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Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia(EOCA-HA; EAOH; AOA; AOA1)

MedGen UID:
395301
Concept ID:
C1859598
Disease or Syndrome
Synonyms: Adult onset ataxia with oculomotor apraxia; Ataxia with Oculomotor Apraxia 1; Ataxia-oculomotor apraxia syndrome; Ataxia-oculomotor apraxia type 1; Ataxia-telangiectasia-like syndrome; Early-onset cerebellar ataxia with hypoalbuminemia
SNOMED CT: Autosomal recessive cerebellar ataxia with oculomotor apraxia type 1 (715366004); Autosomal recessive ataxia with oculomotor apraxia type 1 (715366004); AOA1 (ataxia oculomotor apraxia type 1) (715366004); Ataxia oculomotor apraxia type 1 (715366004)
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): APTX (9p21.1)
 
Monarch Initiative: MONDO:0008842
OMIM®: 208920
Orphanet: ORPHA1168

Authors:
Susan Perlman   view full author information

Additional descriptions

From OMIM
Ataxia-oculomotor apraxia syndrome is an early-onset autosomal recessive cerebellar ataxia with peripheral axonal neuropathy, oculomotor apraxia (defined as the limitation of ocular movements on command), and hypoalbuminemia (Moreira et al., 2001). Genetic Heterogeneity of Ataxia-Oculomotor Apraxia See also AOA2 (606002), caused by mutation in the SETX gene (608465) on chromosome 9q34; AOA3 (615217), caused by mutation in the PIK3R5 gene (611317) on chromosome 17p; and AOA4 (616267), caused by mutation in the PNKP gene (605610) on chromosome 19q13.  http://www.omim.org/entry/208920
From MedlinePlus Genetics
Ataxia with oculomotor apraxia type 2 usually begins around age 15. As in type 1, affected individuals may have chorea or myoclonus, although these movement problems persist throughout life in type 2. Neuropathy is also common in this type.

People with some types of ataxia with oculomotor apraxia may have characteristic blood abnormalities. Individuals with type 1 tend to have reduced amounts of a protein called albumin, which transports molecules in the blood. The shortage of albumin likely results in elevated levels of cholesterol circulating in the bloodstream. Increased cholesterol levels raise a person's risk of developing heart disease.

Type 1 begins around age 4. In addition to ataxia and oculomotor apraxia, affected individuals can have involuntary jerking movements (chorea) or muscle twitches (myoclonus); these movement problems tend to disappear over time. Individuals with this type may also develop muscle wasting in their hands and feet, which further impairs movement. As in all forms of ataxia with oculomotor apraxia, nearly all people with type 1 develop nerve abnormalities (neuropathy). Neuropathy impairs reflexes and leads to limb weakness and an inability to sense vibrations. Many individuals with ataxia with oculomotor apraxia require wheelchair assistance, typically 10 to 15 years after the start of movement problems.

There are several types of ataxia with oculomotor apraxia, the most common of which are types 1, 2, and 4. The types are very similar but are caused by mutations in different genes.

Ataxia with oculomotor apraxia is a condition characterized by problems with movement that worsen over time. The hallmark of this condition is poor coordination and balance (ataxia), which is often the first symptom. Most affected people also have oculomotor apraxia, which makes it difficult to move their eyes side-to-side. People with oculomotor apraxia have to turn their head to see things in their side (peripheral) vision.

In ataxia with oculomotor apraxia type 4, albumin levels can be low, and cholesterol or AFP can be elevated. However, the amounts of these molecules are normal in many affected individuals.

Ataxia with oculomotor apraxia type 4 begins around age 4. In addition to ataxia and oculomotor apraxia, individuals with this type typically develop dystonia, which is involuntary, sustained muscle tensing that causes unusual positioning of body parts. Dystonia can be the first feature of the condition, and it tends to disappear gradually over time. Muscle wasting in the hands and feet and neuropathy are also common in individuals with type 4.

A key feature of ataxia with oculomotor apraxia type 2 is high amounts of a protein called alpha-fetoprotein (AFP) in the blood. (Raised levels of this protein are normally seen in the bloodstream of pregnant women.) Individuals with type 2 may also have high amounts of a protein called creatine phosphokinase (CPK) in their blood. This protein is normally found primarily in muscle tissue. The effect of abnormally high levels of AFP or CPK in people with ataxia with oculomotor apraxia type 2 is unknown. Although individuals with type 2 usually have normal albumin levels, cholesterol may be elevated.

Intelligence is usually not affected by ataxia with oculomotor apraxia, but some people with the condition have intellectual disability.  https://medlineplus.gov/genetics/condition/ataxia-with-oculomotor-apraxia

Clinical features

From HPO
Pes cavus
MedGen UID:
675590
Concept ID:
C0728829
Congenital Abnormality
An increase in height of the medial longitudinal arch of the foot that does not flatten on weight bearing (i.e., a distinctly hollow form of the sole of the foot when it is bearing weight).
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.
Dystonic disorder
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Tremor
MedGen UID:
21635
Concept ID:
C0040822
Sign or Symptom
An unintentional, oscillating to-and-fro muscle movement about a joint axis.
Areflexia
MedGen UID:
115943
Concept ID:
C0234146
Finding
Absence of neurologic reflexes such as the knee-jerk reaction.
Mental deterioration
MedGen UID:
66713
Concept ID:
C0234985
Mental or Behavioral Dysfunction
Loss of previously present mental abilities, generally in adults.
Cognitive impairment
MedGen UID:
90932
Concept ID:
C0338656
Mental or Behavioral Dysfunction
Abnormal cognition is characterized by deficits in thinking, reasoning, or remembering.
Truncal ataxia
MedGen UID:
96535
Concept ID:
C0427190
Sign or Symptom
Truncal ataxia is a sign of ataxia characterized by instability of the trunk. It usually occurs during sitting.
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.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue. Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event.
Limb ataxia
MedGen UID:
196692
Concept ID:
C0750937
Finding
A kind of ataxia that affects movements of the extremities.
Gait ataxia
MedGen UID:
155642
Concept ID:
C0751837
Sign or Symptom
A type of ataxia characterized by the impairment of the ability to coordinate the movements required for normal walking. Gait ataxia is characteirzed by a wide-based staggering gait with a tendency to fall.
Loss of ambulation
MedGen UID:
332305
Concept ID:
C1836843
Finding
Inability to walk in a person who previous had the ability to walk.
Axonal degeneration
MedGen UID:
332464
Concept ID:
C1837496
Finding
Distal sensory impairment
MedGen UID:
335722
Concept ID:
C1847584
Finding
An abnormal reduction in sensation in the distal portions of the extremities.
Impaired distal vibration sensation
MedGen UID:
381262
Concept ID:
C1853767
Finding
A decrease in the ability to perceive vibration in the distal portions of the limbs.
Decreased number of large peripheral myelinated nerve fibers
MedGen UID:
395303
Concept ID:
C1859606
Finding
A reduced number of large myelinated nerve fibers.
Oculomotor apraxia
MedGen UID:
483686
Concept ID:
C3489733
Disease or Syndrome
Ocular motor apraxia is a deficiency in voluntary, horizontal, lateral, fast eye movements (saccades) with retention of slow pursuit movements. The inability to follow objects visually is often compensated by head movements. There may be decreased smooth pursuit, and cancelation of the vestibulo-ocular reflex.
Peripheral axonal degeneration
MedGen UID:
871339
Concept ID:
C4025830
Finding
Progressive deterioration of peripheral axons.
Impaired executive functioning
MedGen UID:
1617231
Concept ID:
C4544271
Mental or Behavioral Dysfunction
A disturbance of executive functioning, which is broadly defined as the set of abilities that allow for the planning, executing, monitoring, and self-correcting of goal-directed behavior while inhibiting task-irrelevant behavior. At least some degree of executive skill is needed to complete most cognitive tasks, and deficits in executive abilities are central to many clinical conditions, including fronto-temporal dementia.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Distal amyotrophy
MedGen UID:
338530
Concept ID:
C1848736
Disease or Syndrome
Muscular atrophy affecting muscles in the distal portions of the extremities.
Hypercholesterolemia
MedGen UID:
5687
Concept ID:
C0020443
Disease or Syndrome
An increased concentration of cholesterol in the blood.
Hypoalbuminemia
MedGen UID:
68694
Concept ID:
C0239981
Finding
Reduction in the concentration of albumin in the blood.
Elevated circulating creatine kinase concentration
MedGen UID:
69128
Concept ID:
C0241005
Finding
An elevation of the level of the enzyme creatine kinase (also known as creatine phosphokinase (CK; EC 2.7.3.2) in the blood. CK levels can be elevated in a number of clinical disorders such as myocardial infarction, rhabdomyolysis, and muscular dystrophy.
Progressive external ophthalmoplegia
MedGen UID:
102439
Concept ID:
C0162674
Disease or Syndrome
Progressive external ophthalmoplegia is a condition characterized by weakness of the eye muscles. The condition typically appears in adults between ages 18 and 40 and slowly worsens over time. The first sign of progressive external ophthalmoplegia is typically drooping eyelids (ptosis), which can affect one or both eyelids. As ptosis worsens, affected individuals may use the forehead muscles to try to lift the eyelids, or they may lift up their chin in order to see. Another characteristic feature of progressive external ophthalmoplegia is weakness or paralysis of the muscles that move the eye (ophthalmoplegia). Affected individuals have to turn their head to see in different directions, especially as the ophthalmoplegia worsens. People with progressive external ophthalmoplegia may also have general weakness of the muscles used for movement (myopathy), particularly those in the neck, arms, or legs. The weakness may be especially noticeable during exercise (exercise intolerance). Muscle weakness may also cause difficulty swallowing (dysphagia).\n\nWhen the muscle cells of affected individuals are stained and viewed under a microscope, these cells usually appear abnormal. These abnormal muscle cells contain an excess of cell structures called mitochondria and are known as ragged-red fibers.\n\nAlthough muscle weakness is the primary symptom of progressive external ophthalmoplegia, this condition can be accompanied by other signs and symptoms. In these instances, the condition is referred to as progressive external ophthalmoplegia plus (PEO+). Additional signs and symptoms can include hearing loss caused by nerve damage in the inner ear (sensorineural hearing loss), weakness and loss of sensation in the limbs due to nerve damage (neuropathy), impaired muscle coordination (ataxia), a pattern of movement abnormalities known as parkinsonism, and depression.\n\nProgressive external ophthalmoplegia is part of a spectrum of disorders with overlapping signs and symptoms. Similar disorders include ataxia neuropathy spectrum and Kearns-Sayre syndrome. Like progressive external ophthalmoplegia, the other conditions in this spectrum can involve weakness of the eye muscles. However, these conditions have many additional features not shared by most people with progressive external ophthalmoplegia.
Hypometric saccades
MedGen UID:
98065
Concept ID:
C0423082
Finding
Saccadic undershoot, i.e., a saccadic eye movement that has less than the magnitude that would be required to gain fixation of the object.
Gaze-evoked nystagmus
MedGen UID:
1808161
Concept ID:
C5574666
Disease or Syndrome
Nystagmus made apparent by looking to the right or to the left.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVAtaxia, early-onset, with oculomotor apraxia and hypoalbuminemia
Follow this link to review classifications for Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia in Orphanet.

Professional guidelines

PubMed

Renaud M, Moreira MC, Ben Monga B, Rodriguez D, Debs R, Charles P, Chaouch M, Ferrat F, Laurencin C, Vercueil L, Mallaret M, M'Zahem A, Pacha LA, Tazir M, Tilikete C, Ollagnon E, Ochsner F, Kuntzer T, Jung HH, Beis JM, Netter JC, Djamshidian A, Bower M, Bottani A, Walsh R, Murphy S, Reiley T, Bieth É, Roelens F, Poll-The BT, Lourenço CM, Jardim LB, Straussberg R, Landrieu P, Roze E, Thobois S, Pouget J, Guissart C, Goizet C, Dürr A, Tranchant C, Koenig M, Anheim M
JAMA Neurol 2018 Apr 1;75(4):495-502. doi: 10.1001/jamaneurol.2017.4373. PMID: 29356829Free PMC Article
Yokoseki A, Ishihara T, Koyama A, Shiga A, Yamada M, Suzuki C, Sekijima Y, Maruta K, Tsuchiya M, Date H, Sato T, Tada M, Ikeuchi T, Tsuji S, Nishizawa M, Onodera O
Brain 2011 May;134(Pt 5):1387-99. Epub 2011 Apr 12 doi: 10.1093/brain/awr069. PMID: 21486904

Recent clinical studies

Etiology

Renaud M, Moreira MC, Ben Monga B, Rodriguez D, Debs R, Charles P, Chaouch M, Ferrat F, Laurencin C, Vercueil L, Mallaret M, M'Zahem A, Pacha LA, Tazir M, Tilikete C, Ollagnon E, Ochsner F, Kuntzer T, Jung HH, Beis JM, Netter JC, Djamshidian A, Bower M, Bottani A, Walsh R, Murphy S, Reiley T, Bieth É, Roelens F, Poll-The BT, Lourenço CM, Jardim LB, Straussberg R, Landrieu P, Roze E, Thobois S, Pouget J, Guissart C, Goizet C, Dürr A, Tranchant C, Koenig M, Anheim M
JAMA Neurol 2018 Apr 1;75(4):495-502. doi: 10.1001/jamaneurol.2017.4373. PMID: 29356829Free PMC Article
Quinzii CM, Hirano M
Biofactors 2011 Sep-Oct;37(5):361-5. Epub 2011 Oct 11 doi: 10.1002/biof.155. PMID: 21990098Free PMC Article
Yokoseki A, Ishihara T, Koyama A, Shiga A, Yamada M, Suzuki C, Sekijima Y, Maruta K, Tsuchiya M, Date H, Sato T, Tada M, Ikeuchi T, Tsuji S, Nishizawa M, Onodera O
Brain 2011 May;134(Pt 5):1387-99. Epub 2011 Apr 12 doi: 10.1093/brain/awr069. PMID: 21486904
Tada M, Yokoseki A, Sato T, Makifuchi T, Onodera O
Adv Exp Med Biol 2010;685:21-33. doi: 10.1007/978-1-4419-6448-9_3. PMID: 20687492
Date H, Onodera O, Tanaka H, Iwabuchi K, Uekawa K, Igarashi S, Koike R, Hiroi T, Yuasa T, Awaya Y, Sakai T, Takahashi T, Nagatomo H, Sekijima Y, Kawachi I, Takiyama Y, Nishizawa M, Fukuhara N, Saito K, Sugano S, Tsuji S
Nat Genet 2001 Oct;29(2):184-8. doi: 10.1038/ng1001-184. PMID: 11586299

Diagnosis

Imamura R, Saito M, Shimada M, Kobayashi J, Ishiai M, Matsumoto Y
J Radiat Res 2023 May 25;64(3):485-495. doi: 10.1093/jrr/rrad007. PMID: 36940705Free PMC Article
Renaud M, Moreira MC, Ben Monga B, Rodriguez D, Debs R, Charles P, Chaouch M, Ferrat F, Laurencin C, Vercueil L, Mallaret M, M'Zahem A, Pacha LA, Tazir M, Tilikete C, Ollagnon E, Ochsner F, Kuntzer T, Jung HH, Beis JM, Netter JC, Djamshidian A, Bower M, Bottani A, Walsh R, Murphy S, Reiley T, Bieth É, Roelens F, Poll-The BT, Lourenço CM, Jardim LB, Straussberg R, Landrieu P, Roze E, Thobois S, Pouget J, Guissart C, Goizet C, Dürr A, Tranchant C, Koenig M, Anheim M
JAMA Neurol 2018 Apr 1;75(4):495-502. doi: 10.1001/jamaneurol.2017.4373. PMID: 29356829Free PMC Article
Saghazadeh A, Hafizi S, Hosseini F, Ashrafi MR, Rezaei N
Acta Med Iran 2017 Feb;55(2):128-130. PMID: 28282710
Tada M, Yokoseki A, Sato T, Makifuchi T, Onodera O
Adv Exp Med Biol 2010;685:21-33. doi: 10.1007/978-1-4419-6448-9_3. PMID: 20687492
Shimazaki H, Takiyama Y, Sakoe K, Ikeguchi K, Niijima K, Kaneko J, Namekawa M, Ogawa T, Date H, Tsuji S, Nakano I, Nishizawa M
Neurology 2002 Aug 27;59(4):590-5. doi: 10.1212/wnl.59.4.590. PMID: 12196655

Prognosis

Hirano M, Matsumura R, Nakamura Y, Saigoh K, Sakamoto H, Ueno S, Inoue H, Kusunoki S
J Neurol Sci 2017 Jul 15;378:75-79. Epub 2017 Apr 29 doi: 10.1016/j.jns.2017.04.049. PMID: 28566184
Shimazaki H, Takiyama Y, Sakoe K, Ikeguchi K, Niijima K, Kaneko J, Namekawa M, Ogawa T, Date H, Tsuji S, Nakano I, Nishizawa M
Neurology 2002 Aug 27;59(4):590-5. doi: 10.1212/wnl.59.4.590. PMID: 12196655

Clinical prediction guides

Kato T, Tamura Y, Matsumoto H, Kobayashi O, Ishiguro H, Ogawa M, Tsujikawa K, Hasegawa Y, Sakamoto M, Konagaya M, Houzen H, Takagi M, Imai K, Morio T, Yokoseki A, Onodera O, Nonoyama S
Clin Immunol 2021 Aug;229:108776. Epub 2021 Jun 9 doi: 10.1016/j.clim.2021.108776. PMID: 34118401
Hirano M, Yamamoto A, Mori T, Lan L, Iwamoto TA, Aoki M, Shimada K, Furiya Y, Kariya S, Asai H, Yasui A, Nishiwaki T, Imoto K, Kobayashi N, Kiriyama T, Nagata T, Konishi N, Itoyama Y, Ueno S
Ann Neurol 2007 Feb;61(2):162-74. doi: 10.1002/ana.21078. PMID: 17315206
Shimazaki H, Takiyama Y, Sakoe K, Ikeguchi K, Niijima K, Kaneko J, Namekawa M, Ogawa T, Date H, Tsuji S, Nakano I, Nishizawa M
Neurology 2002 Aug 27;59(4):590-5. doi: 10.1212/wnl.59.4.590. PMID: 12196655
Moreira MC, Barbot C, Tachi N, Kozuka N, Mendonça P, Barros J, Coutinho P, Sequeiros J, Koenig M
Am J Hum Genet 2001 Feb;68(2):501-8. Epub 2001 Jan 22 doi: 10.1086/318191. PMID: 11170899Free PMC Article

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