Prognostic factors and clinical outcome in a rare form of spastic paraplegia (Spoan syndrome): a 10-year follow-up


 Background: Spastic paraplegia, optic atrophy and neuropathy (Spoan syndrome) is an autosomal recessive disease with approximately 70 cases recorded in Brazil and Egypt. Methods: This is a prospective longitudinal study performed with 47 patients affected with Spoan syndrome of seven communities of Rio Grande do Norte (Brazil) to investigate prognostic factors and clinical outcome based on comparative data obtained from a 10-year follow-up. Results: The mean age of the participants was 47.21±12.42 years old, and the mean ages at loss of ambulation and hand function were 10.78±5.55 and 33.58±17.47 years old, respectively. Spearman’s correlation analysis between the score on the Modified Barthel Index and the investigated variables evidenced statistical significance for age (p<0.001) and right- and left-hand grip strength (p=0.042 and p=0.021, respectively). Statistical significance was not evidenced for the remainder of the variables, including age at onset of symptoms (p=0.634), age at loss of ambulation (p=0.664) and age at loss of hand function (p=0.118). Conclusions: Our analysis allows asserting that the participants exhibited slight dependence until age 35. The greatest losses occurred from ages 35 to 41, and starting at 50, practically all patients become completely dependent. In fact, age is the main prognostic factor of impaired motor function among Spoan syndrome patients.

3 and spine deformities 1,2 . More than 70 cases have been recorded, two in Egypt and all others in Brazil, three in the South and Southeast regions and the remainder mainly in the Northeast 3 .
The mutation involved consists of a 216-bp microdeletion in the 11q13 chromosome region, which upregulates the expression of the KLC2 gene product, a kinesin related to axonal transport 4 . The initial diagnosis of Spoan syndrome is made in the clinic, based on neurological examination, followed by genetic testing aiming at detecting the aforementioned mutation, which is performed at the Centre of Studies of the Human Genome, University of São Paulo.
In the area known as Alto Oeste Potiguar, Rio Grande do Norte, Brazil, the prevalence of Spoan syndrome is 1:250 inhabitants, and it is estimated that 1 in 15 inhabitants are heterozygous carriers of the mutation 5 . Spoan syndrome is thus a genetic disease that causes severe physical disability and has high prevalence in the Brazilian Northeast region. However, the incidence of the disease may be underestimated globally given that some cases might not be diagnosed, as Spoan can be confounded with other simple or complex forms of spastic paraplegia 6 .
The aim of this study was to investigate prognostic factors and clinical outcome in a rare form of spastic paraplegia (Spoan syndrome) based on comparative data obtained from a 10-year follow-up. This data are relevant for communicating prognosis to patients and for selecting adequate outcome measures for future clinical studies.

Methods
The present was a prospective and longitudinal study on the motor function of individuals with confirmed diagnosis of Spoan syndrome in which data collected in 2007 and 2017 were compared. Of the 61 participants in the first assessment, 47 resided in municipalities 4 in Alto Oeste Potiguar, Rio Grande do Norte, and could be located with the help of community health workers. These patients were assessed at home by occupational therapists.
The 47 participants in the present study were assessed using the same protocols as the ones used by Graciani and colleagues (2010). The participants were first interviewed to collect data such as date of birth, educational level, age at onset of symptoms and ages at loss of ambulation and hand function. Next, we applied the following instruments for the measurement of motor function parameters: Modified Barthel Index (MBI), described by   8 : this index determines the degree of dependence of individuals relative to 10 functional categories -(1) personal hygiene, (2) bathing, (3), feeding, (4) toilet use, (5) stair climbing, (6) dressing, (7) bladder control, (8) bowel control, (9) ambulation and (10) transfers. The total score ranges from 0 to 100, and the results are categorised as follows: 0-20 -total dependence; 21-60 -severe dependence; 61-90 -moderate dependence; 91-99 -slight dependence; and 100 -independence.
Spastic Paraplegia Rating Scale (SPRS) 9 : this instrument consists of 13 variables to measure the severity of spastic paraplegia. The individual scores of variables range from 0, normal, to 4, severe impairment. The maximum total score is 52. There was no significant difference (p>0.05) in the mean age between females and males. On the last assessment, the age of the participants varied from 22 to 81 years old.
The median age at onset of symptoms was one year old, with the variations for the first and third quartiles being 1 and 2 years, respectively. The mean age at loss of ambulation was 10.78±5.5 years old. Only eight of the participants had preserved hand grip strength as assessed with the Jamar® dynamometer (Table 1). Only two participants were still able to walk with some aid.
The Anderson-Darling normality test evidenced that the following variables had non- The median score on the MBI differed significantly (p<0.001), indicating that the level of dependence increased over time. The U test did not detect significant differences in the median scores on SPRS and FHSPRS from 2007 to 2017 (Table 1). These scales were used 7 to assess ambulation ability and the influence of spasticity on ambulation. In 2007, 68.08% of the patients with Spoan syndrome were already confined to a wheelchair; 10 years later, almost all of them (97.87%) were wheelchair-bound.  Relative to loss of hand function in association with dependence for feeding, among the 26 participants who fully lost their hand function, 15 were total dependent for feeding, while 11 were still able to handle eating utensils, albeit with constant assistance; the scores on the MBI domain feeding ranged from 0 to 2. Relative to the other 21 participants, the scores on the MBI domain feeding ranged from 5 to 8; six were able to eat with supervision, while 15 were able to eat independently.
Non-parametric correlation analysis (Spearman's correlation) between the score on the MBI and the investigated variables evidenced statistical significance for age (p<0.001) and right-and left-hand grip strength (p=0.042 and p=0.021, respectively). Statistical 8 significance was not evidenced for the remainder of the variables, including age at onset of symptoms (p=0.634), SPRS (p=0.832), age at loss of ambulation (p=0.664) and age at loss of hand function (p=0.118).
Since we found correlation between variation in age and MBI, we fit a simple linear regression model to investigate the effect of the level of loss of independence over time.
The equation that represents the relationship between these two variables is y=52.37-0.30x, where y is variation in age, and x the MBI. The p-value for coefficients β 0 and β 1 was <0.05, i.e., statistically significant. Figure 2 depicts the regression line fitted to the data.
In 2017, 87.23% of the participants exhibited severe or total dependence according to the score on the MBI. Since the level of dependence increased with age, we performed an analysis of profile plots for a closer look into age ranges, as shown in Figure 3. Among the three participants (6.38% of the sample) within the age range of 20 to 30 years old in 2017, one was still able to walk at home with a walker and exhibited more autonomy in performing activities of daily living. Throughout the 10-year period, his level of dependence shifted from moderate (score: 73) to minimal (score: 87), with functional gain in the ability to perform transfers ( Figure 3). Another participant within the same age range exhibited considerable functional losses, shifting from moderate (score: 70) to severe (score: 28) dependence due to loss of the ability to perform transfers together with the loss of ambulation and the need for assistance when using the toilet. The third participant within this age range shifted from moderate (score: 57) to severe (score: 26) dependence due to impaired ability with personal hygiene and using the toilet. The participants within this age range exhibited a large variation in motor performance (Figure 3).
More than half of the participants (58.33%) within the age range of 31 to 40 years old 9 (25.53% of the sample) were able to perform transfers and self-care activities, albeit with some degree of dependence. The remainder of the participants within this age range progressively lost their autonomy over time (Figure). Only one participant from this group was able to walk at home with some aid.
Most of the participants from the group aged 41 to 50 years old (23.40%) exhibited total dependence. However, half of them were still able to eat by themselves with spoons and under continued supervision. The remainder of this group had only their bladder and bowel control preserved. One case exhibited major losses in bathing, dressing and transfer ability ( Figure 3).
Most of the participants over 50 years old (44.68%) exhibited total dependence and had their bladder and bowel control preserved. Only three patients were still able to participate at some level in their feeding. The most severe case experienced substantial losses over time in toilet use, bathing, feeding and transfer ability (Figure 3).

Discussion
The present study is the first prospective study of a rare genetic disease prevalent in the semi-arid Northeast region of Brazil. Forty-seven out of the originally 61 described cases could be located and were reassessed with the help of municipal community health agents. The results showed that Spoan syndrome is extremely disabling, similar to other previously described neuromuscular disorders 15  Significant variation in the age at onset of the first symptoms was not found in the population of Spoan patients. Such symptoms are optic atrophy and spastic paraparesis, which appear before age five, most frequently during the first year of life. For this reason, no correlation was found between age at onset of symptoms and motor impairment or between motor impairment and sex, as described in follow-up studies of other rare genetic diseases 15,16,17,18 .
Peripheral neuropathy might develop earlier in some cases, resulting in earlier loss of ambulation; this condition might be associated with more severe motor impairment.
Among the 47 participants, 36 (76.59%) lost the ability to ambulate between the ages of 5 and 20 years. No correlation was found between age at loss of ambulation and level of dependence (MBI). Therefore, our results do not confirm the hypothesis that age at onset of neuropathy is a predictor of clinical progression.
No significant difference was found on Schüle's SPRS, Fink's FHSPRS or the Ambulation Index revised by Chiaravalloti and DeLuca between 2007 and 2017. The participants' ambulation was already highly impaired at the first assessment in 2007, as 70.21% of the sample spent more than 50% of their time in a wheelchair, and only three were able to walk. In 2017, 45 individuals (97.87%) had completely lost their ambulation ability and spent their entire days in a wheelchair. In most (85.10%), the limbs were fixed in adduction, flexion or extension due to spasticity. Only two participants were able to walk with assistance. One of them was able to take some steps but used the wheelchair more than 50% of the time, and the other walked with a walker during the day and used the 11 wheelchair only in the evening for longer distances.
The loss of hand grip strength over the 10-year period was associated with higher levels of dependence, as expected. For the eight participants with preserved hand grip strength, the values obtained with the Jamar® dynamometer were less than half of the expected values. Unexpectedly, 21 of the participants with no hand grip strength were able to feed themselves somehow without any adaptation of the utensils. This is the first study to obtain a regression line and equation to analyse the variation in the MBI according to age. Our analysis allows asserting that the participants exhibited slight dependence until age 35. The greatest losses occurred from ages 35 to 41, and starting at 50, practically all patients become completely dependent. In fact, age is the main prognostic factor of impaired motor function among Spoan syndrome patients.
Although the patients' life expectancy was not investigated using suitable methods, it does not seem to decrease, since six participants were 60 years old or older, and one was 81 years old. Regarding causes of death, no repeated respiratory problems (pneumonia) were detected, as in other studies on rare genetic diseases 15 ; 19 . Therefore, Spoan syndrome is different from conditions such as Duchenne muscular dystrophy, in which the life expectancy is limited to two or three decades as a function of cardiac and respiratory involvement 20 , and amyotrophic lateral sclerosis, with a life expectancy of two to five years after diagnosis 21 ; 22 . Some patients exhibited dysphagia, none required a feeding tube. The causes of death bore no relationship to the disease, and included cancer, infarction, stroke and congenital heart disease.
One of the limitations of the present study concerns the number and variety of the instruments applied at the time Spoan syndrome was first described, which restricted the number of predictive variables. For instance, psychological aspects of patients and their quality of life were not investigated on the earlier assessment. Residents of the state of Rio Grande do Norte still lack access to specialised medical services; therefore, it was not possible to investigate the optic atrophy evolution, dysphagia or establish whether rehabilitation and assistive technology might influence the speed of motor function impairment and the development of deformities.

Conclusions
For the first time, age was described as a prognostic factor of clinical outcome in Spoan syndrome. These findings might be relevant for determining the prognosis as well as suitable treatment, rehabilitation and assistive technology for these individuals.

Declarations
Ethics approval and consent to participate The present study was approved by the Ethics Committee of the University of São Paulo (CAEE 55137316.4.0000.0065). All participants or their guardians received verbal and written explanations regarding the study procedures, and when they agreed, they signed the informed consent form and institutional declaration of approval in accordance with the principles of Resolution 466/12 of the Brazilian National Health Council. The results will be presented to the participants after publication of the study.

Consent for publication
Not applicable. No personal information is provided in your manuscript.

Availability of data and material
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests. 13

Funding
The current study was funded by Universidade Estadual da Paraíba (PROPESQ) and  Numbers in brackets represent the interquartile range.
*Mann-Whitney U test, p-value were calculated between first and second visit.