Analysis of the participants in the baseline study and the follow-up
Twenty-four of the 41 SD patients in the baseline study  could be recruited to the follow-up study. The participants, the non-participants, and the deceased patients differed at baseline visit in age and mental and motor developmental ages (Table 2). Further analysis revealed that the eight deceased subjects differed significantly from the 24 participants and from the six non-participants (Mann–Whitney U test). At baseline, the deceased subjects were older and their mental and motor developmental ages were lower than those of the participants and non-participants. The participants and non-participants did not differ from each other.
The 41 patients with SD who had participated in the baseline study were included in a survival analysis. The analysis showed excess mortality among patients with SD after the age of 30 years (Fig. 1). No difference was noted between the genders (mean survival 57.2 years for women, 59.0 years for men; p = 0.88, log-rank analysis). Interestingly, four out of the eight deceased persons had died at the age of 27 years (range, 20–40 years) younger than expected, while four subjects had died 7 years (range, −1–9 years) older than expected. There are no previous studies on mortality of SD patients, and hence, it is not known whether such subgroups are true. Anyhow, these two groups did not differ with respect to mental developmental age (p = 0.69, Mann–Whitney U test) or motor developmental age (p = 0.89) at the baseline visit. All the eight deceased persons had epilepsy during life, but unfortunately, we could not find out whether epilepsy was the cause of death. Patients with SD live longer than those with aspartylglucosaminuria (AGU), another lysosomal storage disorder belonging to the Finnish disease heritage. On average, women with AGU live to 40 years and men to 35 years .
Changes in motor and cognitive skills during the 13-year follow-up
The median age of the 24 SD patients was 34 years (range, 16–65 years) at the follow-up visit. The rate of change in motor and mental developmental age was calculated for each patient (Fig. 2). Between the baseline study and the follow-up study, the change in motor developmental age (Fig. 2a) was positive till the age of 20 years in most patients, but after that age, motor skills declined. There was no correlation between the rate of change in motor developmental age and the chronological age (Pearson r = −0.395, p = 0.056). There was an increase in mental developmental age in most patients till their late thirties (Fig. 2b), but beyond that, there was no further change. Indeed, there was an inverse correlation between the rate of change in mental developmental age and the chronological age (Pearson r = −0.481, p = 0.017). Finally, there was a correlation between the rate of change in mental developmental age and that in motor developmental age (Pearson r = 0.685, p = 0.0002).
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.
Concentration skills varied markedly among the patients. Compared to the results of healthy children of the age of 3.5 years described in the test manual of BSID-II, visual tracking and visual attention tasks were performed well, as well as tasks that demanded eye-hand coordination (e.g., use of a spoon or comb). Tasks related to visuospatial reasoning revealed cognitive deficits in all patients and visuomotor performance was slow. All patients recognized familiar faces and voices and responded to a smile and showed emotional states either verbally or non-verbally. Talkative patients were able to remember songs and phraseologies and to learn new ones. Most of the patients who could speak had dysarthria or dyspraxia, but none of the patients had aphasia. The caregivers described that the patients learned daily routines and could keep short instructions in mind. Patients could not perform the subtests of PANESS. Performance in the dynamic cerebellar tests, verbal tasks of NEPSY, and the TUG test is described in Table 3.
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.
The maximal motor developmental age was 27 months, and the maximal mental developmental age was 42 months among the 24 SD patients. The developmental ages of four subjects (age range, 16–34 years) were significantly lower than those of other patients with a similar age. These four patients presented with the severe phenotype of SD, and they were compound heterozygotes harboring the R39C mutation only in one allele. There was a significant inverse correlation between the motor developmental age and the chronological age (Fig. 3a) and between the mental developmental age and chronological age (Fig. 3b). Motor and mental developmental ages at the follow-up visit correlated well with each other (Pearson correlation coefficient r = 0.88, p = 0.001), and this was the case also for the data obtained at the baseline visit. The motor developmental age at the follow-up visit was dependent on that at the baseline visit, but not on age, sex, or baseline mental developmental age. In a similar fashion, the mental developmental age at the follow-up visit was dependent on that at the baseline visit, but not on age, sex, or motor developmental age at baseline.