Hereditary spastic paraplegia (HSP) is an inherited, neurodegenerative disorder characterized by progressive spasticity and weakness of the lower limbs. 1 Spastic paraplegia (SPG)-56 is a rare, autosomal-recessive HSP caused by genetic mutations in CYP2U1 and is associated with a relatively early onset [1]. The CYP2U1 gene encodes a member of the cytochrome P450 superfamily of enzymes. Cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and the synthesis of cholesterol, steroids, and other lipids. The reported clinical features of SPG include upper limb dystonia, cerebellar ataxia, visual impairment, dysarthria, cognitive impairment, atrophy of the corpus callosum and cerebellum, white matter abnormalities, and calcification of the basal ganglia [1]. To date, only four patients with SPG56 have been reported to exhibit upper limb or neck dystonia [2,3]. This report is the first on the use of deep brain stimulation (DBS) for the treatment of focal hand dystonia in a patient with SPG56.

The patient, a 44-year-old male with an unremarkable birth history and a father and mother of Japanese and Chinese descent, respectively, was first noticed to have bilateral concave feet at the age of three years. However, there was no obvious delay in his motor or intellectual development. At the age of 39 years, he developed a right lateral thalamic lacunar infarction. At the age of 40 years, he developed stiffness in the right upper limb and dysarthria. Physical examinations revealed hyperreflexia in the bilateral lower extremities, dysdiadochokinesia, postural instability, bilateral concave feet, and weakness in the bilateral extensor hallucis longus muscles. The patient’s walking ability was normal. Given the slowly progressive worsening of symptoms and the bilateral concave feet noted since childhood, a hereditary neurological disorder was suspected. Whole-genome sequencing revealed the following CYP2U1 mutations: two novel heterozygous variants, including a missense (c. G1463A:p.R488Q) and nonsense (c.C20A:p.S7*) mutation (Figure 1A). Mutation of CYP2UI with c.G1436A:p.R488Q was also confirmed in the patient’s mother (Figure 1A); however, we were unable to perform genetic testing of the patient’s father. Therefore, we used InterVar (https://wintervar.wglab.org/) to determine the pathogenicity of the detected variants [4]. The results showed that both variants were classified as “likely pathogenic” according to the American College of Medical Genetics and Genomics 2015 guidelines [5]. The criteria of the nonsense variant and missense variant were PVS1 + PM2 and PM1 + PM2 + PM3 + PP3, respectively. The missense mutation, previously reported in a patient with SPG56, results in a loss of enzyme activity [6]. This missense mutation results in a short peptide that lacks functional domains, thereby rendering the protein nonfunctional. Therefore, this mutation is considered a loss-of-function mutation. No other family members with HSP or other neurological diseases were identified in this patient’s lineage (Figure 1B). Head computed tomography revealed calcification of the bilateral basal ganglia, and brain magnetic resonance imaging revealed atrophy of the cerebellum (Figure 1C and D). On the basis of the neuroimaging and genetic testing findings and the clinical manifestations, the patient was diagnosed with a very high probability of SPG56. Right-hand dystonia severely impaired hand movements and fine motor skills during daily activities; there were no apparent walking disturbances (Supplementary Video 1 in the online-only Data Supplement). Botulinum toxin injection was not administered due to the lack of insurance coverage for dystonia in the upper extremities. DBS (Vercise Cartesia; Boston Scientific Corp., Valencia, California, USA) of the left thalamic ventro-oral nucleus was performed without any complications (Figure 1E), and symptomatic improvements in writing and other manual tasks were observed after stimulation. During the 12-month postoperative follow-up period, the dystonic symptoms did not worsen (Supplementary Video 2 in the online-only Data Supplement). We utilized the Arm Dystonia Disability Scale (ADDS) (0%–100%, with lower scores indicating greater disability) to evaluate the patient’s condition before and after surgery. The preoperative ADDS score was 17.1%, while the final postoperative assessment at the 12-month postoperative evaluation showed an improvement of 51.4%. The final stimulation parameters were set at 2-(25%)/4-(75%)/C+, and 120 ms; 60 Hz; and 5.0 mA.

There are no reports regarding the treatment of SPG56-related dystonia. In the present case, upper extremity dystonia was task-specific in the early stages of dystonia symptom onset; however, the patient later developed involuntary movements of the right upper extremity, even at rest; thus, the symptoms of dystonia in patients with SPG56 may be progressive . To date, 17 cases of SPG56 have been reported, four of which were noted to have dystonia [2,3,7,8]. The two cases described by Tesson et al. [2] involved upper extremity dystonia, whereas the two cases reported by Kariminejad et al. [3] involved motion-induced dystonia affecting both upper extremities, the neck, and the lower extremities (Supplementary Table 1 in the online-only Data Supplement). Neurosurgical treatment for upper extremity dystonia involves DBS or thermal coagulation of the thalamic ventro-oral nucleus [9]. In most patients with SPG56, onset occurs at approximately 1 year of age; however, an age of onset of approximately 30 years was reported in three cases [7]. Age of onset and motor and cognitive symptoms are diverse among patients with SPG56; therefore, careful follow-up is needed to determine whether the effects of DBS are sustained in the long term.

The online-only Data Supplement is available with this article at https://doi.org/10.14802/jmd.24022.

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