A 13-year follow-up of Finnish patients with Salla disease
© Paavola et al. 2015
Received: 24 November 2014
Accepted: 10 June 2015
Published: 13 July 2015
Salla disease (SD) is a rare lysosomal storage disorder leading to severe intellectual disability. SD belongs to the Finnish disease heritage, and it is caused by mutations in the SLC17A5 gene. The aim of the study was to investigate the course of neurocognitive features of SD patients in a long-term follow-up.
Neuropsychological and neurological investigations were carried out on 24 SD patients, aged 16–65 years, 13 years after a similar examination.
The survival analysis showed excess mortality among patients with SD after the age of 30 years. The course of the disease was progressive, but follow-up of SD patients revealed that motor skills improved till the age of 20 years, while mental abilities improved in most patients till 40 years of age. Verbal comprehension skills did not diminish during the follow-up, but productive speech deteriorated because of dyspraxia and dysarthria. Motor deficits were marked. Ataxia was prominent in childhood, but it was replaced by athetotic movements during the teens. Spasticity became more obvious with age especially in severely disabled SD patients.
Younger SD patients performed better in almost every task measuring mental abilities that then seem to remain fairly constant till early sixties. Thus, the results indicate better prognosis in cognitive skills than earlier assumed. There is an apparent decline in motor skills after the age of 20 years. The early neurocognitive development predicts the later course of motor and cognitive development.
Salla disease (SD; OMIM 604369) is a rare lysosomal storage disease that belongs to the Finnish disease heritage [1–3]. SD is caused by mutations in the SLC17A5 gene encoding a protein, sialin that is responsible for sialic acid transport across lysosomal membranes and that is required for normal CNS myelination . The prevalence of the major founder mutation, R39C (SallaFIN mutation), is high in the northeast of Finland, where founder effect contributes to the high carrier frequency of 1:100 [5, 6]. Most Finnish SD patients are homozygous for the R39C mutation , while a few patients are compound heterozygotes harboring this SallaFIN mutation and another SLC17A5 mutation. The phenotype of patients with compound heterozygous mutations is more severe than that in patients with homozygous mutations [6, 7]. The severe phenotype is characterized by young age at onset of neurodevelopmental symptoms, motor retardation, cerebral dysmyelination, cerebral and cerebellar atrophy, as well as peripheral nerve involvement [7, 8]. Mutations in the SLC17A5 gene cause also infantile sialic acid storage disease (ISSD; OMIM 269920) that represents the most severe form of lysosomal free sialic acid diseases [9, 10]. The children are severely affected already in utero or the first signs of the disease appear immediately after birth [6, 11, 12], and they usually survive less than 2 years. Mutations found in these patients are different from those in SD patients.
The first symptoms of SD include nystagmus, muscular hypotonia, ataxia, and delayed motor development [2, 7, 13], and they are usually noticed at the age of 3–12 months. All patients become intellectually disabled, but life expectancy is only slightly decreased . Epilepsy is a common symptom. On the basis of disease severity, a conventional and a severe phenotype of SD have been defined . In addition, a few patients have been reported with relatively mild symptoms [7, 14]. Cerebral and cerebellar atrophy, dysmyelination, and corpus callosum hypoplasia are typical for all patients with SD [15–17].
Motor handicap in SD begins to develop in early infancy, and the decline in motor skills is more pronounced than that in cognition after the second decade of life. We have previously carried out a cross-sectional study on neurological findings and neurocognitive profile in 41 Finnish SD patients [7, 18]. Motor disability was severe in these patients, and the characteristic cognitive profile consisted of spatial and visual constructive impairments. Interestingly, the interactive and non-verbal communication skills were quite strong. Here we describe results from a longitudinal study on changes in neurocognitive findings during a 13-year follow-up of 24 Finnish SD patients. We found that the course of the disease was progressive, but follow-up of SD patients revealed that motor skills improved till the age of 20 years, while mental abilities improved in most patients till 40 years of age.
Forty-one patients with SD were examined in our previous study . Eight patients (six women) had died after this baseline study, six patients (one woman) declined to participate, and three patients (two women) were excluded, because they had not been evaluated with the Bayley Scales of Infant Development (BSID-II) at baseline. The subjects of the follow-up study thus comprised of 24 SD patients (nine women) that were examined 13 years after the baseline study. Nineteen patients were homozygous for the SallaFIN mutation, and five were compound heterozygotes.
The study was approved by the Ethics Committee of Oulu University Hospital. The written informed consent was obtained from the patients and their caregivers.
Methods of neuropsychological evaluation
Full name of test
Focus of test
Bayley Scales of Infant Development 2nd ed.
Motor and mental skills
Children’s Neuropsychological Test Battery (3–6 years)
Comprehension of instructions
Repetition of nonsense words
Physical and Neurological Examination for Soft Signs
Test of corpus callosum functions
Static and dynamic cerebellar tests
Test of cerebellar functions
Timed Up and Go test
The basic and functional mobility
A survival analysis was performed on the 41 patients with SD who had participated in the baseline study. Kaplan-Meier survival analysis and log-rank statistics were used to compare the observed lifetimes of the patients with their life expectancies at birth. The life expectancies were obtained from statistics kept by Statistics Finland [http://www.stat.fi/tup/tilastotietokannat/index_en.html] and were available separately for both sexes and for each year of birth.
BSID-II sum variables were tested for reliability by calculating Cronbach’s alpha. Two groups defined by age (16–30 years, over 30 years) or by gender were compared for differences in neurocognitive development by using Student’s t test or Mann–Whitney U test, as appropriate. In order to study differences between the developmental ages and the results of BSID-II mental and motor scales after the follow-up period, the paired-sample t test was used.
Results in the NEPSY and TUG tests and in cerebellar tasks were used to classify the subjects into three groups. Subjects with no deficits, those with mild to moderate deficits, and those with severe deficits were defined by comparison with the reference values of each test [20, 23–25]. The statistical analyses were conducted using Statistical Package for Social Sciences (SPSS) 20.0 (IBM Corporation, New York, NY, USA) for Windows.
Results and discussion
Analysis of the participants in the baseline study and the follow-up
Comparison of participants and non-participants
Mental DA, months
Motor DA, months
Changes in motor and cognitive skills during the 13-year follow-up
Neurocognitive deficits develop in childhood , but the children acquire mental and motor skills till their teens. The baseline study  has suggested that several neurodevelopmental periods can be outlined in the clinical progression of SD. The first period includes a normal fetal development as well as the first months after birth, but muscular hypotonia, a delayed motor development, and ataxia then emerge during the first year of life. In the second period, slow development continues until puberty. Severe ataxia is evident in childhood but disappears between ages of 10 and 15 years. The present follow-up study showed that motor development continues till twenties in spite of arising athetosis and spasticity, and mental development continues till thirties. The slowly progressive decline in motor abilities starts after mid-thirties, while mental abilities seem to remain constant till early sixties. Three neurocognitive periods have been described in AGU, another lysosomal storage disease belonging to the Finnish disease heritage . In AGU, a period of positive development in childhood is followed by a gradual loss of skills in the teens and a rapid decline in the twenties, which progression is more severe than that in SD. The phenotype of AGU is less variable than that in SD and, furthermore, resembles more the conventional phenotype of SD . Brain MRI findings of AGU differ from those of SD as the thalami are affected in AGU , while corpus callosum hypoplasia, dysmyelination, and cerebral and cerebellar atrophy are constant findings with SD .
Neurological features at the follow-up visit
Neurological evaluation revealed that motor functions were severely affected. Eleven patients were able to walk independently, but all of them had problems in coordination. Seven patients used a walking aid, and six patients (severe phenotype, five; conventional phenotype, one) were non-ambulatory. The non-ambulatory patients were able to make stepping movements and to sit with support. All patients had spastic lower limbs, and the patellar reflexes were abnormally brisk. They also had severe planovalgus, and Achilles reflex was absent. Babinski sign was positive in ten cases.
Twenty-three patients were able to use a partial thumb opposition to grasp an object, and some of them also used the pads of fingertips in grasping or holding a pen. None of the patients could draw a circle or trace designs, but two patients could copy a plus sign.
Dynamic cerebellar tests showed severe deficits in motor sequencing and timing, but none of the patients had ataxia, whereas mild to moderate athetosis was present in 22 patients and two had severe athetosis since the teens. Indeed, ataxia impaired fine motor skills in childhood, but in adults, ataxia was replaced by athetosis. Nystagmus was not observed, but all patients had a moderate to severe strabismus.
Twelve patients had a history of epileptic seizures, but EEG was available only from four patients. Based on case histories, both primary and secondary generalized epilepsies were assumed. Eight patients were on monotherapy, while the remaining four were on polytherapy. In addition, three patients presented with startle-type reaction to auditory stimulus. The median age at onset of epilepsy was 29 years, and the patients with epilepsy were significantly older than those without (p = 0.007). An analysis of 121 patients with AGU has shown that 28 % of the adults but only 2 % of the children have epileptic seizures [29, 30]. These figures suggest that SD and AGU differ from each other in the onset of epilepsy.
Comparison of the clinical features at baseline [7, 18] and at the follow-up visit suggested that spasticity becomes more obvious with age especially in severely disabled SD patients. Severe motor handicap is typical for the conventional phenotype as well as the severe phenotype. One third of the affected children examined at baseline had learned to walk, and in the follow-up examination, a similar proportion of patients were ambulatory. Dysmyelination of the CNS probably explains the decline in motor and mental skills. The dysmyelination is expressed as homogeneous or periventricular white matter disease in most patients and as thin corpus callosum in all patients .
Neurocognitive functions at the follow-up visit
The receptive verbal skills were better than speech production (p = 0.003; related samples Wilcoxon signed-rank test), e.g., the patients were able to perform tasks that demand comprehension of instructions. All the patients were able to vocalize a single sound, and the patients with the conventional phenotype were able to use at least two words appropriately, while patients with the severe phenotype could not imitate words.
Frequency and severity of deficits in language and fine motor skills among 24 patients with SD
No. of deficits (n)
Mild or moderate deficit (n)
Severe deficit (n)
Comprehension of instructions
Repetition of nonsense words
Dynamic cerebellar tests
Finger to thumb
The median age of 30 years was used to define two groups. The younger group performed better in almost every task of the mental scale. Significant differences were found in constructive skills (p = 0.026), basic counting (p = 0.016), and immediate visual recognition (p = 0.026). No differences were detected in visual attention and interactive skills between the two groups.
In this study, we examined the course of clinical features in patients with SD in a 13-year follow-up study. The results of this follow-up study suggest better prognosis in cognitive skills than previous cross-sectional studies. Motor development continues till twenties and mental development till thirties. The slowly progressive decline in motor abilities starts after mid-thirties, while mental abilities seem to remain constant till early sixties. The motor handicap is severe, whereas the cognitive skills related to verbal comprehension and interactive skills do not deteriorate in adulthood. The early neurocognitive development predicts the later course of motor and cognitive development.
The authors are grateful to the patients with SD and their families for their cooperation. The study was supported in part by the Finnish Brain Foundation, the Finnish Cultural Foundation, and the Maire Taponen Foundation.
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