself, and his acquaintances reported he walked with a slight limp. The impaired gait began 3 years after he had undergone subtotal gastrectomy and chemotherapy for 6 months. Thereafter, he felt tingling sensations in the hands and feet and acquired gait difficulties. He denied having a family history of abnormal gait or developmental problems. He had quit smoking and drinking alcohol many years prior to his diagnosis.\nUpon neurological examination, his muscle strength was normal. The limbs did not reveal any spasticity or rigidity. He responded normally to pin prick and thermal stimulation. However, there was a severely decreased response to vibration in both big toes, particularly in the left. The ankle jerk reflexes were bilaterally decreased, whereas the reflexes of other joints were normal. Both toes showed extensor toe signs. Other pathologic reflexes were not observed. Cranial nerve and cerebellar functions were normal. He did not exhibit scissoring or spastic gait, but rather a limping gait. Thus, he had mixed neurological signs that involved the upper motor neuron and peripheral nerves.\nConsidering his previous medical history, we investigated his brain, spinal cord, meninges, and peripheral nerve by using magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) analysis, blood tests, and electrodiagnostic studies. Notable results included the lower-normal limit of serum vitamin B12 (363 pg/ml; reference range 200-1,000 pg/ml) and generalized sensory dominant polyneuropathy with axonal involvement. Blood tests, including those for syphilis, HIV, diabetes, connective tissue disease, vasculitis, and renal and liver function, were normal. CSF chemistry and cell counts were also in the reference range. Mild small vessel disease and a small amount of chronic subdural hematoma were observed in the left cerebral convexity. Whole-spine MRI revealed normal signal intensity in the cord, except for disc extrusion with mild cord indentation, which did not seem relevant to the exhibited neurological symptoms. Nerve conduction studies showed mild sensory dominant peripheral polyneuropathy with axonal involvement.\nWe diagnosed him with SCD. He was intramuscularly administered cyanocobalamin regularly for 6 months. However, there was no improvement in his condition. After reconsidering his abnormal neurological signs and laboratory tests, we examined HSP mutations in his genomic DNA. As a result, the SPAST mutation was detected from the gene sample of the proband (). The mutation, a novel splicing mutation, is c.870+1delG (IVS5; heterozygote). The deletion of 188 bp of exon 5 was confirmed by RT-PCR. We compared this result with the mutation database (), and there was no previous information of this polymorphism or mutation at this locus.\nWe brought his children into the clinic for neurological examination. His 32-year-old son complained of subjective gait difficulty, even though there was no abnormality in his walking. However, he showed hyper-reflexic knee jerks, ankle clonus, and bilateral extensor toe signs. His 29-year-old daughter with an intellectual disability of unknown origin did not have any abnormalities upon examination. Genetic tests revealed that his son had the same SPAST mutation. The symptoms and signs of the patient and his son were different and are described in . Other relatives were not available to perform genetic analyses.