Participant demographics

In this study, we included a total of 160 CDG relatives/family caregivers and people living with CDG, from now on referred as “CDG families”, and 35 CDG professionals, including healthcare professionals, clinicians, and basic researchers. The CDG families’ group was composed of 151 CDG relatives/caregivers (94.4%) and 9 people who has CDG participating (5.6%, Fig. 1A). In the CDG professionals’ group, clinicians were the most represented (51.4%, n = 18) followed by basic researchers (31.4%, n = 11) and healthcare professionals (17.2%, n = 6) (Fig. 1B).

Fig. 1

Socio-demographic Profile of Study Participants: (A) Families and (B) Professionals’ Relationship to the CDG Community, (C) Families geographic dispersion, and (D) Academic qualifications

The study had a diverse distribution of participants among CDG families and professionals, with a higher incidence of individuals between the ages of 35–54 in both groups (68.8%, n = 110 and 57.1%, n = 20, respectively), and from the female gender (88.1%, n = 141 and 62.9%, n = 22, respectively; Additional File 3). In terms of geographical dispersion, the largest proportion of family respondents were from Europe (41.3%, n = 66), followed by North America (30.6%) and Central and Southern America (Latin America), making up 21.3% (n = 34). Smaller numbers of respondents were from other countries like Australia (3.1%; n = 5), South Africa (2.5%; n = 4), Armenia (0.63%; n = 1) and New Zealand (0.63%; n = 1, Fig. 1C). Further details on the distribution of respondents are described on Additional File 3. Professionals display a similar geographic distribution as described by Francisco et al. [30] Concerning their academic qualifications, 67.6% (n = 108) participants from the CDG families’ group had at least a bachelor’s degree (Fig. 1D), while 68.6% (n = 22) of professionals hold a PhD, indicating a high level of education in both groups.

Clinical characterization of CDG participants

The CDG families’ group represented a total of 30 genetic causes of CDG, including 16 N-linked glycosylation defects, 5 GPI biosynthesis defects, and 9 disorders of multiple glycosylation pathways. O-linked glycosylation defects and lipid glycosylation defects were not reported (Additional File 3). PMM2-CDG (MIM: 212065) was the most common CDG (55.6%, n = 89), followed by ALG6-CDG (MIM: 603147; 7.5%, n = 12) and PIGA-CDG (MIM: 300868; 5.6%, n = 9; Fig. 2A). The frequency of each CDG among respondents, reflects the worldwide prevalence these diseases [12, 36, 37]. Due to the overrepresentation of PMM2-CDG and in order to gain a thorough understanding of the differences between this and other CDG regarding the clinical-related aspects of their journey, the CDG families group was divided into two, namely PMM2-CDG and non-PMM2-CDG, in line with previous studies [29, 38].

Signs and symptoms onset is the first hallmark of a patient’s journey, and the nature of their manifestations can vary depending on the CDG. Our findings showed that all three groups included in our study reported that CDG typically manifested before the first year of life, most often even before the age of 6 months old (PMM2-CDG − 93.3%, n = 83, non-PMM2-CDG − 76.1%, n = 54, Professionals − 79.2%, n = 19, Fig. 2B).

Fig. 2

CDG clinical characterization: (A) Distribution of CDG as reported by participating families, (B) Perceived age of symptom onset in CDG patients

We identified a range of clinical signs and symptoms at onset in each CDG (Additional File 4). Several symptoms were observed to have a frequency of at least 50% in PMM2-CDG or non-PMM2-CDG groups, aligning with responses from the professionals’ group. However, other symptoms were recorded with lower frequencies, falling below the 50% threshold (Table 1). Hypotonia and developmental disability were consistently reported as the most common onset symptoms across all groups. Notably, people with PMM2-CDG demonstrated a slightly higher percentage of hypotonia and developmental disability compared to non-PMM2-CDG patients. In contrast, seizures were also identified as a primary symptom by both professionals and the non-PMM2-CDG group, but not by those with PMM2-CDG, as evidenced by the lower OR when compared to the non-PMM2-CDG. Furthermore, feeding problems, ataxia, and strabismus were frequently observed at the onset for the PMM2-CDG group, with a significantly higher OR for these symptoms in this group compared to the non-PMM2-CDG group. Concerning the frequency of these symptoms, some inconsistencies were noted in the professionals’ group when compared with the other two groups. The percentage of feeding problems was more similar to the PMM2-CDG group, while strabismus and ataxia were more aligned with the non-PMM2-CDG group.

In order to understand the incidence of a combination of symptoms in people with CDG during symptom onset, a MCA was performed. This MCA aimed to verify the potential unreported relationships of clinical presentations during the onset. Also, it is important to characterize a general profile of a person living with CDG, apart from the heterogeneity that is seen within CDG. Therefore, besides the PMM2-CDG and non-PMM2-CDG groups, we also considered the whole CDG family’s group to identify potential common traits and signs and symptoms (Additional File 5: Fig. 1). All three groups display a combination of symptoms, but seizures did not aggregate with the other onset symptoms in PMM2-CDG compared to non-PMM2-CDG. Thus, seizures are less frequently part of the onset of PMM2-CDG patients which is also clear from the overall prevalence of this symptom in this CDG.

We also aimed to examine any associations between the time of manifestation and specific symptoms, with a particular focus on the identification of early onset symptoms in CDG. Early onset in this clinical context typically refers to symptom manifestation in the first months of life (< 3 months). To do this, we used the time of manifestation and the main identified onset symptoms as reference points. We found some associations between certain symptoms and their onset in PMM2-CDG and the whole CDG families group. In PMM2-CDG, there was a weak association between feeding problems and earlier onset (V = 0.30, FDR = 3.8 × 10− 9). For the CDG family’s group, we observed a weak association between an earlier onset and hypotonia (V = 0.34, FDR = 7.0 × 10− 3).

Table 1 Number of patients presenting with specific symptoms at onset in two subcohorts: PMM2-CDG and non-PMM2-CDG, along with professional perspectivesThe encounter with healthcare professionals and the time to arrive at a diagnosis

CDG families were asked who raised the possibility of a CDG diagnosis and who provided the final diagnosis (Fig. 3A, B). In both cases, the most common experts involved who contributed to the final diagnosis were geneticists (raise the possibility − 36.9%, n = 59; definitive diagnosis − 51.9%, n = 83) and neurologists (raise the possibility − 33.1%, n = 53; definitive diagnosis − 28.1%, n = 45). Professionals, on the other hand, reported a broader distribution of potential specialists for both situation, with metabolic specialists being the most likely to raise the suspicion of a CDG diagnosis (29.2%, n = 7) and geneticists the definitive diagnosis (33.3%, n = 8).

To get a full picture of the participants’ quest for a diagnosis, we inquired about the number of doctors consulted. Firstly, our data shows that it usually took at least the consultation of 3 to 5 doctors between the onset of signs and symptoms and raising the possibility of a CDG diagnosis (PMM2-CDG – 73.0%, n = 65; non-PMM2-CDG – 80.3%, n = 57; Professionals − 75.0%, n = 18) (Fig. 3C, D). Secondly, between this first suspicion to a definitive diagnosis, it was common to consult at least 3 to 5 doctors (PMM2-CDG – 52.8%, n = 47; non-PMM2-CDG – 49.3%, n = 35; professionals − 41.7%, n = 12) or more. In fact, 6 to 10 doctors were required to get a final diagnosis in 29.4% (n = 26) of the PMM2-CDG and in 29.6% (n = 21) of non-PMM2-CDG patients. The percentage of respondents that stated this interval is even higher from the professionals’ perspective (41.7%, n = 10).

Regarding the time to get a definitive CDG diagnosis, approximately a third of the professionals (37.3%, n = 9) stated that patients usually have their diagnosis between the age of 1–3 years. Likewise, approximately a third of PMM2-CDG (27.0%, n = 24) and non-PMM2-CDG (29.6%, n = 21) families had indicated the same. Notably, 50.5% (n = 45) of the PMM2-CDG and 39.5% (n = 28) of the non-PMM2-CDG groups received their diagnosis in less than a year (Fig. 3E). However, there were still patients for whom the diagnosis took more than 4 years (Additional File 3).

Fig. 3

Healthcare Professionals Involved in CDG Diagnostic Journey: (A) Specialists Raising CDG Possibility, and (B) Giving Final Diagnosis, both from the insights of families and professionals. Number of Doctors that families faced to raise the possibility of a CDG and between this first possibility and the definitive diagnosis, (C) Symptoms Onset to Raise the Possibility, (D) Time from Suspicion to Definitive Diagnosis, and (E) Estimated Time to Definitive Diagnosis

Also, the participants’ country of living might influence the number of medical doctors consulted before the diagnosis was made. To address this, our cohort was divided into four groups: North America (30.6%, n = 49), Europe (41.3%, n = 66), Latin America (21.3%, n = 34) and Other-countries (6.8%; n = 11) (Additional File 5: Fig. 2). Although no statistical differences were found, there is a noticeable trend in the number of doctors consulted between the first suspicion to the definitive diagnosis of CDG across these groups. In Latin America, there is a tendency for patients to consult more doctors (6–10 doctors) with 47.1% (n = 75) falling into this group. In contrast, in Europe, 45.5% (n = 30) of individuals sought fewer doctors (3–5 doctors) during the same period. (Additional File 5: Fig. 2B). Regarding the time to obtain a definitive diagnosis, no statistical differences were found, but slight variations can be seen between groups. In Europe, 53.0% (n = 35) of respondents were able to get a definitive diagnosis in less than a year, compared to 40.8% (n = 26) in North America, 29.4% (n = 10) in Latin America, and 73.6% (n = 8) in Other Countries. In Latin America, most respondents (47.1%; n = 16) received their diagnosis within 1–3 years. Furthermore, it important to point out that across all groups, there were cases where diagnosis took more than 3 years, up to 20 years.

Another key factor that could potentially accelerate the diagnostic journey is the possibility of testing for CDG by the serum TIEF test, and its results normal or abnormal (type 1 or type 2 pattern, Additional File 3) [27]. By a similar analysis, we found no significant differences between the normal TIEF (n = 24) and abnormal TIEF (n = 136) groups (Additional File 5: Fig. 3).

Perception of CDG families regarding diagnosis accuracy

The majority of the CDG families demonstrated a general acceptance of the final CDG diagnosis, as 85.6% of respondents did not seek a second opinion (Fig. 4A). This finding indicates a high level of trust in the initial diagnostic process among the participating families. Nevertheless, a considerable proportion of families (56.9%, n = 91) expressed the belief that the diagnosis could have been reached at an earlier stage. In contrast, 18.8% (n = 30) of the families reported uncertainty regarding the potential for an earlier diagnosis, while 24.4% (n = 39) had the opinion that an earlier diagnosis was not feasible (Fig. 4B).

In rare diseases, there is an increase in misdiagnoses largely due to the lack of awareness and knowledge among healthcare professionals [39,40,41]. Concerning misdiagnoses, 87.5% (n = 21) of professionals stated that CDG patients normally have misdiagnoses, and 64.8% (n = 46) and 44.9% (n = 40) of the non-PMM2-CDG and PMM2-CDG groups, respectively, reported a misdiagnosis during their diagnosis-seeking journey (Phi = 0.21, OR = 2.3, FDR = 0.014, Fig. 4C). However, the type of misdiagnosis may differ significantly between and within each CDG (Additional File 3). There were also some differences between countries where Europe seems to have a lower number of misdiagnoses in comparison to the other countries worldwide (FDR = 0.025, V = 0.24, Additional File 5: Fig. 2D).

Fig. 4

Illustration of a patient’s journey through the healthcare system. Perceptions of families (PMM2-CDG and non-PMM2-CDG) and professionals: (A) Misdiagnosis (Differences in the presence or absence of Misdiagnosis between groups with a FDR = 0.014, Odds Ratio: 2.3 and Phi Coefficient: 0.21, (B) Families who sought a second opinion following a CDG diagnosis, (C) Families’ opinions on the overall time taken to obtain their diagnosis

Journey of family with multiple CDG diagnosis

As CDG are genetic and mostly inherited diseases, it was important to determine whether there were families in our cohort who had multiple offspring with CDG, and to learn about their experiences (Fig. 5). In the present study, 11.3% (n = 18) of the families had more than one relative with CDG (Fig. 5A), encompassing 9 families with PMM2-CDG, 2 with ALG6-CDG (n = 2/18), and 1 with FUT8-, ALG1-, PIGN-, DDOST-, PGM1-, PIGA-, and ALG11-CDG. The most pronounced difference between the CDG relatives’ journey was the age of diagnosis (n = 9/18) (Fig. 5B). One third (n = 6/18) of the respondents stated that there were no significant differences, while another third (n = 6/18) stated that there was a difference in coping (e.g., information needs, and emotional impact), and/or time of diagnosis. Also, 4 families reported differences in the presenting signs and symptoms.

Fig. 5

Families with multiple CDG relatives (A) Overall prevalence of Multiple CDG relatives in the stakeholder group of families, (B) Identified differences between family members (Multi-Choice Close Question)

Information sources and formats

Given the rarity of CDG and the frequent lack of available information, this study sought to examine the informational needs of CDG families from both the perspectives of the families themselves and the professionals involved in their care. We specifically asked about the format in which CDG-related information was provided at the time of diagnosis, as well as what was and currently is their primary source of information (Fig. 6).

At the time of diagnosis (Fig. 6A), verbal communication was identified as the most common format for conveying information by both professionals (100%, n = 24) and families (67.5%, n = 108). Professionals with experience in CDG diagnosis indicated that they share leaflets (75%, n = 18) and social media channels (50%, n = 12) as supplementary sources of information for CDG families. However, only a small proportion of families received information through any of these two formats (leaflets − 28.1%, n = 45; social media – 10.6%, n = 17).

During the diagnostic period, families primarily sought information from genetic counselors and geneticists (51.3%, n = 82) and healthcare professionals (37.5%, n = 60, Fig. 6B). Over time, there has been a shift towards other sources, such as fellow CDG family members (64.4%, n = 103), social media (56.9%, n = 91), and Patient Organizations (POs) (48.8%, n = 78).

Fig. 6

Assessment of Patients’ Access to CDG Information during Diagnostic Journey: (A) Information Format at Time of Diagnosis, and (B) Information Sources for Families at Diagnosis and Present

POs and support groups are extremely important for rare disease communities like CDG. Therefore, we assessed respondents’ knowledge of CDG-related POs and support groups (Fig. 7A). The majority of both groups (Families − 75.0%, n = 120; Professionals − 85.7%, n = 30) reported being aware of at least one CDG-oriented organization or support group.

Considering the established role of support groups and POs as information providers [42], we aimed to elucidate the significance of these organizations for the families and professionals in our cohort. In regard to POs, both groups deemed the provided information to be either Very important (Families − 36.9%, n = 59; Professionals − 34.3%, n = 12) or Essential (Families – 40.6%, n = 65; Professionals − 48.6%, n = 17) for the community (Fig. 7B). Additionally, nearly half of the families (43.8%, n = 70), access this information on a weekly basis, with only a small percentage accessing it Rarely (4%, n = 6) or Never (13%, n = 21) (Fig. 7C).

Social media has emerged as a versatile tool with various applications, including information dissemination and support group formation. Our study surveyed participants to determine their familiarity with CDG social media groups, revealing that a considerable proportion of respondents were acquainted with such groups (67.5% of families, n = 108; and 71.4% of professionals, n = 25) (Fig. 7D). Furthermore, both groups identified potential opportunities associated with social media. While a substantial number of prospective opportunities were documented (Additional File 5: Fig. 4), there was a consensus that increasing CDG awareness holds the most potential in the context of social media platforms.

Fig. 7

Depiction of the importance of CDG-specific support groups for families. (A) Awareness of the existence of CDG-specific Patient Organizations (POs) among families and professionals, (B) Recognition of the value of information provided by POs. from both family and professional perspectives. (C) Family access to POs-tailored information. (D) Familiarity with CDG social media groups among families and professionals