Table 1.

Biochemical, clinical, and genetic data of the 13 affected members in the 11 studied families with ACP.

Characteristic	Family 1	Family 2	Family 3	Family 4	Family 4	Family 5	Family 6	Family 7	Family 8	Family 8	Family 9	Family 10	Family 11	Normal Values
	II.3	II.3	II.3	II.2 (proband)	II.3	II.1	II.2	II.3	II.3 (proband)	II.2	II.2	II.1	II.1
Country of Origin	Lithuania	Spain	India	India	India	Poland	Italy	Italy	Brazil	Brazil	Brazil	India	Pakistan
Sex	F	F	M	M	M	F	M	M	F	F	F	F	M
Age at Dx (years)	75	33	40	66	61	40	46	62	37	29	46	25	16
Hb (g/dl)	11.1	10.9	12.1	11.6	10.7	11.1	12.5	12.2	11.7	12.3	9.4	9.2	13.4	12–16
MCV (fl)	82,0	85.1	77	66.8	81	88.0	84	70.6	75.2	71.4	64.5	71.5	69	79–99
Retyculocytes (%)	0.5	0.8	n/a	0.9	1.2	n/a	0.58	1	1.77	1.1	1.77	0.51	n.a.	1.1–2.7
RDW (%)	16.8	15.2	14.3	17.3	15.5	15.5	15.4	16.1	16	17.2	18	17.1	18	11.3–14.5
Serum iron (µg/dl)	82.8	15	28	19	39.1	81.0	33	215	23	23	22	9.5	33.5	37–170
Ferritin (ng/ml)	12159	355.4	1077	1112	3845	1143	2100	3650	791	732	1060	757	1065	10–290
Transferrin Saturation (%)	12.4	4.3	10	5	12	39	9	88	9.24	9.83	8.2	4	8.8	20–55
CP (mg/dl)	< 0.02	< 2.0	< 0.03	< 0.03	< 0.03	0.12	undetectable	0.12	11	9	< 2	n.a.	< 0.02	17–65
ALT (U/l)	55	12	32	24	36	19	37	113	26	179	37	24	87	14–36
AST (U/l)	43	17	n.a	n.a	24	16	20	80	12	82	29	n/a	n/a	8–40
Clue to ACP diagnosis	Low level of Cp. No Cu urine excretion Hepatocellular siderosis. Iron deposition in basal ganglia.	Low level of Cp. Low serum Cu and low urine Cu. Hepatic iron overload. Iron deposit in basal ganglia.	Iron deposition at brain MRI, Unexplained hyperferritinemia, low CP	Iron deposition at brain MRI, Unexplained hyperferritinemia, low CP	Iron deposition at brain MRI, Unexplained hyperferritinemia, low CP	Symptoms (including tremor) and very low CP	unexplained hyperferritinemia	overexpressed HFE Hemochromatosis, supposed additional non-HFE mutation(s) tested with NGS	Iron deposition at brain MRI	Familial investigation	Low CP in investigation of iron-refractory anaemia	Hair loss, mild executive dysfunction on formal neurocognitive assessment	low CP level
Clinical presentation (symptoms and signs)	Moderate dementia with prevalent frontal features, cerebellar ataxia, oromandibular dystonia, torsion of the trunk, severe chorea-athetosis with choreiform movements. Mild type-2 DM. Retinal degeneration. Mild anaemi	Unspecific symptoms: Fatigue; abdominal discomfort and chronic anaemia. Liver ultrasonografy showed hepatic lesions that justified a MRI, that showed iron overload	Neurological symptoms: progressive cognitive decline, diabetes, mild bradykinesia with mild finger nose ataxia and dysdiadochokinesia .Unexplained anaemia	Neurological symptoms: progressive(over 5 years) cognitive decline, diabetes, tremor left hand Unexplained anaemia	Concentration and intellectual ability decline. Unexplained anaemia, DM.	Head and postural tremor of upper and lower limbs, slight dysmetria, ataxia, proximal weakness of lower extremities, horizontal nystagmus, and tunnel vision.	Liver iron overload and mild anaemia	Iron overload. Mild anaemia was consistent also with b-thalassemia trait	Choreiform movement disorder, mild anaemia, DM-2, asymptomatic retina pigmentation	Asymptomatic. Familial investigation	Mild anaemia, DM-2, asthenia, mild movement disorder	April 2015 acute psychotic episode with catatonia, hair loss, mild executive dysfunction on formal neurocognitive assessment	Concentration/memory lapses
Anaemia	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes	Yes	No
Neurological symptoms	Yes	No	Yes	Yes	Yes	Yes	No	No	Yes	No	Yes	Yes	Yes
Liver Iron overload	Yes	Yes	n.a.	Yes	Yes	No	Yes	n.a.	n.a.	Yes	n.a	Yes	Yes
Diabetes	Yes	No	Yes	Yes	Yes	No	No	No	Yes	No	Yes	No	No
Retinopathy	Yes	No	No	No	No	Not evaluated	Yes but not typical for aceruloplasminemia	No	Yes	Not evaluated	Not evaluated	No	Yes
Brain MRI (sites of iron accumulation, in brief)	Iron overload in putamen	Iron overload in lenticular, dentate and thalamus	SWI increased susceptibility involving the cerebelum, basal ganglia, thalami, red and dentate nuclei.	MRI SWI with marked susceptibility predominantly involving the lateral putamen, red nucleus, striaum, thalamic, pulvinar, cerebellar dentate nucleus	Iron overload in lentiform caudate, dorsal lateral thalami and dentate nuclei	FLAIR and T2 hypointenseties in the putamen and substantia nigra	no iron overload	no iron overload	Iron overload in thalami, basal ganglia, and cerebellum	Iron overload in thalami, basal ganglia, red nuclei, dentate, cerebellum and brain cortex	Iron overload in thalami, basal ganglia, dentate, and cerebellum	Iron overload in choroid plexus, bilateral dentate nuclei thalamic and basal ganglia	n.a.
Liver MRI or (biopsy)	hepatocellular siderosis grade III	HII = 9.58, severe iron overload	n.a.	Feriscan LIC: 9.4 mg/g dw	LIC by Ferriscan: 6.3 mg/g dw	Biopsy: small depositions of yellow-brown pigment (stain for ferrum - negative) - probably lipofuscin	LIC 340 µM/g = HII 7.9 (severe iron overload)	n.a.	not performed	Iron overload in liver and pancreas (qualitative)	not performed	LIC by Ferriscan 9.0 mg/g/dw	LIC by Ferriscan: 5.3 mg/g dw	HII < 1.9
Diagnostic delay	20 years	1.5 years	5 years	2 years	4 years	13 years	3 years	30 years	1 year	Not applicable	32 years	3 years	Not known
Iron chelation or other therapy	No Iron chelation therapy.	Deferasirox from 10/2014 to 11/2015; Deferiprone from 11/2015; Vitamin E.	Started on FFP OctaplasLG every 2 weeks on diagnosis. Later added Deferiprone	Deferiprone started on diagnosis (25 mg/kg/d)	Deferiprone started 2011	Zinc	Deferasirox and desferoxamine both suspended for renal insufficiency, actually on deferiprone	Desferoxamine and “micro”-phlebotomies	Deferiprone	Desferoxamine, combination with deferiprone	Deferiprone	Deferiprone
Other clinical data	Bilateral cataracts	Psoriasis	None	hypertension, previous CVA, low Vitamin B12, bilateral cataracts	2013: DM, 2011: hearing loss	Hypertension	3-4 alcoholic units/day, arterial hypertension, overweight, central serous chorioretinopathy	Beta-Thal trait; fully penetrant HFE-related HH (C282Y homozygous) in the 3rd decade of life	Hypercholesterolemia, macroalbuminuria	Hypothyroidism, lower limb venous thrombosis, migraine	Hypothyroidism, glaucoma, kidney stones, chronic diarrhea	Iatrogenic iron overload due to oral iron supplementation for microcytic anaemia, hypothyroid, amenorhoea (thought to be due to polycystic ovaries), microcytic anaemia, hypothyroid, borderline oral glucose tolerance test.	White nails, Acquired leukopenia, Bilateral lattice degeneration of fundi-risk of retinal detachment. Vit D depletion
Genetics CP gene NM_000096.3; NP_000087.1	c.[1783_1787delGATAA(;)2520_2523delAACA] p.(Asp595Tyrfs*2;Thr841Argfs*52)	c.[2050_2051delAC]; [2050_2051delAC] p.(Thr684Alafs*6); (Thr684Alafs*6)	c.[1864+5G>A];[1864+5G>A]	c.[1864+5G>A];[1864+5G>A]	c.[1864+5G>A];[1864+5G>A]	c.[389A>C]; [=] p.(His130Pro); (=)	c.[1012T>A(;)2972T>C] p. (Cys338Ser);(Ile991Thr)	c.[2684G>C(;)1602T>G] p. (Gly895Ala);(Cys534Trp)	c.[2879-1G>T];[2879-1G>T]	c.[2879-1G>T];[2879-1G>T]	c.[2756T>C];[2756T>C] p.(Leu919Pro);(Leu919Pro)	c.[1679G>T];[1679G>T] p.(Cys560Phe);(Cys560Phe)	c.[1713+1delG];[1713+1delG]

Reference values are indicated in the last column. Sex: M: male, F: female; ACP: Aceruloplasminemia; CP: ceruloplasmin; MRI: magnetic resonance imaging; SWI Susceptibility weighted imaging; HII hypoxic-ischemic injury; LIC: liver iron content; Hb: Hemoglobin; MCV: mean corpuscular volume; RDW: red cell distribution width; DM-2: Diabetes mellitus type 2; NGS: next-generation sequencing; n.a.: not available.