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). Autosomal recessive inheritance (Orphanet)

Gene (location): Gene(s) directly associated with this condition or phenotype.	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).

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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.

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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.

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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).

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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).

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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.

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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.

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Anemia

MedGen UID:: 1526
•Concept ID:: C0002871
•: Disease or Syndrome

A reduction in erythrocytes volume or hemoglobin concentration.

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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).

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Diabetes mellitus