Rare 1 (2023) 100010

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Rare
journal homepage: www.journals.elsevier.com/rare

New view of aceruloplasminemia: Systematic review and meta-analysis

tracking dots from onset to disease development and iron-related features
Imen Ketata a, b, *, 1, Emna Ellouz a, b, 2
a
Neurology Department, University Hospital of Gabes, 6014 Gabes, Tunisia
b
Sfax University, Sfax, Tunisia

A R T I C L E I N F O A B S T R A C T

Keywords: Background and purpose: Aceruloplasminemia is an uncommon genetic disorder with considerable diversity in
Aceruloplasminemia clinical manifestations and tissue iron overload, whose underlying mechanisms are unclear. We aim to explain
Iron overload early and follow-up clinical/biological signs, suggesting novel theories about these manifestations and brain iron
Neuropsychiatric symptoms
uptake.
Systemic signs
Consanguinity
Methods: This systematic review and meta-analysis adhered to the 2020 PRISMA guidelines. PubMed and Europe
PMC databases, with Web searches (Google Scholar, Science Direct), were investigated using mesh terms and
keywords to identify case reports with no limit for publication date. Screening for eligibility was made by two
investigators.
Results: Overall, 110 cases were included. During the disease’s initial phase, male, consanguinity and ferritin
level≥ 700 ng/ml were linked to increased diabetes risk (adjusted odds ratio (aOR)= 3.6 [95% CI= 1–12.2],
aOR= 6 [95% CI= 1–35.4], aOR= 12.32 [95% CI= 1.8–82.4] respectively) and female (aOR=6.5 [95%
CI=1.7–23.8]) and ferritin < 700 ng/ml (aOR=5.7 [95% CI=1.7–19]) were associated with higher risk of
anemia. While consanguinity was negatively correlated with neuropsychiatric symptoms in the initial phase, it
was positively associated with them in follow-up. Although initial systemic signs were linked to elevated
neuropsychiatric and brain iron overload risks, starting with neuropsychiatric symptoms showed an inverse
association with systemic signs onset and brain iron uptake. Onset of the disease by diabetes, diabetes in follow-
up, and homozygosity were the common risk factors for thalamus, basal ganglia, and dentate nuclei iron
overload.
Conclusion: Despite the intricate physiopathological mechanism of aceruloplasminemia involving various factors,
our systematic reviews help comprehend the clinical signs range and illustrate the disease course. Additional
studies are required to delve deeper into these identified connections.

1. Introduction relatively uncommon neurodegenerative illness that affects one in every

2,000,000 persons worldwide [3]. The illness usually appears in adult­
Aceruloplasminaemia (ACP) is an autosomal recessive hereditary hood. Affected subjects often suffer from long-term diabetes and
disorder that is caused by a mutations in the ceruloplasmin (CP), which microcytic anemia [3]. The clinical signs encompass a range of neuro­
is located on chromosome 3q23-q24 [1,2]. This mutation hampers the logical, psychiatric, ophthalmic, and hepatic symptoms. Nevertheless, a
functional capability of CP ferroxidase activity, which is crucial for subset of patients might initially exhibit neuropsychiatric (NP) symp­
oxidizing ferrous iron to ferric iron and essential for iron incorporation toms without the subsequent development of diabetes, anemia. Lack of
into transferrin [3]. As a consequence, CP deficiency leads to iron de­ specific symptoms makes it difficult to diagnose ACP [3]. The identifi­
posits in numerous tissues, prominently in the brain and liver [3]. ACP, a cation of iron overload (IO) in the gray nuclei of the brain through
form of neurodegeneration with brain iron accumulation (NBIA), is a magnetic resonance imaging (MRI) is a highlighting hallmark of ACP.

* Corresponding author at: Neurology Department, University Hospital of Gabes, 6014 Gabes, Tunisia.
E-mail address: imen.ketata.fmss@gmail.com (I. Ketata).
1
ORCID: https://orcid.org/0000-0002-3057-8028
2
ORCID: https://orcid.org/0000-0002-2180-9445

https://doi.org/10.1016/j.rare.2023.100010
Received 25 August 2023; Received in revised form 17 October 2023; Accepted 25 October 2023
Available online 28 October 2023
2950-0087/© 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
I. Ketata and E. Ellouz Rare 1 (2023) 100010

Meanwhile, the precise pathological mechanism behind this accumula­ data were removed.
tion remains uncertain. Biochemical analysis might reveal elevated
ferritin levels alongside decreased serum iron and copper levels, and 2.4. Data extraction
reduced transferrin saturation (TS). Iron chelators are frequently
employed as the primary treatment, although ACP can unfortunately The researchers manually gathered the following information from
lead to fatal outcomes in many cases [3]. eligible reports: paper title, first author, publication year, patient origin,
Faced clinical manifestations that exhibit a gradual progression, patient demographics, medical history, gender, age, age at disease
together with the infrequency of studies on ACP, we aim, through this diagnostic, age at systemic signs and NP symptoms onset, clinical fea­
systemic review and meta-analysis, to elucidate and explain the varia­ tures, biological liver disorders (elevated liver transaminase), auxiliary
tions in initial clinical presentations among patients as well as the examination findings and genetic study outcomes.
evolution of symptoms during the disease course and the emergence of
brain iron overload (BIO). Additionally, we aim to identify potential 2.5. Evaluation of biases risk
correlations between NP symptoms and BIO, and suggest alternative
explanations for these symptoms. Furthermore, we propose new path­ To assess the reports’ quality, the Joanna Briggs Institute (JBI) crit­
ophysiological mechanisms to account for the observed distinctions ical assessment instrument for case reports was applied [9]. The
between homozygous and heterozygous patients based on eight-question checklist was used to evaluate each case report’s aspects
consanguinity. like patient demographics, medical history, current clinical features,
diagnosis details, treatment, post-intervention status, adverse events,
2. Methods and takeaway lessons. A case report was considered acceptable if it met
5 out of 8 criteria, making it eligible for the systematic review. The
2.1. Study design evaluation was conducted by two independent reviewers.

This systematic review and meta-analysis were performed in accor­ 2.6. Data analysis and interpretation
dance with the Preferred Reporting Items for Systematic Reviews and
Meta Analyse (PRISMA) guidelines 2020 [4]. We applied the SPSS software, developed by IBM, in its Windows
26.0 edition for data input and analysis. We combined the quantitative
2.2. Literature search value units into a single unit: blood glucose (mmol/l), serum iron (μg/
dL), ferritin (ng/ml), copper (μg/dL), CP (g/l), triglyceride levels (TG)
We investigated the PubMed and Europe PMC databases, and Web (mmol/l), total cholesterol (TC) (mmol/l). Categorical variables were
search (Google Scholar and Science Direct) for case reports, case series, described using percentages and frequencies. For normal distribution
letters to the Editor, Editorials and short communications. We included confirmation, we applied tests such as Kolmogorov-Smirnov (sample
published papers and accepted manuscript. Mesh terms were selected size >50 cases) or Shapiro-Wilk (sample size ≤ 50 cases), along with
using the following site: www.hetop.eu, and the terms retained were: skewness and QQ-plots. When data wasn’t normally distributed, we
"aceruloplasminemia", "familial apoceruloplasmin deficiency", "cerulo­ used median (interquartile range), otherwise, we employed mean,
plasmin deficiency", "hereditary hypoceruloplasminemia", "hypocer­ standard deviation, and extremes. For categorical variables, we used
uloplasminemia". We also used the following keywords: "ceruloplasmin either the chi-square test or Fisher’s exact test in independent samples,
gene", "genetic iron overload". Search terms were linked using the respecting the conditions of application of each test. To explore re­
boolean search operators "OR". The search syntax for gathering biblio­ lationships, both unadjusted odds ratios (OR) and adjusted odds ratios
graphic data was adapted for each database and Web search when (aOR) with 95% confidence intervals [95% CI] were applied using bi­
appropriate: aceruloplasminemia OR "familial apoceruloplasmin defi­ nary or multinomial logistic regression. When data wasn’t normally
ciency" OR "hereditary hypoceruloplasminemia" OR hypocer­ distributed, we employed the Mann-Whitney test to compare medians. If
uloplasminemia OR "ceruloplasmin deficiency" OR "ceruloplasmin gene" the distribution was normal, the student t-test for independent samples
OR "genetic iron overload". We used advanced search adapted for each was used to compare means. Statistical significance was determined at p
database and Web search to select the publication type (case reports, < 0.05.
case series, short communications, Editorials, letters to the Editor). This
search was restricted to human species. We did not limit the articles 3. Results
according to their publication date. The last search was run in July 2023.
To identify duplicates, all papers were imported into Mendeley. 3.1. Study characteristics
Screening was carried out in two stages. Two authors independently
screened for eligibility based on titles and abstracts using Rayyan After reviewing initial literature searches from various sources (Da­
(https://www.rayyan.ai/) for systematic review. The next step was to tabases: 299, Web Searches: 322, and references from other reviews: 4),
screen free and full-text papers for eligibility. Furthermore, the refer­ we pinpointed 83 articles encompassing 110 individual patient cases
ences of literature review were also screened for eligibility to identify adhering to the inclusion criteria [7–89]. The findings of our literature
additional cases [5–8]. search and selection process are summarized in Fig. A.1.

2.3. Eligibility criteria 3.2. Risk of Bias in included papers

We included all case reports, case series, letters to the Editor, short The JBI-assessed average bias score was 6.29/8. Of the included
communications, and Editorials in which: (a) full-and free text were articles, scores were as follows: 5 in 40 papers, 7 in 10 papers, 8 in 27
available; (b) diagnosis of aceruloplasminemia was confirmed either by articles, and 6 in 6 articles. All reports provided clear details on patient
genetic study or low CP level and MRI findings (c) English was used; (d) demographics, satisfying the first criterion. Regarding the second and
available data included patient’s demographic characteristics, patient’s third criteria, patient history and current clinical state were present in
history, age at onset of the disease/systemic signs (diabetes, anemia, all 83 papers (consanguinity details were provided in 54/83 papers and
biological liver disorder)/NP symptoms, and/or auxiliary examination. 68/110 cases). Diagnostic tests or assessment methods were accessible
Non-free full-text articles, poorly documented cases, case series missing in all papers, fulfilling the fourth criterion. Genetic studies confirmed
primary data, or analyses pooled without a description of each patient’s the diagnosis in 59 papers, with 24 articles using CP levels and MRI

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I. Ketata and E. Ellouz Rare 1 (2023) 100010

results for confirmation. Treatment details were available in 42 papers, found that ferritin level < 700 ng/ml was more likely in patients who
while thorough explanations of post-intervention clinical states and started with anemia than without anemia (14/24 (58.3%) vs 12/67
adverse events were in 37 articles. Takeaway lessons were reported in 75 (17.9%), p < 0.001, OR= 6.4 [95% CI= 2.3–17.8]). Likewise, serum
articles. copper level ≤ 40 µg/dl (serum copper available in 72/110 cases) was
observed more frequent in patients with diabetes onset (37/38 (97.4%)
vs 27/34 (79.4%), p = 0.04, OR= 9.6 [95% CI= 1.1–82.6]). Otherwise,
3.3. Patient demographics
iron levels didn’t show any connection with diabetes onset (p = 0.5) or
anemia onset (p = 0.3) and copper was not associated with anemia onset
Patients originated from 24 different nations, with Japan (n = 41/
(p = 1).
110, 37.3%), Italy (n = 15/110, 13.6%), and the United States (n = 13/
Multivariate analysis revealed that male (p = 0.04, aOR=3.6 [95%
110, 11.8%) accounting for the highest prevalence (Fig. B.1). Of 110
CI=1–12.2]), ferritin ≥ 700 ng/ml (p = 0.01, aOR=12.32 [95%
cases, 56 (50.9%) were female.
CI=1.8–82.4]) and consanguinity (p = 0.046, aOR=6 [1.35–35.4]) were
significantly associated with diabetes. Anemia remained significantly
3.4. Initial clinical signs associated with female gender (p = 0.005, aOR=6.5 [95%
CI=1.7–23.8]) and with ferritin< 700 ng/ml (p = 0.004, aOR=5.7 [95%
The most clinical finding at the disease onset were diabetes (n = 51, CI=1.7–19]). Only consanguinity was inversely associated with NP
46.4%) and anemia (n = 30, 27.3%) (Fig. B.2). Meanwhile, diabetes did symptoms (p = 0.04, aOR=0.2 [95% CI=0.03–0.9]). Meanwhile, con­
not exhibit an association with the pancreas IO (p = 0.7). Fig. B.3 sanguinity and homozygotes were both associated with systemic sign
summarizes distinct ages at initial clinical/biological signs onset and age onset (p = 0.04, aOR=5.2 [95% CI=1.1–27.1], p = 0.001, aOR=9.8
at disease diagnosis. As initial clinical signs, diabetes was observed to be [2.5–37.8] respectively). Fig. C.1 summarizes the evolution of initial
significantly higher among males (n = 31/54 (57.4%) vs n = 20/56 clinical/biological signs according to the age at disease onset and shows
(36%), p = 0.013, OR= 2.65 [95% CI= 1.2–5.7]), whereas anemia was the predictive factor for each sign.
significantly the most common initial clinical sign among females (n =
23/56 (41.1%) vs n = 7/54 (13%), p = 0.001, (OR=4.68 [95% CI=
3.5. Clinical sign in follow-up
1.8–12.17]) (Fig. B.4). No significant difference by gender was observed
in NP symptoms (p = 0.26) or biological liver disorders (p = 0.92). Men
Among patients who initiated the disease with systemic signs, 63/88
started with diabetes 7 years earlier than women (36 (range: 24–42
(71.6%) developed NP symptoms after a median time of 13.5 (range:
years) vs 43 (range: 32–51 years), p = 0.006) (Fig. B.5). There was no
4–24.25 years). Among those patients, the median age when NP symp­
significant difference in gender in the age at anemia onset (p = 0.74),
toms appeared during follow-up was 52 years (range: 48–57 years).
biological liver disorder onset (p = 1) and NP symptoms onset (p =
After adjusting for gender and consanguinity, while NP symptoms in
0.093) or age at ACP diagnosis (p = 0.11). Patients with consanguinity
follow-up were negatively associated with patient aged lower than 30 (p
were 5.7 times more likely to onset the disease with systemic signs (p =
= 0.027, aOR=0.5 [95% CI=0.004–0.72]) and between 30 and 50 years
0.033, OR=5.7 [95% CI=1.15–28.7]). In particular, they exhibited a
(p = 0.04, aOR=0.23 [95% CI=0.06–0.9]), it was positively associated
3.5-fold increased probability of presenting diabetes as the initial clin­
with patients aged equal or above 50 years (p = 0.002, aOR=10 [95%
ical manifestation (p = 0.015, OR=3.5 [95% CI=1.26–9.4]) (Table A.1).
CI=2.4–43]).
Moreover, consanguinity was negatively correlated with NP symptoms
Of 22 patients started with NP symptoms, 6 (27.3%) developed
(p = 0.033, OR=0.17 [95% CI=0.03–0.8]) (Table A.1). Homozygotes
anemia and 4 (18.2%) diabetes, with median time equal to 2
was significantly associate with systemic sign onset (p = 0.001, OR=8
(range:0.5–6 years) and 1 (range: 0.75–18.5 years) respectively. Addi­
[95% CI=2.4–26.4]) and with diabetes onset (p = 0.03, OR=3.4 [95%
tionally, after adjusting for consanguinity, gender, and age, presentation
CI=1.1–10.3]), otherwise, it was inversely associated with NP symptoms
with NP symptoms as initial clinical signs remained negatively associ­
(p = 0.001, OR=0.12 [95% CI=0.03–0.4]). We found that 58 (90.6%) of
ated with diabetes and anemia during the patient’s follow-up (p <
homozygotes and 12 (80%) of compound heterozygotes (CH) initiate the
0.001, aOR=0.024 [95% CI=0.003–0.18], p = 0.008, aOR=0.1 [95%
disease with systemic signs, whereas, none of heterozygotes had initiate
CI=0.021–0.5] respectively), meanwhile, presentation with systemic
by these signs (p < 0.001). Likewise, 6 (9.4%) of homozygotes, 3 (20%)
signs at the onset of illness and consanguinity were two predictor of NP
of CH and 7 (100%) of heterozygotes had initiate the disease by NP
symptoms occurrence in follow-up (p = 0.033, aOR=15.16 [95% CI=
symptoms (p < 0.001).
1.2–195], p = 0.04, aOR=4.5 [95% CI=1–20.1] respectively). Fig. C.2
Under the age of 30 years, women were more likely to have anemia
summarizes the evolution of clinical signs during the patient’s follow-up
(56.3% vs 20%, p = 0.046, OR=5.14 [95% CI=1–25.6]) whereas males
according to the patient’s age and different predictive factors.
were more predisposed to diabetes (73.3% vs 12.5%, p = 0.002,
OR=19.2 [95% CI= 2.9–125.1]). Between the age of 30 and 50, the risk
of anemia was also significantly greater in women whose risk increased 3.6. Disease’s features
4.66 times (p = 0.008, OR=9.8 [1.8–53.7]). This age range was asso­
ciated with diabetes regardless of gender (56% vs 33.3%, p = 0.018, The median age at diagnosis was significantly higher compared to
OR=2.5 [95% CI=1.2–5.5]). Otherwise, NP symptoms were strongly the age at anemia onset, diabetes onset, hepatic disorder onset, and NP
significant for patients above the age of 50 (54.5% vs 21.6%, p = 0.003, symptoms onset (p < 0.001, p < 0.01, p = 0.001, p < 0.01 respectively).
OR=4.3 [95% CI= 1.6–11.6]). Male also was shown to be associated Diabetes started significantly earlier in man 12 years than women (p <
with high risk of occurrence of NP symptoms after the age of 50 years (p 0001). Prevalence of dystonia was significantly higher in women (p =
= 0.02, OR=7.5 [95% CI=1.4–40.2]). Meanwhile, diabetes was nega­ 0.014, OR=3.92 [95% CI=1.3–11.63]). Table B.1 outlines the disease’s
tively associated with those patients aged 50 years and above (p = 0.03, demographic and clinical characteristics.
OR=0.4 [95% CI=0.1–0.9]). Patients started with diabetes had a level of Abdominal exploration was done in 90 patients. It revealed isolated
ferritin ≥ 700 ng/ml (ferritin available in 91/110 cases) more likely hepatic IO in 68 cases (75.5%), hepatic IO associated with splenic IO in 3
than patients who did not start with diabetes (40/47 (85.1%) vs 25/44 cases (3.3%), with pancreatic IO in 8 cases (8.9%), with kidney IO in 1
(56.8%), p = 0.004, OR= 4.34 [95% CI= 1.6–11.8]). Meanwhile, we case (1.1%). Ten patients had a normal abdominal examination (11.1%).

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I. Ketata and E. Ellouz Rare 1 (2023) 100010

Pancreatic IO was not associated with diabetes (p = 0.7). Similarly, liver were similar to those reported in a review including 55 patients [91].
IO showed no connection with either diabetes or anemia (p = 0.1, p = Meanwhile, we found a median age at anemia onset (31 years) more
0.4 respectively). younger (39.5 years) [91]. Likewise, several studies reported a similar
Biology assay indicated a significant lower hemoglobin level in median age at disease diagnosis (≃40 years) [19,91,93,94]. We
women than men (p = 0.001) and a higher level of HbA1c and ferritin in observed that the median age at diagnosis closely resembled the median
men (p = 0. 039 and p = 0.028 respectively) (Table C.1). The median age of NP symptoms onset. However, it was notably significantly older
level of blood glucose was significantly lower in patient presenting with compared to the median age when systemic signs appeared (p < 0.001).
seizure than those without seizure (1.8 mmol/l vs 8.3 mmol/l, p = This discovery was also consistent with the findings of Vroegindeweij
0.019). Table D.1 summarizes MRI findings and the association between et al. and Bianca et al. [91,94]. Our study revealed that the diagnosis of
NP symptoms and BIO. Exclusive correlations were observed between ACP commonly occurs after the emergence of NP symptoms, whereas
abnormal movements and the putamen and pallidum IO (p < 0.05), diagnosis based on systemic signs is less frequent. The initiation of the
while cognitive disorders displayed an association with the cerebral disease through anemia and/or diabetes presents a challenging clinical
cortex IO (p < 0.05). Fig. D.1, Fig. D.2, Fig. D.3 and Fig. D. 4 summarize diagnostic situation [90]. Our data highlights the importance of raising
the predictor factors of BIO and the basal ganglia, thalamus and dentate awareness about the disease to reduce the unfavorable delay in diag­
nuclei involvement. After adjusting for age and gender, anemia was nosing the initial symptoms. Consequently, ACP warrants early recog­
associated significantly with midbrain IO (p = 0.007, aOR=17.5 [95% nition and should not be overlooked, particularly in cases involving
CI=2.1–141]). After adjusting for diabetes onset as initial clinical sign or diabetes or anemia, since we identified them as the two most prevalent
in follow-up, male was also negatively associated with BIO (p = 0.02, indications of disease onset and progression. This outcome is consistent
aOR=0.19 [0.5–0.7]). We had not found association between CH and with findings from earlier investigations [7,19,90,91]. Previous studies
BIO (p = 0.7) and basal ganglia IO (p = 0.15). have shown that the presence of diabetes in ACP can be attributed to an
Genetic study was performed in 86 cases with highest prevalence of excessive iron overload within the pancreas [95]. Nonetheless, we did
homozygous mutations (n = 64, 74.4%) followed by CH (15, 17.4%) and not ascertain any notable correlation between either the initiation of
heterozygotes (7, 8.1%). The most common mutation was missense diabetes or its occurrence during follow-up and the IO within pancreatic
mutation (n = 51, 59.3%) followed by frameshift mutation (n = 31, tissue. Otherwise, we assume also that liver IO may be included in the
36%) and frameshift and missense mutation (n = 4, 4.6%). Our available mechanism of diabetes occurrence, since it plays a role in glucose he­
data on consanguinity and on mutation type showed that homozygotes mostasis and in insulin sensibility [96]. Liver has a functional cross-talk
patients had frequently consanguinity (23/43 (53.5%)) than CH (1/5 with adipose tissue, another master regulator of the energy balance that
(20%)). Meanwhile, no one of patients with consanguinity had hetero­ plays a fundamental role in insulin resistance, dibetes development and
zygous mutation. This difference was significant (p = 0.024). Likewise, obesity [97,98]. While in our included cases the description of obesity
heterozygotes (6/6 (100%)) and CH (4/5 (80%)) were more likely in was not noted, the occurrence of diabetes in ACP can be elucidated by
patients without consanguinity than homozygotes (20/43 (46.5%)) with considering the influence of adipose tissue [97,98]. In fact, cerulo­
significant difference (p = 0.024). Missense mutation was found to be plasmin is produced and secreted as adipokine by the adipose tissue and
more likely in heterozygotes patients (6/7 (85.7%)) and in CH patients adipose tissue functionality is affected by iron homeostasis [97,98].
(9/15 (60%)), while, frameshift was found to be more likely in homo­ While the precise mechanism behind the emergence of diabetes in ACP
zygotes (28/64 (43.8%)) than CH (2/15 (13.3%) and heterozygotes (1/7 remains poorly comprehended, our meta-analysis proposes a novel
(14.3%)). This difference was strongly significant (p < 0.001). Available pathophysiological hypothesis. This implies that diabetes might poten­
data on brain MRI and genetic study demonstrated that among homo­ tially be linked to an irregular metabolic process involving disruptions in
zygotes patients or CH, those who had frameshift had more likely BIO ferritin, iron, and copper serum levels. Our findings suggest that
than those having missense mutation (25 (100%) vs 30 (75%), p = elevated ferritin levels surpassing 700 ng/ml could contribute to the
0.017). Additionally, all patients who had CH carried both frameshift early onset of diabetes. Recent reports have demonstrated an increased
and missense mutations had BIO (n = 3 (100%)). risk of diabetes with elevated serum ferritin levels in healthy individuals
[99]. These results had been supported by two other meta-analysis [19,
4. Discussion 20]. In fact, Aregbesola et al. have demonstrated that among healthy
individuals, ferritin concentrations ranging from 228 to 939 ng/ml have
To the best of our knowledge, this is the first meta-analysis and the been associated with an approximately 1.5-fold increase in the likeli­
largest series of ACP published cases from diverse countries across the hood of developing diabetes [100]. Furthermore, several recent in­
globe conducted thus far. This meta-analysis provides an update on ACP vestigations have highlighted an elevated incidence of diabetes within
epidemiology in worldwide, broad insight of clinical symptoms, bio­ 5–15 years among otherwise healthy individuals with elevated serum
logical and radiological findings, improves our understanding of initial ferritin levels [99,101]. Conversely, we noticed that remarkably low
clinical signs and its progression in men and women, and suggests novel levels of copper serum (≤40 µg/dl) have emerged as a significant factor
pathophysiological hypotheses for clinical signs and brain IO. associated with diabetes onset. This discovery was corroborated by
Aligned with previous literature reviews, Japan and Italy consis­ multiple studies that have investigated the relationship between serum
tently had the greatest prevalence of ACP [90,91]. We found that the levels of copper and the occurrence of diabetes in healthy individuals
United States constituted the third group with a high frequency. This [102–105]. They found that the perturbation of copper metabolism
finding was not reported previously. Nevertheless, ACP has been docu­ gives rise to diabetes both directly and indirectly by means of the
mented in other European countries, and additionally in Asia and Africa. oxidative stress mechanism, involving reactions such as Fenton and
Based on the age of disease onset, anemia emerged as the primary Haber–Weiss reactions [104,106]. This oxidative stress leads to the
initial symptom observed in individuals below 30 years of age. In pa­ impairment of pancreatic islet beta-cells, affecting insulin secretion,
tients aged between 30 and 50, diabetes was more frequent than anemia. contribute to peripheral insulin resistance and heightening the vulner­
Conversely, NP symptoms predominantly manifested in patients aged 50 ability to diabetes [102,103]. Similarly, aside from ACP, instances of
and above. Except for the age at anemia onset (<20 years old), our result pronounced copper deficiency in the body result in insufficient synthesis
was similar to that described by Miyajima et al. [92]. The median age at of the Glut-2 transporter protein, causing a disturbance in insulin gen­
disease onset, diabetes onset, NP symptoms onset and disease diagnosis eration [102]. On the other hand, it has been established that elevated

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I. Ketata and E. Ellouz Rare 1 (2023) 100010

insulin levels can trigger the uptake of cellular iron [102]. This suggests a rise in the uptake of cellular iron [111]. Hence, in conditions of insulin
that patient who started with diabetes can develop anemia by iron resistance, hyperinsulinemia may play a role in the circulation of soluble
deficiency in ACP. Likewise, Jeppu et al. discovered that there exists an transferrin receptors level [111]. Otherwise, it was demonstrated that
inverse association between the serum CP level and fasting blood high ferritin level was negatively correlated with insulin sensitivity
glucose among patients without ACP [106]. All these discoveries [111]. Additionally, we found that TS ≤ 20% was significantly associ­
corroborate our findings and propose that the connection between ACP ated with BIO and this suggesting a higher transferrin soluble in the
and diabetes forms a vicious cycle. Thus, diabetes is associated with blood and might in the brain during ACP. Given that ACP is character­
various factors and with the deterioration of pancreatic tissue due to ized by high ferritin level, diabetes poorly controlled under insulin
oxidative stress, rather than an overload of iron in the pancreas. suggesting insulin resistance and low TS, it’s clear that diabetes, through
A further unique finding is that males were more likely to develop an indirect effect, can be one of multiple mechanism of BIO in ACP. This
the disease through diabetes and females through anemia, otherwise, no interesting finding may help us to understand why patients started with
significant difference had been shown for other symptoms. As ferritin diabetes had more likely BIO than others patients and could provide an
was identified as a trigger for diabetes onset and it was shown to be explanation for the occurrence of normal or mild BIO in patients who
varied by sex and ethnicity [107], our results showed that males had initially manifest NP symptoms and do not subsequently develop sys­
more likely ferritin level ≥ 700 ng/ml than females who had more temic signs. Meanwhile, other research is still needed to establish
frequent a level < 700 ng/ml. Thus, while we had found that a level definitive causal relationships. Although we discovered a significant
higher than 700 ng/ml was associated with diabetes onset and a level correlation between anemia and basal ganglia and thalamus IO. Miao
under 700 was associated to anemia onset, this discrepancy prompts us et al. showed an increased level of deoxyhemoglobin in hypoxic regions
to propose that the elevated ferritin levels in males than women might in anemic patients and that might even have a role in determining BIO
contribute to the heightened susceptibility to diabetes onset in males [112]. Meanwhile, the exact physiological and pathological mechanism
and anemia in females. Our investigation unveiled that female exhibited responsible for this connection has yet to be definitively established.
lower median iron, higher copper serum level and notably reduced While we found diabetes is significantly associated with BIO and its
ferritin levels than men. This difference might account for the increased occurrence was more likely in male, we anticipated that the male gender
of anemia rather than diabetes in women. Similarly, when compared to would be a factor risk, yet, we found that females were more likely to
males among healthy individuals, women face additional sources of iron have BIO. Although after adjusting for diabetes onset as initial clinical
deficiency due to menstruation, pregnancy, and breastfeeding, factors signs or in follow-up, male remained also negatively associated with
that could contribute to decreased ferritin levels [108]. Additional BIO. The literature raised debates regarding the IO specific to gender. In
research is needed to provide a more comprehensive understanding of Alzheimer patients or Parkinson patients, searches found that BIO was
the reasons behind the divergence in disease onset, with diabetes higher in men than women, however, several studies have shown that
occurring predominantly in men and anemia in females. women accumulate more iron in the brain than men either during ge­
Another interesting finding is that among the six included cases with netic mutation of the HFE [112–114]. It was suggesting that brains of
available data on TC levels, 3 had high TC levels. Meanwhile, TG was females might be more susceptible to iron deficiency compared to those
available in three studies, with normal levels in all cases. In a of males, leading to more BIO [112–114].
ceruloplasmin-deficient mice model, Raia et al showed a link between According to our data, while only abnormal movements were asso­
iron and lipid dysmetabolism [109]. In fact, their research demonstrated ciated with the putamen and pallidum IO and cognitive disorders with
that treating these mice with ceruloplasmin limited macrophage infil­ the cerebral cortex IO, there were no others statistically significant as­
tration in both adipose and hepatic tissues, reduced serum TG levels, and sociation between NP symptoms and BIO. Meanwhile, the influence of
partially restored adipokine levels in adipose tissue. [109]. Moreover, BIO on the emergence of NP symptoms cannot be dismissed. So, we
heterozygous Cp variants carriage associated with high ferritin level in propose considering alternative hypotheses. We observed that in­
serum and liver iron deposition has been considered as risk factor for dividuals with epileptic seizures exhibited significantly lower blood
Non Alcoholic Fatty Liver Disease/ Non Alcoolic Steato Hepatitis sugar levels compared to those without seizure. This suggests a potential
(NAFLD/NASH) progression [110]. Yet, we found only one reported association between hypoglycemia and the onset of seizures, rather than
case of ACP with steatosis in our included research, while no one had BIO. Furthermore, insulin has been demonstrated to enhance memory
NAFLD/NASH [46]. These findings emphasize the crucial connection by regulating synaptic plasticity in the hippocampus [115], thus, the
between iron regulation and lipid metabolism. Further investigations insulin resistance in ACP may lead to cognitive impairment. Addition­
are necessary to unravel and clarify this relationship. ally, research demonstrated a notable reduction in dopamine synthesis
Together with the previously elucidated pathophysiological process within the synaptosomes of the striatum in diabetic rats compared to the
of BIO in ACP, the current meta-analysis presents an innovative expla­ control group [115]. As consequence, we can suggest that parkinsonism
nation. We assume that diabetes could play an indirect, crucial role. Our could be also attributed to insulin resistance and glucose metabolic
univariate analysis revealed proof that diabetes represented a significant disorder. Basing on these findings, we can suggest that apart from the
common risk factor of brain, basal ganglia, thalamus, and dentate nuclei BIO, NP symptoms can also be induced by metabolic disruptions
IO. Likewise, it was observed in recent research that brain iron levels in resulting from diabetes and anemia in ACP. While the reasons behind
individuals with diabetes (aside from ACP) were notably higher in patients with extremely low CP levels starting the disease with systemic
specific areas like the striatum encompassing the caudate, putamen, and symptoms and later developing NP symptoms and BIO are evident in our
pallidum and the cortex of the frontal lobe, in comparison to healthy data, the pathological link between mild low CP levels and the initiation
controls [30]. In fact, increased glucose levels can result in the creation of the disease by NP signs, particularly in patients with normal brain
of advanced glycation end-products which have the potential to trigger MRI remains unclear.
inflammation and oxidative stress, potentially influencing the BIO [102, Normal conventional MRI may be explained by a low amount of iron
106]. Furthermore, oxidative stress has the potential to disturb the deposition that can’t be detected by conventional brain MRI. This hy­
integrity of the blood-brain barrier, potentially facilitating the passage pothesis was supported by case reports in which the patient without BIO
of a greater amount of iron into brain tissue [102,106]. Although, evi­ initiated with NP symptoms whereas the anatomopathological analysis
dence obtained through in vitro studies demonstrates that insulin causes showed mild IO in basal ganglia and thalamus, with mild decrease in the
the relocation of transferrin receptors to the surface of cells, resulting in number of neurons and significant depletion of Purkinje cells within the

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I. Ketata and E. Ellouz Rare 1 (2023) 100010

cerebellar cortex [30]. higher than those in CH with frameshift (0.0 g/l) and homozygotes with
Particular attention is paid to the association between consanguinity, frameshift (0.0 g/l). Thus, we can suggest that missense mutation had
mutation type and clinical signs in different stage of ACP evolution. Our lower pathogenicity than frameshift. That finding can explain why ho­
results suggest that patients with consanguinity had significant higher mozygous patient with consanguinity can have NP symptoms as initial
probability of initiating the disease with systemic symptoms. Therefore, clinical signs but with very lower risk, in fact, they might have missense
those patients carried an elevated risk of experiencing NP symptoms and mutation with lower pathogenicity or with modifier gene or with
an excess of BIO. In contrast, patients without consanguinity typically incomplete penetrance. Similar explanations have been proposed in
displayed initial NP symptoms whom prevalence of developing systemic other studies, suggesting that both genetic and environmental factors
signs or BIO was lower. This interesting result can be explained by others might affect ceruloplasmin activity [19]. As highlighted by Myajima
oxidase enzymatic activities described by CP, particularly the oxidase et al. and by Wang et al., factors such as aging, lifestyle choices, habits,
activity on the biogenic amines (norepinephrine, epinephrine, seroto­ blood sugar, and estrogen and progesterone level could potentially
nin, dopamine). This activity could play a role in the case of heterozy­ modify the expression of clinical symptoms [19,119]. Therefore, we can
gous that exhibit neurological/psychiatric as initial clinical symptoms in explain also why patients without consanguinity can initiate with sys­
the absence of both brain and systemic iron overload [116–118]. Indeed, temic signs since they had CH. We assume that ACP initiate in all cases
a low level of functional CP, as it occurs in heterozygous, might be with liver IO which remains biologically and clinically silent. Mean­
enough to maintain para-physiological iron homeostasis but not suffi­ while, this liver IO with low CP level led to systemic signs and NP
cient, or critical, for the maintenance of para-physiological levels of the symptoms. According to our data, we suggest in Fig. E.1 the course of
others oxidase activity of the ceruloplasmin [116]. ACP in both consanguineous and non-consanguineous patients. Mean­
We had noticed that patients with consanguinity were more likely while, further investigation is warranted to comprehensively understand
homozygotes and patients without consanguinity were heterozygotes or the relationship between different genetic mutation, consanguinity, CP
CH. Likewise, we found that missense mutation was significantly more level and ACP course.
likely in heterozygotes and in CH patients, while, frameshift mutation Our meta-analysis was limited by the number of published cases
was significantly found to be more likely in homozygotes. Additionally, about this rare disease. Furthermore, the published studies did not al­
given that ferroxidase levels were not consistently assessed in previous ways include all data like consanguinity and biological or brain MRI
case reports, we were particularly interested in examining the connec­ findings.
tion between CP levels (as an indicator of ferroxidase activity) and
mutation type. Meanwhile, results should be approached with caution, 5. Conclusion
as it’s important to note that for missense mutations, there may not be a
direct correlation between protein levels and ferroxidase activity. In In our current meta-analysis, we discovered that in the early stage of
some patients, the protein can be expressed and secreted but may not be aceruloplasminemia, males tend to develop diabetes first, while females
functional, depending on the specific amino acid mutation. Our data are more likely to suffer from anemia initially. On the other hand, in­
showed that homozygotes patients exhibited CP levels that were 1/50 of dividuals under 50 years are more likely to have systemic signs and
those found in CH, whereas, heterozygotes had a CP level half of the those above the age of 50 tend to primarily exhibit neuropsychological
normal. While homozygous individuals generally display significantly symptoms. Our findings demonstrated that multiple factors contribute
reduced CP levels, CH had significant higher level but sufficient to to these varied phenotypes. The prevalent factor linked to brain iron
induce similar course of ACP in homozygotes, since we found that CH overload was diabetes.
had more risk to initiate with systemic signs. Otherwise, it remains to
further studies to understand the severity of the disease between the two Data Availability
groups. Our data found that median CP in CH with missense mutation
(0.04 g/l) and in homozygotes with missense mutation (0.001 g/l) were Data will be made available on request.

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I. Ketata and E. Ellouz Rare 1 (2023) 100010

Appendix

Fig. A.1. : PRISMA flow diagram demonstrating information selection through the various stages of a systematic review and meta-analysis.

7
I. Ketata and E. Ellouz Rare 1 (2023) 100010

Fig. B.1. : Demographic characteristics of patients and initial clinical/biological signs of aceruloplasminemia. (Fig. B.1) Case origins reveals that Japan was observed
to have the highest prevalence of published cases, followed by Italy, the United States, and Germany. (Fig. B.2) The relative proportion of initial clinical/biological
signs shows that diabetes and anemia were the most common. (Fig. B.3) The age at disease diagnosis was close to the age at onset of neuropsychiatric symptoms,
whereas the age at diabetes, anemia, and biological liver disorder onset was close. Meanwhile, they were younger than the age at disease diagnosis. (Fig. B.4) Initial
clinical/biological signs according to gender shows that anemia is more frequent in women and diabetes is more common in men. (Fig. B.5) Box plot of age at onset of
initial clinical/biological signs in males and females shows that the median age at diabetes onset was younger in men and older in women. Others’ median ages
were close.

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I. Ketata and E. Ellouz Rare 1 (2023) 100010

Fig. C.1. : Evolution of clinical signs in initial presentation and in follow-up. (Fig. C.1) Evolution of initial clinical/biological features according to age at disease
onset. The risk of neurological/psychiatric symptoms increased with age, whereas, systemic signs increased between the ages of 30 and 50 and then decreased.
Patients aged under 50 years had a higher risk of starting the disease with systemic signs, and patients aged equal to or above 50 years, had a higher risk of presenting
neurological/psychiatric symptoms. Consanguinity decreases the risk of neurological/psychiatric symptoms at the disease’s onset. Consanguinity, male and ferritin
≥ 700 ng/ml were potential factors for diabetes, and female and Ferritin < 700 ng/ml were predictive factors for anemia. (Fig. C.2) Evolution of clinical mani­
festations and liver iron overload in follow-up. Among patients with systemic signs’ onset, the risk of neurological/psychiatric symptoms increased significantly with
age. Consanguinity and disease onset with systemic signs were the two predictive factors for the occurrence of neurological/psychiatric symptoms. Patients with
neurological/psychiatric symptoms had a lower risk of developing systemic signs. Grey shading indicates the age to screen for aceruloplasminemia in men with
diabetes and in females with anemia by screening for mild neurological/psychiatric symptoms and biological liver disorders or liver iron overload.

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I. Ketata and E. Ellouz Rare 1 (2023) 100010

(caption on next page)

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I. Ketata and E. Ellouz Rare 1 (2023) 100010

Fig. D.1. : Forest plot of predictor factors for iron overload in the brain. (Fig. D.1) Factors associated with brain iron overload. (Fig. D.2) Factors associated with
basal ganglia overload. (Fig. D.3) Factors associated with thalamus iron overload. (Fig. D.4) Factors associated with dentate nucleus iron overload. The scale in the x-
axis represents the OR risk estimated. The red vertical line shows no association (OR=1). The black square indicates the OR estimated for each studied variable, and
the line indicates the 95% confidence interval of the estimates. An odds ratio greater than 1 indicates that iron overload is more likely to occur, and an odds ratio less
than 1 indicates that this event is less likely to occur.

(caption on next page)

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I. Ketata and E. Ellouz Rare 1 (2023) 100010

Fig. E.1. : The course of ACP in both consanguineous and non-consanguineous patients. Consanguineous patients had a higher risk to be homozygotes for frameshift
mutation inducing a very low ceruloplasmin level with higher risk to have anemia in female/diabetes in male as initial clinical signs, thus, these systemic indications
contribute to an accumulation of iron in the brain, and to neuropsychiatric symptoms by oxidative stress, neurodegenerative processes, insulin resistance, and a
deficiency of iron. Additionally, brain iron overload can increase iron deficiency and lead to anemia. In contrast, non-consanguineous patients had higher risk to be
heterozygotes for missense mutation with ceruloplasmin level equal to half of normal, thus, they start with neuropsychiatric symptoms with less common risk of brain
iron overload and anemia or diabetes. Regardless to consanguinity, compound heterozygotes were found to have a higher likelihood of having a missense mutation,
causing ceruloplasmin levels higher than those found in frameshift homozygotes but lower than in heterozygotes, and with higher risk to start with anemia or
diabetes. They can start with neuropsychiatric symptoms in case of modifier gene or incomplete penetrance. Otherwise, liver iron overload is the common element
that happen in all cases and represent the primum movens in aceruloplasminemia. This figure indicates that consanguineous patients might start the disease by
neuropsychiatric symptoms in the case of compound heterozygotes or homozygotes with missense mutation. Non-consanguineous patients can start with diabetes/
anemia in case of compound heterozygotes. This figure elucidates various potential pathways for the progression of aceruloplasminemia and shows that this disease
represents a vicious cycle.

.
.
.
. A.1
Table
Initial clinical/biological signs according to consanguinity, mutation type, gender and age at disease onset.

Anemia Diabetes Biological liver disorder Neurological/psychiatric

symptoms

Results p OR [95% Results p OR [95% CI] Results p OR [95% CI] Results p OR [95% CI]
(n,%) CI] (n,%) (n,%) (n,%)
Consanguinity*
All (N) 26 (49.1) 0.5 1§§ 10 (31.3) 0.015§ 1§§ 2 (47) 1 1§§ 30 (53.6) 0.033§ 1§§
All (Y) 6 (40) 0.7 22 (61.1) 3.5 2 (50) 1.1 2 (16.7) 0.17
[0.2–2.2] [1.26–9.4] [0.15–8.5] [0.03–0.8]
Age at disease
onset
< 30 years
All (N) 19 (23.8) 0.095 1§§ 18 (30) 0.64 1§§ 29 (28.2) 1 1§§ 27 (30.7) 0.24 1§§
All (Y) 12 (40) 2.1 13 (26) 0,82 2 (28.6) 1 [0.18–5.5] 4 (18.2) 0.5
[0.8–5.2] [0,35–1,8] [0.15–1.6]
M (Y) 3 (20) 0.046§ 1§§ 11 (73.3) 0.002§ 19.2 1 (6.7) 1 1§§ 0 0.1 -
[2.9–125.1]
F (Y) 9 (56.3) 5.14 2 (12.5) 1§§ 1 (6.3) 0.93 4 (25%) -
[1–25.6] [0.05–16.3]
30–50 years
All (N) 38 (47.5) 0.2 1§§ 20 (33.3) 0.018§ 1§§ 44 (42.7) 0.5 1§§ 48 (54.5) 0.09 1§§
All (Y) 10 (33.3) 0.5 28 (56) 2,5 [1.2–5.5] 4 (57.1) 1.7 [0.4 − 6 (27.3) 0.4
[0.2–1.3] 8.4] [0.14–1.14]
M (Y) 2 (10) 0.008§ 1§§ 19 (63.3) 0.2 1 4 (13.8) 0.14 - 4 (13.8) 0.74 1§§
F (Y) 8 (42.1) 9.8 9 (47.4) 0.47 0 - 2 (10.5) 0.74
[1.8–53.7] [0.14–1.5] [0.12–4.4]
> 50 years
All (N) 23 (28.7) 0.8 1§§ 22 (36.7) 0.03§ 1§§ 30 (29.1) 0.67 1§§ 19 (21.6) 0.003§ 1§§
All (Y) 8 (26.7) 0.9 9 (18) 0.4 [0.1–0.9] 1 (14.3) 0.4 12 (54.5) 4.3
[0.35–2.3] [0.05–3.5] [1.6–11.6]
M (Y) 2 (20) 1 1§§ 1 (11.1) 0.13 1§§ 0 1 - 7 (70) 0.02§ 7.5
[1,4–40.2]
F (Y) 6 (28.6) 1.6 8 (38.1) 5.5 1 (4.8) - 5 (23.8) 1§§
[0.25–9.8] [0.6–52.3]
Mutation type**
Heterozygous (Y) 0/6 (40) 0.5 1§§ 0/5 0.03§ 1§§ 0/1 (6.7) 0.9 1§§ 7 (100)/ 0.001§ 1§§
/CH (Y) (3.33) 3 (20)
Homozygous (Y) 22 (34.4) 0.76 32 (50) 3.4 3 (4.7) 1 [0.1–10.4] 6 (9.4) 0.12
[0.2–2] [1.1–10.3] [0.03–0.4]
*Available in 68 cases; ** Available in 86 cases (64 homozygous, 7 heterozygous, 15 compound heterozygous); OR, unadjusted odds ratio; CI, confidence interval; F,
female; M, male; N, patients without the symptom; Y, patients with the symptom; CH, compound heterozygous; §statistically significant at p < 0.05; §§ reference.

Table B.1
Disease’s features.

All Male‡ Female P OR [95% CI]

Age at disease onset (years) 37.9 ± 13.9[10–71] 36.8 ± 12,15[10–62] 39 ± 15,53[12–71] 0,36 -
Age at disease diagnosis (years) 54 (range: 43.75–59.25) 52 (range: 45–56) 56 (range: 45.25–61.7) 0.49 -
Age at anemia onset (years) 50 (range: 29–56) 50 (range: 29.5–56) 49 (range: 25–56) 0.89 -
Age at diabetes onset (years) 41.87 ± 14.2[10–72] 38 (range: 26–42.7) 50 (range: 38–60) < 0.001§ -
Age at biological liver disorder onset (years) 36.5 (range: 30.25–50.5) 35 (range: 30–38) 51 (range: 27–62) 0.29 -
Age at neurological/psychiatric onset (years) 50.5 ± 12.67[15–75] 50 (range: 45–56) 55 (range: 48–61) 0.09 -
Isolated systemic signs 25 (22.7%) 13 (24.1%) 12 (21.4%) 0.7 -
Isolated neurological symptoms 10 (9.1%) 6 (11.1%) 4 (7.1%) 0.47 -
Isolated psychiatric symptoms 1 (0.9%) 1 (1.9%) NP - -
Neurological and psychiatric signs 5 (4.5%) 3 (5.6%) 2 (3.6%) 0.23 -
(continued on next page)

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I. Ketata and E. Ellouz Rare 1 (2023) 100010

Table B.1 (continued )

All Male‡ Female P OR [95% CI]

Neurological and systemic signs 42 (38.2%) 19 (35.2%) 23 (41.1%) 0.62 -

Psychiatric and systemic signs 3 (2.7%) NP 3 (5.4%) - -
Neurological and psychiatric and systematic signs 24 (21.8%) 12 (22.2%) 12 (21.4%) 0.92 -
Systemic signs 93 (84.5%) 44 (81.5%) 49 (87.5%) 0.38 1.59 [0.55–4.53]
Diabetes 69 (62.7%) 34 (63%) 35 (62.5%) 0.96 0.98 [0.45–2.12]
Type 1* 18 (25.3%) 13 (37.1%) 5 (13.9%) 0021§ 0.25 [0.07–0.81
Type 2* 53 (74.6%) 22 (62.8%) 31 (86.1%) 0.021§ 1.23 [1.23–12.7]
Not controlled** 14 (73.7%) 9 (100%) 5 (50%) 0.033§ -
Glucose intolerance 4 (3.6%) 1 (1.9%) 3 (5.4%) 0.34 3 [0.3–29.7]
Anemia 74 (67.3%) 28 (51.9%) 46 (82.1%) 0.001§ 1.23 [1.23–12.7]
Not controlled† 15 (100%) 6 (100%) 9 (100%) - -
Neurological synmptoms
Symptomatic 82 (74.5%) 40 (74.1%) 42 (75%) 0.91 0.95 [0.4–2.23]
Asymptomatic 28 (25.5%) 14 (25.9%) 14 (25%) - -
Cognitive impairment 52 (47.3%) 26 (48.1%) 26 (46.4%) 0.85 0.9 [0.4–1.97]
Ataxia 42 (38.2%) 21 (38.9%) 20 (37%) 0.88 0.94 [0.43–2.03]
Parkinsonism 23 (21%) 10 (18.5%) 13 (23.2%) 0.56 1.3 [0.5–3.19]
Abnormal movements 38 (34.5%) 15 (27.7%) 23 (41.1%) 0.09 2 [0.8–4.47]
Dystonia 21 (19.1%) 5 (9.3%) 16 (28.6%) 0.014§ 3.92 [1.3–11.63]
Blepharospasm 8 (7.3%) 1 (1.9%) 7 (12.5%) - -
Cervical and mandibular 5 (4.5%) 1 (1.9%) 4 (7.1%) - -
Langual 1 (0.9%) NP 1 (1.8%) - -
Inferior member 1 (0.9%) NP 1 (1.8%) - -
Missing 6 (5.4%) 2 (3.7%) 4 (7.1%) - -
Oral dyskinesia 14 (12.7%) 6 (11.1%) 8 (14.3%) - -
Chorea 9 (8.2%) 2 (3.7%) 7 (12.5%) - -
Chorea-athetosis 2 (1.8%) 1 (1.9%) 1 (1.8%) - -
Myoclonia 2 (1.8%) 1 (1.9%) NP - -
Tremor 4 (3.6%) 1 (1.9%) 3 (5.3%) - -
Akathisia 1 (0.9%) 1 (1.9%) NP - -
Hyperkinesia 1 (0.9%) NP 1 (1.8%) - -
Dysarthria 25 (22.7%) 14 (25.9%) 11 (19.6%) 0.43 0.7 [0.28–1.7]
Dizziness 5 (4.5%) 1 (1.9%) 4 (7.1%) - -
Seizure 4 (3.6%) 2 (3.7%) 2 (3.6%) - -
Swallowing disorder 4 (3.6%) 2 (3.7%) 2 (3.6%) - -
Frontal lobe syndrom 3 (2.7%) 2 (3.7%) 1 (1.8%) - -
Consciousness disorders 2 (1.8%) 2 (3.7%) NP - -
Lower extremity heaviness 2 (1.8%) 2 (3.7%) NP - -
Psychiatric symptoms
Symptomatic 30 (27.3%) 14 (25.9%) 16 (28.6%) 0.7 1.1 [0.5–2.6]
Asymptomatic 80 (72.7%) 40 (74.1%) 40 (71.4%) - -
Behavioral disorders (Aggressiveness) 15 (13.6%) 7 (13%) 8 (14.3%) 0.84 1.19 [0.37–3.3]
Depression 12 (10.9%) 7 (13%) 5 (8.9%) 0.5 0.65 [0.19–2.2]
Anxiety 6 (5.5) NP 6 (10.7%) 0.027§ -
Apathy 5 (4.5) 3 (5.6%) 2 (3.6%) 0.62 0.63 [0.1–3.9]
Hallucination 2 (1.8%) 1 (1.9%) 1 (1.8%) 0.97 0.96 [0.05–15.8]
Bipolar disorder 2 (1.8%) NP 2 (3.6%) 0.49 -
Schizophrenia-like psychosis 1 (0.9%) 1 (1.9%) NP 0.6 -
Other clinical signs
Asthenia 15 (13.6%) 6 (11.1%) 9 (16.1%) - -
Hearing loss 3 (2.7%) 2 (3.7%) 1 (1.8%) - -
Muscle cramps 2 (1.8%) 2 (3.7%) NP - -
Nyctalopia 1 (0.9%) 1 (1.9%) NP - -
Paroxysmal febrile peak (/6 months) 1 (0.9%) 1 (1.9%) NP - -
*Diabetes type available in 71 cases (35 males and 36 females); **available in 19 cases (9 males and 10 females); † available in 15 cases (6 males and 9 females); ‡
reference; NP, no patient; § statistically significant at p < 0.05.

Table C.1
biological findings.

Normal range Results p

Hb (g/dl)* M ≥ 13 M 11.5 (range: 9.9–13) 0.001‖‖

F ≥ 12 F 9.8 (range: 9–10.6)
Anemia M (26, 74.3%) 0.003‖‖
F (39, 97.5%)
MCV (fl)** MCV ≥ 80 76.1 ± 7.6[50–95]
Serum iron (μg/dL)† 26 (range: 17–34.5)
M 70–175 M 26.2 (range: 16–38) 0.19
F 50 – 150 F 22 (range:17–31)
Collapsed M< 70 M 36 (85.7%)
F< 50 F 39 (83%) 0.6
Ferritin (ng/ml)‡ 1111.4 (range: 540–1530)
M 18–270 M 1225 [835–1699] 0.028‖‖
F 18–160 F 891 [461–1499]
High 85 (93.4%)
(continued on next page)

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I. Ketata and E. Ellouz Rare 1 (2023) 100010

Table C.1 (continued )

Normal range Results p

Ferrtin > 700 ng/ml M 38 (86.7%) 0.002‖‖

F 27 (57.4%)
Transferrin saturation (%)‡‡ 11 (range: 6.8–13.7)
20–50 M 11.5 (range: 8.6–17.5) 0.09
F 9.5 (range: 6–12)
Low < 20 34 (87.2%)
Plasma Copper levels (μg/dL)‖ 70 − 140 9 (range: 5.2–16.5)
M 8 (range: 5.2–15.2) 0.4
F 9.4 (range: 5.2–19.6)
Low Copper levels < 70 73 (100%)
Ceruloplasmin serum (g/l)¶ 0.2–0.6 0.01 (range: 0–0.2)
M 0.006 (range: 0–0.02) 0.8
F 0.0 (range: 0–0.023)
HM 0.0005 (range 0–0.02) -
CH 0.026 (range 0–0.075) < 0.001‖‖
HZ 0.11 (range 0.1–0.11) < 0.001‖‖
Low ceruloplasmin serum levels < 0.2 108 (99%)
Liver function test¶¶
ALT (U/L) 7–55 25 (range: 17–54)
High 9 (20.9)
AST (U/L) 8 – 48 23.5 (range: 17–41.5)
High 7 (16.3%)
Fasting blood sugar (mmol/l)¶¶¶ < 5.6 8 (range: 5–11.8)
M 8.8 (range: 5–13.9)
F 6.5 (range: 4.8–9.3)
HbA1c (%)§ < 5.7 8.5 ± 2.3 [5.3–14.5]
M 9.4 ± 2.4 [6–14.5] 0039‖‖
F 7.8 ± 1.9 [5.3–11.9]
TG (mmol/l)+ < 1.7 Normal in 3 cases
TC < 5.17 Normal in 3/6 cases
Elevated in 3/6 cases (5.7 ± 0.28 [5.5–5.9]
Hb, hemoglobin; MCV, mean corpuscular volume; ALT, alanine transaminase; AST, aspartate transaminase; HbA1c, glycated hemoglobin, M, male; F,
female; HZ, heterozygotes; HM, homozygotes (reference); CH, compound heterozygotes; NP, no patient; TG, triglyceride levels; TC, total cholesterol; *
available in 75 cases (35 in male, 40 in female); * * available in 66 cases; †available in 89 cases (42 in male and 47 in female); ‡ available in 91 cases (44
in male, 47 in female); ‡‡ available in 39 cases; ‖available in 72 cases; ¶ available in 109 cases; ¶¶ available in 43 cases; ¶¶¶ available in 34 cases;
§available in 28 cases; ‖‖ statistically significant at p < 0.05; + , TG available in 3 cases, + +; TC available in 6 cases.

Table D.1
Magnetic resonance imaging findings and its association with neurological symptoms.

Magnetic resonance imaging* Results (All) NP symptoms‡ Cognitive impairment‡‡ Ataxia¶ Abnormal movement¶¶

Normal 6 (6.2%)
Brain iron overload 81 (83.5%) 62 (81.6%)** 36 (83.7%)** 33 (86.8%)** 32 (88.9%)**
Basal ganglia 79 (81.1%) 61 (80.2%)** 35 (81.4%)** 32 (84.2%)** 27 (75%)**
Caudate nucleus 37 (38.1%) 27 (35.5%)** 11 (25.6%)** 16 (42.1%)** 12 (33.3%)**
Putamen 34 (35%) 29 (38.1%)** 19 (44.2%)** 13 (34.2%)** 7 (19.5%)†
Pallidium 9 (9.2%) 8 (10.5%)** 4 (9.3%)** 6 (15.7%)** 9 (25%)†
Striatium 14 (14.4%) 10 (13.1%)** 4 (9.3%)** 4 (10.5%)** 2 (5.5%)**
Lentiform nuclei 10 (10.3%) 7 (9.2%)** 5 (11.6%)** 4 (10.5%)** 1 (2.7%)**
Dentate nucleus 59 (60.8%) 44 (57.9%)** 25 (58.1%)** 25 (65.8%)** 23 (63.9%)**
Thalamus 57 (58.7%) 41 (53.9%)** 25 (58.1%)** 22 (57.9%)** 21 (58.3%)**
Midbrain 25 (25.8%) 21 (27.6%)** 17 (39.5%)** 12 (31.6%)** 11 (30.5%)
Subtantia nigra 15 (15.4%) - - - -
Red nuceleus 13 (13.4%) - - - -
Cerebellar peduncle 2 (2.06%) - - - -
Cerebral cortex 16 (16.5%) 15 (19.7%) 12 (27.9%)† 9 (23.7%)** 9 (25%)**
White matter T2 hyperintensity 9 (9.2%) - - - -
Periventricular 2 (2.06%) - - - -
U-fiber 1 (1.03%) - - - -
Cerebral atrophy 16 (16.5%) - - - -
Cerebellar atrophy 5 (5.1%) - - - -
Global atrophy 5 (5.1%) - - - -
Global atrophy without iron overload 1 (1.03%) - - - -
Superficial siderosis 4 (4.1%) - - - -
*Available in 97 cases; ** not statistically significant at p ≥ 0.05; † Statistically significant at p < 0.05; ‡ among patients having neuropsychiatric symptoms, 76 patients
had magnetic resonance imaging; ‡‡ among patients having cognitive impairment, 43 had magnetic resonance imaging, ¶ among patient with ataxia, magnetic
resonance imaging was available in 38 patients; ¶¶ among patient having abnormal movements, magnetic resonance imaging was available in 36 patients; NP,
neuropsychiatric symptoms.

14
I. Ketata and E. Ellouz Rare 1 (2023) 100010

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