axonal neuropathy

Perrault Syndrome

Clinical Characteristics
Ocular Features: 

Nystagmus and limited extraocular movements are usually present in PRLTS1.  Optic atrophy and poor visual acuity have been reported. Ptosis may be present.  The clinical manifestations are variable among and within the types.  Rod dysfunction and ‘retinal atrophy’ were reported in one patient.  The majority of patients have had only limited ocular evaluations.

Systemic Features: 

This is a sex-influenced condition in which both sexes have a sensorineural hearing deficit and neurodegenerative disease (both central and peripheral) but only the females have gonadal dysgenesis.  Motor development is often delayed and ataxia along with a peripheral sensory neuropathy and a variable degree of limb weakness can be present.  Learning difficulties, cognitive decline, and frank mental retardation are frequently described.  The cerebellum may be atrophic.

There is considerable variability in the clinical signs.

Genetics

The combination of hearing loss in males and females, ovarian dysgenesis in females, and variable neurologic signs including external ophthalmoplegia and sometimes optic atrophy is known as Perrault syndrome.  The ocular movement abnormalities are seen primarily in PRLTS1. 

At least 5 unique mutations have been found accounting for types PRLTS1-5.  PRLTS1 (233400) results from mutations in HSD17B4 (5q23.1), type PRLTS2 (614926) is caused by mutations in the HARS2 gene, PPRLTS3 (614129) by mutations in the CLPP gene, PRLTS4 (615300) by mutations in the LARS2 gene, and PRLTS5 (616138) by mutations in C10orf2 (listed in this database as External Ophthalmoplegia, C10orf2, and mtDNA mutations,.

The inheritance pattern among different types may be autosomal recessive or autosomal dominant.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is known.

References
Article Title: 

Perrault syndrome: further evidence for genetic heterogeneity

Jenkinson EM, Clayton-Smith J, Mehta S, Bennett C, Reardon W, Green A, Pearce SH, De Michele G, Conway GS, Cilliers D, Moreton N, Davis JR, Trump D, Newman WG. Perrault syndrome: further evidence for genetic heterogeneity. J Neurol. 2012 May;259(5):974-6.

PubMed ID: 
22037954

Perrault syndrome in sisters

McCarthy DJ, Opitz JM. Perrault syndrome in sisters. Am J Med Genet. 1985 Nov;22(3):629-31.

PubMed ID: 
4061497

Ataxia with Oculomotor Apraxia 2

Clinical Characteristics
Ocular Features: 

Patients with this disorder have difficulty initiating voluntary ocular movements upon command or following targets (oculomotor apraxia).  This feature is not as prominent or frequent in AOA2 (56%) as it is in ataxia with oculomotor apraxia 1 (208920).  Gaze changes are often initiated first by head thrusting, followed by saccadic eye movements. One may test for this by holding the head whereupon the patient is unable to move the eyes.  Strabismus and nystagmus are present in a significant proportion of patients.  Optokinetic nystagmus is impaired.

Systemic Features: 

Initial development proceeds normally but cerebellar ataxia with significant gait problems appear toward the end of the first decade of life and sometimes not until the third decade (mean age of onset 15 years).   Distal muscle weakness and atrophy are often seen.  Mental decline has been observed in a few individuals but does not occur until midlife.  Sensorimotor deficits are present in many patients.  Tremors, dystonia, and choreiform movements are sometimes seen.  Many patients become wheelchair-bound by the 4th decade of life.

Cerebellar atrophy is revealed by MRI.  Serum alpha-fetoprotein concentrations are usually elevated while serum creatine kinase is increased in some patients.  Circulating cholesterol may also be above normal.  Mild serum changes in these components may be seen in heterozygotes.  Hypoalbuminemia is not present in AOA2.

Genetics

Homozygous mutations in SETX (9q34.13) are responsible for this disorder.  Ataxia with oculomotor apraxia 2 is distinguished from ataxia-telangiectasia (208900) by the lack of telangiectases and immunological deficiencies. It differs from ataxia with oculomotor apraxia 1 (208920) in having a somewhat later onset, somewhat slower course, and milder oculopraxic manifestations. Cogan-type oculomotor apraxia (257550) lacks other neurologic signs. Oculomotor apraxia may be the presenting sign in Gaucher disease (230800, 230900, 231000).

See also Ataxia with Oculomotor Apraxia 3 (615217), and Ataxia with Oculomotor Apraxia 4 (616267).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no beneficial treatment for the neurological disease but physical therapy, speech therapy, and sometimes special education can be helpful.

References
Article Title: 

Epidemiological, clinical, paraclinical and molecular study of a cohort of 102 patients affected with autosomal recessive progressive cerebellar ataxia from Alsace, Eastern France: implications for clinical management

Anheim M, Fleury M, Monga B, Laugel V, Chaigne D, Rodier G, Ginglinger E, Boulay C, Courtois S, Drouot N, Fritsch M, Delaunoy JP, Stoppa-Lyonnet D, Tranchant C, Koenig M. Epidemiological, clinical, paraclinical and molecular study of a cohort of 102 patients affected with autosomal recessive progressive cerebellar ataxia from Alsace, Eastern France: implications for clinical management. Neurogenetics. 2010 Feb;11(1):1-12.

PubMed ID: 
19440741

Ataxia with oculomotor apraxia type 2: a clinical, pathologic, and genetic study

Criscuolo C, Chessa L, Di Giandomenico S, Mancini P, Sacc?+ F, Grieco GS, Piane M, Barbieri F, De Michele G, Banfi S, Pierelli F, Rizzuto N, Santorelli FM, Gallosti L, Filla A, Casali C. Ataxia with oculomotor apraxia type 2: a clinical, pathologic, and genetic study. Neurology. 2006 Apr 25;66(8):1207-10.

PubMed ID: 
16636238
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