The present study of familial Glut1-DS focused on five families with up to three affected generations. We analyzed the clinical picture in children and adults and reported the evolution of the disease over time and how it has affected adult patients’ QoL and life achievements. The literature to date offers little information about the natural evolution of Glut1-DS beyond childhood and in relatives of different ages [7, 8, 11]. We found great clinical variability between patients, including individuals belonging to the same family. We did not find specific correlation between clinical severity and CSF/blood ratio, moreover the small number of patients tested with lumbar punction, do not allow to perform statistical studies.

Epilepsy occurred in 62.5% of our cohort, with a median age at onset of 2 years. Seizures were reported in 50% of the adult cases (median age at onset: 6 years). Epilepsy was found to be more frequent in the children than the adults, with onset tending to occur earlier than in their parents/grandparents.

Movement disorders were the most prominent clinical feature in the adult patients, consisting almost exclusively of PED (88% of affected individuals). PED was observed in one third of the children. The median age at onset of PED, like epilepsy, was found to be lower in the children (7 years) than in the adults (12 years). However, we had only two pediatric cases of PED, and a cohort this small obviously limits possible statistical speculation. In most cases, PED, being a paroxysmal disorder induced by movement, interferes little with autonomy in daily life and tends to improve spontaneously over time. One subject presented ataxia.

In other regards, too, our results are in line with the literature [7], according to which the first symptom recorded is usually epilepsy, which is the most prominent feature during childhood, often being the major symptom leading to the Glut1-DS diagnosis. In many cases, seizures tend to decrease or cease, either after the introduction of a KD or, later on, spontaneously. The rate of epilepsy is lower among adults, even though they rarely follow a KD [7, 8, 11]. MDs typically appear or worsen in early adolescence, when they may constitute the most disabling feature, even when not associated with other disorders. In early adulthood, movement disorders often improve in terms of frequency even though it does not necessarily disappear over time and characteristically worsens in stressful or physically demanding situations [7, 11].

Fatigue and migraine are known to be associated with Glut1-DS [7, 8, 11]. In our cohort, fatigue was reported by 60% and migraine by 50% of adult patients. Therefore, together with PED and epilepsy, they are the most frequent associated disorders in adults with Glut1-DS. Fatigue and migraine were, instead, rarely reported in the children (16.7% and 17% respectively).

Three adults (30%) presented an acute transient focal neurological disturbance with spontaneous regression. This neurological condition is a newly identified feature of Glut1-DS that needs to be carefully investigated and characterized. Its identification opens the possibility of including Glut1-DS among the causes of transient acute neurological deficits in adults, and thus of increasing diagnostic accuracy in this setting, even in patients with poorly characterized or no other symptoms.

Psychiatric disorders, a known comorbidity of Glut1-DS [9, 12], seemed to be age dependent in our study, being found to consist of depression and panic attacks in adults and ADHD in children.

In line with previous research by our group [13], intelligence was frequently below normal range across our entire cohort: only four subjects (two adults and two adolescents) showed average intelligence, while just two showed higher-than-average intelligence. These subjects belonged to three families. This is the first report of high intellectual function in Glut1-DS patients. One of the two with high IQ never displayed any symptoms; the other showed lower limb PED from adolescence until the age of 20 years. It should be emphasized that none of the aforementioned subjects has ever tried a KD. Overall, the children in this study showed lower intelligence than their parents and grandparents, suggesting a generation-by-generation decrease in cognitive functioning.

The data on life achievement in adulthood showed that all the patients got married, indicating that social functioning was such that a satisfactory relationship could be established and continued. Two thirds (66.7%) of adults had a driving license, implying the ability to pass a standard driving test and therefore enjoy total autonomy in traveling.

Taken as a whole, these observations show at least some familial Glut1-DS adults can enjoy regular and fulfilling lives. This agrees with the findings of Klepper et al. [9], who showed that social adaptive behavior in adult patients is often well developed, apparently allowing patients to lead normal daily lives.

QoL has never previously been analyzed in adults with Glut1-DS. Our investigation shows that this population has a similar QoL to the general population, as documented by the absence of statistical differences in QoL between patients and a sex- and age-matched control group.

Moreover, no relationship was found between adult patients’ QoL and the two most frequent neurological symptoms: PEDs and fatigue. A potentially clinically relevant difference in the QoL variables, albeit not statistically significant (p = 0.123), emerged between the group with high intelligence and the patients with low/normal intelligence. This finding, suggesting that high intelligence can act as a protective factor in terms of QoL, emphasizes the importance of early implementation tools geared at promoting better QoL, also in asymptomatic or paucisymptomatic subjects.

Albeit in a small sample, the present data on Glut1-DS in families with affected individuals of different ages suggest that a clinical deterioration (of epilepsy, MDs and intelligence) may occur from generation to generation. This hypothesis, while based on clinical experience, seems to be supported by a series of considerations.

First, all the adult patients were diagnosed with Glut1-DS after their children and/or grandchildren had received the same diagnosis, and none of them had ever previously undergone medical investigations prompted by neurological symptoms. In other words, while Glut1-DS had never been suspected in the adults, their children or grandchildren came to medical attention very early. This clinical observation supports the idea that Glut1-DS symptoms can arise increasingly early in successive generations. However, it would be necessary to evaluate further possible generations within these family groups; therefore, if possible, follow-up of current patients and possible subsequent generations will be maintained. Moreover, we should consider a potential inclusion bias in adults, since a population of adults with mild symptoms may be underdiagnosed if they have mildly affected children, who will not come to medical attention.

Second, even though similar proportions of adults and children had or still have educational and developmental difficulties, no adult ever had a special needs teacher or received rehabilitation. Conversely, 83.3% of the children receive some help at school and 66.7% are involved in rehabilitation programs. These data should be interpreted in the light of the different periods in which the two groups grew up, given that they are characterized by different approaches to neuropsychiatric disorders and support strategies. However, this also means that these adult patients’ academic and work achievements were reached without any support. On the other hand, the sum of cognitive difficulties, clinical symptoms, and sometimes psychological fragility can, in the absence of treatment or adequate support, exacerbate social issues and eventually lead to impaired personal relationships, job insecurity, and poor management of clinical aspects of the disease. This consideration reinforces the importance of a correct diagnosis in asymptomatic/paucisymptomatic adults.

Third, mild and moderate forms of the disease are most likely associated with missense SLC2A1 variants resulting in 50–70% residual function of GLUT1 transporter. However, genotype–phenotype correlation remained elusive with high interindividual phenotypic variability, even between mutated members of the same family [14]. Moreover, 2 out of 5 identified SLC2A1 mutations (40%) are located on transmembrane helix 4 (TMH4) and transmembrane helix 5 (TMH5) encoded by exon 4, confirming a mutational hotspot in the SLC2A1 gene. [15]. All the patients in our families have missense mutations and then they should belong to minimal and mild phenotypic groups [6]. In particular, the patients in family A and family D with a mutation within exon 4, considered a mutational hot spot, present a more severe phenotype [15].

More strictly genomic consideration of the condition and further molecular studies are needed to explain the progression of the severity through the generations. Epigenetic studies might be useful to assess the phenotypic variability in Glut1-DS. For example, DNA methylation could be implicated in progressive lowering of the age at epilepsy onset [16, 17].

Improving our knowledge of this syndrome will help to clarify the genetic mechanisms underlying a possible generational deterioration. It remains to be established whether adult patients should be treated with a KD, and whether this intervention can help to improve the evolution of the disease. Increased knowledge of Glut1 disease, especially in adulthood, could allow us to diagnose paucisymptomatic cases and provide families with the right genetic advice.

Study limitation

This study presents some limitations. First, Glut1-DS is a rare disorder and therefore the study sample is small. Furthermore, previous research studies are scarce or inconsistent, so we had little literature with which to compare our research.

Finally, adult patients were examined by expert physicians only when their children/grandchildren came to medical attention; therefore their medical history could be collected, from the patients themselves, only retrospectively, and the nature of their clinical conditions during childhood could not be established with precision.

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