Exp Neurobiol 2013; 22(2): 128-131
Published online June 30, 2013
© The Korean Society for Brain and Neural Sciences
Ji Won Yang1, Ji-Young Han1, Moon-Woo Seong2, Jung-Joon Sung1*, Sung Sup Park2* and Kwang-Woo Lee1
Departments of 1Neurology, 2Laboratory Medicines, Seoul National University Hospital, Seoul 110-744, Korea
Correspondence to: *To whom correspondence should be addressed.
TEL: 82-2-2072-1015, FAX: 82-2-762-5684
Sung Sup Park
TEL: 82-2-2072-3206, FAX: 82-2-747-0359
Autosomal dominant hereditary spastic paraplegia (AD-HSP) is due to mutations in the "spastin" gene (
Keywords: hereditary spastic paraplegia, SPAST protein, subacute combined degeneration
Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of neurodegenerative diseases that predominantly involves the lower extremities. The essential features are insidiously progressive spastic leg weakness associated with corticospinal tract and dorsal column degeneration . HSP is classified according to the mode of inheritance (autosomal dominant, autosomal recessive, or X-linked), clinical symptoms ("pure" or "complicated"), and specific gene locus ("SPG1" through "SPG17") . Autosomal dominant HSP (AD-HSP) is the most prevalent mode and includes approximately 70% of cases. Approximately 40-45% of AD-HSP patients have pathogenic mutations in the spastin gene (
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.
Upon 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.
Considering 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.
We 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
We 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
As described, we misdiagnosed this patient with SCD, which is distinct from HSP, because of atypical neurological signs and previous medical history. A genetic test revealed a novel splicing mutation in the
Genetically, HSP is classified according to the mode of inheritance and various gene loci. Among the several autosomal dominant HSP loci, mutations in
In Korea, there are 4 previous reports of novel
In conclusion, we report a novel splicing mutation, c.870+1delG (IVS5), in a Korean family with autosomal dominant-inherited HSP. We confirmed the deletion of exon 5 by using RT-PCR and segregation of the
Table 1. Clinical findings of HSP family