mitral valve prolapse

Spastic Ataxia 6, Charlevoix-Saguenay Type

Clinical Characteristics
Ocular Features: 

Patches of myelinated axons from retinal neurons in the retina are not unusual in the general population but are especially prominent among families in Canada with SPAX6.  These typically appear as striated white or yellowish-white patches with 'fuzzy' borders in the nerve fiber layer of the retina and radiate from the disc.   These findings are usually of no functional significance but if sufficiently large and dense can be demonstrated on perimetry as small scotomas.   OCT studies in two Belgian families have revealed increased thickness of the peri-papillary retinal nerve fiber layer in both patients and carriers without clinical evidence of myelination.  In addition the retinal nerve fiber layer has been described as 'hypertrophied' outside the areas of myelination.   Horizontal gaze nystagmus and deficits in conjugate pursuit movements are often present.   

Systemic Features: 

This neurodegenerative disorder begins in early childhood (12-18 months) with signs of cerebellar ataxia, pyramidal signs, and peripheral neuropathy.  Slightly older children develop a mixed-sensorimotor peripheral neuropathy. Dysarthria, limb spasticity, distal muscle wasting, and mitral valve prolapse are often present.  Knee reflexes are exaggerated while ankle reflexes are often absent.  Extensor plantar responses are usually present.  The EMG can show signs of denervation with slowed conduction while brain neuroimaging demonstrates regional atrophy in the cerebellum, especially the superior vermis.  Most patients eventually become wheelchair-bound.  However, cognitive and daily living skills are preserved into adulthood.  Most patients live into the sixth decade.

Genetics

Homozygous or compound heterozygous mutations in the SACS gene (13q12.12) are responsible for this autosomal recessive disorder.

The largest number of cases is found in the Charlevoix-Saguenay region of Quebec, Canada among the descendents of a founder but families have also been found in Asia and Europe.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment for the general disease is available but specific therapies for some functions such as urinary urgency are available.  Physical and speech therapy as well as special education assistance can be helpful for adaptation.

References
Article Title: 

Location score and haplotype analyses of the locus for autosomal recessive spastic ataxia of Charlevoix-Saguenay, in chromosome region 13q11

Richter A, Rioux JD, Bouchard JP, Mercier J, Mathieu J, Ge B, Poirier J, Julien D, Gyapay G, Weissenbach J, Hudson TJ, Melan?sson SB, Morgan K. Location score and haplotype analyses of the locus for autosomal recessive spastic ataxia of Charlevoix-Saguenay, in chromosome region 13q11. Am J Hum Genet. 1999 Mar;64(3):768-75. Erratum in: Am J Hum Genet 1999 Apr;64(4):1257.

PubMed ID: 
10053011

Brittle Cornea Syndrome 2

Clinical Characteristics
Ocular Features: 

Corneal thinning and extreme fragility are characteristic of BCS2.  Ruptures of the cornea may occur with minimal trauma and repair is often unsatisfactory due to the lack of healthy tissue.  Keratoconus, acute hydrops, keratoglobus, and high myopia are frequently present as well.  Some patients have sclerocornea that obscures the normal limbal landmarks.  The sclera is also thin and the underlying pigmented uveal tissue imparts a bluish discoloration to the globe which is especially evident in the area overlying the ciliary body creating what some call a blue halo.

Systemic Features: 

Skin laxity with easy bruisability, pectus excavatum, scoliosis, congenital hip dislocation, a high arched palate, mitral valve prolapse and recurrent shoulder dislocations are often present.  Hearing impairment with mixed sensorineural/conductive defects is common.

Genetics

This autosomal recessive disorder results from homozygous mutations in PRDM5 (4q27).  Heterozygous carriers may have blue sclerae, small joint hypermobility, and mild thinning of the central cornea. 

BCS2 has many clinical similarities to brittle cornea syndrome 1 (229200) which results from homozygous mutations in ZNF469.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment for specific defects such as joint dislocations and mitral valve malfunction may be helpful.

References
Article Title: 

Brittle cornea syndrome: recognition, molecular diagnosis and management

Burkitt Wright EM, Porter LF, Spencer HL, Clayton-Smith J, Au L, Munier FL, Smithson S, Suri M, Rohrbach M, Manson FD, Black GC. Brittle cornea syndrome: recognition, molecular diagnosis and management. Orphanet J Rare Dis. 2013 May 4;8(1):68. [Epub ahead of print]

PubMed ID: 
23642083

Mutations in PRDM5 in brittle cornea syndrome identify a pathway regulating extracellular matrix development and maintenance

Burkitt Wright EM, Spencer HL, Daly SB, Manson FD, Zeef LA, Urquhart J, Zoppi N, Bonshek R, Tosounidis I, Mohan M, Madden C, Dodds A, Chandler KE, Banka S, Au L, Clayton-Smith J, Khan N, Biesecker LG, Wilson M, Rohrbach M, Colombi M, Giunta C, Black GC. Mutations in PRDM5 in brittle cornea syndrome identify a pathway regulating extracellular matrix development and maintenance. Am J Hum Genet. 2011 Jun 10;88(6):767-77. Erratum in: Am J Hum Genet. 2011 Aug 12;89(2):346.

PubMed ID: 
21664999
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