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Deficiency of ferroxidase(ACEP)

MedGen UID:
168057
Concept ID:
C0878682
Disease or Syndrome
Synonyms: ACEP; Aceruloplasminemia; Ceruloplasmin deficiency; Deficiency of ceruloplasmin; Familial apoceruloplasmin deficiency; Hereditary ceruloplasmin deficiency; NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 10
SNOMED CT: Deficiency of ceruloplasmin (124224004); Deficiency of ferroxidase (124224004)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): CP (3q24-25.1)
 
HPO: HP:0025498
Monarch Initiative: MONDO:0011426
OMIM®: 604290
Orphanet: ORPHA48818

Definition

Aceruloplasminemia is characterized by iron accumulation in the brain and viscera. The clinical triad of retinal degeneration, diabetes mellitus (DM), and neurologic disease is seen in individuals ranging from age 30 years to older than 70 years. The neurologic findings of movement disorder (blepharospasm, grimacing, facial and neck dystonia, tremors, chorea) and ataxia (gait ataxia, dysarthria) correspond to regions of iron deposition in the brain. Individuals with aceruloplasminemia often present with anemia prior to onset of DM or obvious neurologic problems. Cognitive dysfunction including apathy and forgetfulness occurs in more than half of individuals with this condition. [from GeneReviews]

Additional descriptions

From OMIM
Aceruloplasminemia (ACEP) is an autosomal recessive disorder characterized by mild anemia (often microcytic), diabetes mellitus, retinopathy, liver disease, and progressive neurologic symptoms due to iron accumulation in the pancreas, retina, liver, and brain. Anemia is often found in childhood or adolescence, whereas the neurologic and systemic features usually develop in middle age or later. The disorder shows clinical heterogeneity; all symptoms may not be present in every affected individual. Laboratory studies show high ferritin levels, low serum iron levels, and low or undetectable ceruloplasmin. Brain imaging usually shows iron accumulation in specific parts of the brain, particularly in the basal ganglia and thalami, as well as in visceral organs, such as the liver and pancreas. Many reported patients are from Japan, but patients have been reported worldwide (summary by Vila Cuenca et al., 2020). Roy and Andrews (2001) reviewed disorders of iron metabolism, with emphasis on aberrations in hemochromatosis (235200), Friedreich ataxia (229300), aceruloplasminemia, and other inherited disorders. For a discussion of genetic heterogeneity of NBIA, see NBIA1 (234200).  http://www.omim.org/entry/604290
From MedlinePlus Genetics
Aceruloplasminemia is a disorder in which iron gradually accumulates in the brain and other organs. Iron accumulation in the brain results in neurological problems that generally appear in adulthood and worsen over time.

People with aceruloplasminemia develop a variety of movement problems. They may experience involuntary muscle contractions (dystonia) of the head and neck, resulting in repetitive movements and contortions. Other involuntary movements may also occur, such as rhythmic shaking (tremors), jerking movements (chorea), eyelid twitching (blepharospasm), and grimacing. Affected individuals may also have difficulty with coordination (ataxia). Some develop psychiatric problems and a decline of intellectual function (dementia) in their forties or fifties.

In addition to neurological problems, affected individuals may have diabetes mellitus caused by iron damage to cells in the pancreas that make insulin, a hormone that helps control levels of blood sugar, also called blood glucose. Iron accumulation in the pancreas reduces the cells' ability to make insulin, which impairs blood glucose regulation and leads to the signs and symptoms of diabetes.

Iron accumulation in the tissues and organs results in a corresponding shortage (deficiency) of iron in the blood, leading to a shortage of red blood cells (anemia). Anemia and diabetes usually occur by the time an affected person is in his or her twenties.

Affected individuals also have changes in the light-sensitive tissue at the back of the eye (retina) caused by excess iron. The changes result in small opaque spots and areas of tissue degeneration (atrophy) around the edges of the retina. These abnormalities usually do not affect vision but can be observed during an eye examination.

The specific features of aceruloplasminemia and their severity may vary, even within the same family.  https://medlineplus.gov/genetics/condition/aceruloplasminemia

Clinical features

From HPO
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Chorea
MedGen UID:
3420
Concept ID:
C0008489
Disease or Syndrome
Chorea (Greek for 'dance') refers to widespread arrhythmic involuntary movements of a forcible, jerky and restless fashion. It is a random-appearing sequence of one or more discrete involuntary movements or movement fragments. Movements appear random because of variability in timing, duration or location. Each movement may have a distinct start and end. However, movements may be strung together and thus may appear to flow randomly from one muscle group to another. Chorea can involve the trunk, neck, face, tongue, and extremities.
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
Torticollis
MedGen UID:
11859
Concept ID:
C0040485
Sign or Symptom
Torticollis is a twisted neck as a result of shortening of sternocleidomastoid muscle. This short and fibrotic muscle pulls the head laterally and rotates the chin and face to the opposite end. Facial asymmetry may be a manifestation (summary by Engin et al., 1997).
Abnormality of extrapyramidal motor function
MedGen UID:
115941
Concept ID:
C0234133
Sign or Symptom
A neurological condition related to lesions of the basal ganglia leading to typical abnormalities including akinesia (inability to initiate changes in activity and perform volitional movements rapidly and easily), muscular rigidity (continuous contraction of muscles with constant resistance to passive movement), chorea (widespread arrhythmic movements of a forcible, rapid, jerky, and restless nature), athetosis (inability to sustain the muscles of the fingers, toes, or other group of muscles in a fixed position), and akathisia (inability to remain motionless).
Scanning speech
MedGen UID:
116113
Concept ID:
C0240952
Mental or Behavioral Dysfunction
An abnormal pattern of speech in which the words are as if measured or scanned; there is a pause after every syllable, and the syllables themselves are pronounced slowly.
Dementia
MedGen UID:
99229
Concept ID:
C0497327
Mental or Behavioral Dysfunction
A loss of global cognitive ability of sufficient amount to interfere with normal social or occupational function. Dementia represents a loss of previously present cognitive abilities, generally in adults, and can affect memory, thinking, language, judgment, and behavior.
Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
Cogwheel rigidity
MedGen UID:
57469
Concept ID:
C0151564
Sign or Symptom
A type of rigidity in which a muscle responds with cogwheellike jerks to the use of constant force in bending the limb (i.e., it gives way in little, repeated jerks when the muscle is passively stretched).
Diabetes mellitus
MedGen UID:
8350
Concept ID:
C0011849
Disease or Syndrome
A group of abnormalities characterized by hyperglycemia and glucose intolerance.
Decreased circulating iron concentration
MedGen UID:
65918
Concept ID:
C0235988
Finding
The concentration of iron in the blood circulation is below the lower limit of normal.
Increased circulating ferritin concentration
MedGen UID:
69130
Concept ID:
C0241013
Finding
Increased concentration of ferritin in the blood circulation.
Deficiency of ferroxidase
MedGen UID:
168057
Concept ID:
C0878682
Disease or Syndrome
Aceruloplasminemia is characterized by iron accumulation in the brain and viscera. The clinical triad of retinal degeneration, diabetes mellitus (DM), and neurologic disease is seen in individuals ranging from age 30 years to older than 70 years. The neurologic findings of movement disorder (blepharospasm, grimacing, facial and neck dystonia, tremors, chorea) and ataxia (gait ataxia, dysarthria) correspond to regions of iron deposition in the brain. Individuals with aceruloplasminemia often present with anemia prior to onset of DM or obvious neurologic problems. Cognitive dysfunction including apathy and forgetfulness occurs in more than half of individuals with this condition.
Blepharospasm
MedGen UID:
599
Concept ID:
C0005747
Disease or Syndrome
A focal dystonia that affects the muscles of the eyelids and brow, associated with involuntary recurrent spasm of both eyelids.
Retinal degeneration
MedGen UID:
48432
Concept ID:
C0035304
Finding
A nonspecific term denoting degeneration of the retinal pigment epithelium and/or retinal photoreceptor cells.

Conditions with this feature

Deficiency of ferroxidase
MedGen UID:
168057
Concept ID:
C0878682
Disease or Syndrome
Aceruloplasminemia is characterized by iron accumulation in the brain and viscera. The clinical triad of retinal degeneration, diabetes mellitus (DM), and neurologic disease is seen in individuals ranging from age 30 years to older than 70 years. The neurologic findings of movement disorder (blepharospasm, grimacing, facial and neck dystonia, tremors, chorea) and ataxia (gait ataxia, dysarthria) correspond to regions of iron deposition in the brain. Individuals with aceruloplasminemia often present with anemia prior to onset of DM or obvious neurologic problems. Cognitive dysfunction including apathy and forgetfulness occurs in more than half of individuals with this condition.

Professional guidelines

PubMed

Schneider SA, Hardy J, Bhatia KP
Mov Disord 2012 Jan;27(1):42-53. Epub 2011 Oct 26 doi: 10.1002/mds.23971. PMID: 22031173
Squitti R, Salustri C
Curr Alzheimer Res 2009 Dec;6(6):476-87. doi: 10.2174/156720509790147133. PMID: 19747159
Shih DQ, Dansky HM, Fleisher M, Assmann G, Fajans SS, Stoffel M
Diabetes 2000 May;49(5):832-7. doi: 10.2337/diabetes.49.5.832. PMID: 10905494

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