oculomotor apraxia

Adrenoleukodystrophy, X-Linked

Clinical Characteristics
Ocular Features: 

Virtually all patients have visual symptoms.  Loss of acuity, hemianopia, visual agnosia, optic atrophy, and strabismus are the most common features.   Neuropathy may cause a decrease in corneal sensation.  Gaze abnormalities due to ocular apraxia are sometimes seen.  Ocular symptoms often occur after the systemic abnormalities are noted.  However, there is considerable heterogeneity in age of onset and progression of symptoms.

Histopathology of ocular structures reveals characteristic inclusions in retinal neurons, optic nerve macrophages, and the loss of ganglion cells with thinning of the nerve fiber layer of the retina. 

Systemic Features: 

This is a peroxisomal disorder of very-long-chain fatty acid (VLCF) metabolism that leads to progressive neurological and adrenal dysfunction from accumulation of VLCFAs in the nervous system, adrenal glands, and testes.  The age of onset and clinical course are highly variable and there may be several forms.  The childhood form begins between the ages of 4 and 8 years but in other patients with the adult form, symptoms may not appear until the third decade of life.  A viral illness may precipitate the onset.   Symptoms of both central and peripheral neurologic disease are often present with cognitive problems, ataxia, spasticity, aphasia, and loss of fine motor control.  Hearing loss is seen in some patients.  Younger patients tend to have more behavioral problems while older individuals may develop dementia.

Adrenal insufficiency leads to skin hyperpigmentation, weakness, loss of muscle mass and eventually coma.  Impotence in males is common. 

Genetics

This is an X-linked disorder secondary to mutations in the ABCD1 gene (Xp28).  The result is a deficiency in the cellular transporter known as adrenoleukodystrophy protein that is active in perioxosomes.

Although this X-linked disorder is primarily manifest in males, between 20 and 50% of female carriers have at least some symptoms, usually with a later onset than seen in males.

There are also rare cases with an apparent autosomal recessive pattern of inheritance (NALD) (202370) having an earlier onset and more aggressive course. 

Pedigree: 
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

Treatment of adrenal insufficiency is important and can be lifesaving.  Low vision aids, physical therapy and special education may be helpful.  Some young patients with early disease have benefitted from bone marrow transplantation.  "Lorenzo's Oil" (a mixture of oleic acid and erucic acid) has been reported to reduce or delay symptoms in some boys.

Recent reports suggest new treatment modalities may hold promise.  Infusion of autologous CD34+ cells transduced with the Lentin-D lentiviral vector reduced major symptoms in 15 of 17 boys within 29 months after treatment.  Likewise, intrathecal baclofen treatment in two boys with rapidly advancing cerebral manifestations provided symptomatic and palliative improvement.

 

References
Article Title: 

Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy

Eichler F, Duncan C, Musolino PL, Orchard PJ, De Oliveira S, Thrasher AJ, Armant M, Dansereau C, Lund TC, Miller WP, Raymond GV, Sankar R, Shah AJ, Sevin C, Gaspar HB, Gissen P, Amartino H, Bratkovic D, Smith NJC, Paker AM, Shamir E, O'Meara T, Davidson D, Aubourg P, Williams DA. Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy. N Engl J Med. 2017 Oct 4. doi: 10.1056/NEJMoa1700554. [Epub ahead of print].

PubMed ID: 
28976817

X-linked adrenoleukodystrophy

Moser HW, Mahmood A, Raymond GV. X-linked adrenoleukodystrophy. Nat Clin Pract Neurol. 2007 Mar;3(3):140-51. Review.

PubMed ID: 
17342190

Ataxia-Telangiectasia

Clinical Characteristics
Ocular Features: 

The ocular manifestations are striking although of little clinical consequence.  The conjunctivae have prominent telangiectases which usually develop between 3 and 5 years of age.  These apparently do not occur intraocularly.    Oculomotor apraxia is often an earlier sign consisting of difficulty in initiation of smooth pursuit movements which patients may modify by head motion in the direction of attempted gaze.  This aspect can be helpful in diagnosis of AT in young children with cerebellar ataxia. 

Systemic Features: 

Telangiectases are often found in the pinnae, on the cheeks, and on the forearms, usually after the onset of neurological signs.  However, this is also a disorder with multiple systemic signs, the most serious of which are unusual sensitivity to ionizing radiation, excessive chromosomal breakage, a deficiency in the immune system, mild cognitive impairment, and increased risk of malignancies.  Lymphomas, often of B-cell origin, and leukemia, usually of T-cell origin, are the most common malignancies but there is a significantly increased risk of breast cancer as well. Serum IgG2 and IgA levels are often reduced and sinopulmonary infections are common.  Serum alpha-fetoprotein levels are usually increased.  The ataxia is progressive and often begins as truncal unsteadiness with limbs involved later.  It is often accompanied by choreoathetosis and/or dystonia which may result in severe disability by the second decade.  Life span is shortened and many patients succumb to their disease by the 3rd and 4th decades. 

In some famiies with confirmed mutations in ATM the disorder presents with signs of primary torsion dystonia and myoclonus-dystonia.  These signs may resemble an apparent autosomal dominant pattern with parent-child transmission.  It is unclear whether these families represent a variant of AT or a unique disorder.  The latter is suggested by an earlier onset of signs, the lack of cerebellar atrophy,  and the absence of ataxia and ocular telangiectases on initial presentation.  The risk of malignancies in these famiies is high.

Some of these signs have been reported in milder form among heterozygous carriers as well.  The most serious is an increased risk of malignancy, perhaps as much as 6.1 times that of non-carriers.  This combined with the inherent sensitivity to ionizing radiation has led to the suggestion that X-rays should be used with caution, especially when considering mammograms among female relatives.

 

Genetics

This is an autosomal recessive disorder as a result of mutations in the ATM gene located at 11q22-q23.  Affected offspring of consanguineous matings are often homozygous for this mutation whereas those from unrelated parents are usually compound heterozygotes.  There is some evidence of genetic heterogeneity based on both clinical and DNA studies (AT variants).

Other conditions with oculomotor apraxia are: ataxia with oculomotor apraxia 1 (208920), ataxia with oculomotor apraxia 2 (602600), and Cogan type oculomotor apraxia (257550) which lacks other neurologic signs. Oculomotor apraxia may be the presenting sign in Gaucher disease (230800, 230900, 231000).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known for the neurologic manifestations.  However, patients and first degree relatives should be monitored for malignancies.  Childhood vaccinations may lead to widespread viral dissemination as a consequence of the immune defect.

References
Article Title: 

Ataxia telangiectasia: a review

Rothblum-Oviatt C, Wright J, Lefton-Greif MA, McGrath-Morrow SA, Crawford TO, Lederman HM. Ataxia telangiectasia: a review. Orphanet J Rare Dis. 2016 Nov 25;11(1):159. Review.

PubMed ID: 
27884168

Cognitive Phenotype in Ataxia-Telangiectasia

Hoche F, Frankenberg E, Rambow J, Theis M, Harding JA, Qirshi M, Seidel K, Barbosa-Sicard E, Porto L, Schmahmann JD, Kieslich M. Cognitive Phenotype in Ataxia-Telangiectasia. Pediatr Neurol. 2014 May 5.

PubMed ID: 
25037873

Variant ataxia-telangiectasia presenting as primary-appearing dystonia in Canadian Mennonites

Saunders-Pullman R, Raymond D, Stoessl AJ, Hobson D, Nakamura T, Pullman S, Lefton D, Okun MS, Uitti R, Sachdev R, Stanley K, San Luciano M, Hagenah J, Gatti R, Ozelius LJ, Bressman SB. Variant ataxia-telangiectasia presenting as primary-appearing dystonia in Canadian Mennonites. Neurology. 2012 Feb 15. [Epub ahead of print] PubMed PMID: 22345219.

PubMed ID: 
22345219

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