fever

Optic Atrophy, Areflexia, Ataxia, Hearing Loss

Clinical Characteristics
Ocular Features: 

Progressive optic atrophy is a consistent feature of all reported cases.  It may have its onset during the first year or two of life but always before the age of 10 years.  Nystagmus may be seen early during acute febrile episodes but eventually becomes permanent.

Systemic Features: 

Onset of neurological symptoms usually occurs in childhood during or following an acute febrile illness which may be recurrent.  This may consist of cerebellar ataxia, hypotonia, drowsiness, dysarthria, and lethargy.  There may be partial or full recovery following the febrile illness initially but some signs remain after subsequent episodes.  Areflexia and sensorineural deafness can be additional signs and pes cavus eventually appears.

The acute febrile episodes tend to decrease in time along with the progression of neurological signs.  Plantar responses remain normal while peripheral neuropathy and seizures are not consistent features.  MRI imaging of the brain is normal.  Cognitive function usually remains normal but some children have autism features and social adjustment problems have been noted.

Genetics

This is an autosomal dominant condition (which may be considered a form of ‘ataxia-plus’) secondary to heterozygous mutations in the ATP1A3 gene (19q13.31).  The protein product is a subunit of an ATPase enzyme primarily active in neural tissue.

Other mutations in the same gene have been found in dystonia-12 and alternating hemiplegia of childhood.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is known for this condition but physical therapy and mobility-assistive devices may be helpful.  Low vision aids may be useful as well.

References
Article Title: 

A novel recurrent mutation in ATP1A3 causes CAPOS syndrome

Demos MK, van Karnebeek CD, Ross CJ, Adam S, Shen Y, Zhan SH, Shyr C, Horvath G, Suri M, Fryer A, Jones SJ, Friedman JM; FORGE Canada Consortium. A novel recurrent mutation in ATP1A3 causes CAPOS syndrome. Orphanet J Rare Dis. 2014 Jan 28;9:15.

PubMed ID: 
24468074

Blue Diaper Syndrome

Clinical Characteristics
Ocular Features: 

A single patient has been reported with microcornea, optic nerve hypoplasia, and 'abnormal' eye movements.  The full ocular phenotype is unknown but 'visual problems' are sometimes mentioned in other reports.

Systemic Features: 

Nephrocalcinosis and blue urine are the major systemic manifestations of blue diaper syndrome.  Symptoms of fever, constipation, poor weight gain, failure to thrive, and irritability can also be part of the syndrome.

Genetics

This is considered an autosomal recessive disorder although an X-linked defect cannot be ruled out since reported patients have been male.  Parental consanguinity is present in some families.  Nothing is known about the mutation or its locus.  Intestinal transport of tryptophan is defective and bacterial degradation results in excessive indole production.  Oxidation in the urine to indigo blue results in the characteristic discoloration.        

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Restriction of dietary tryptophan has been suggested.

References
Article Title: 

Fabry Disease

Clinical Characteristics
Ocular Features: 

Fabry disease is a lysosomal enzyme (alpha-galactosidase A) deficiency resulting in the accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids throughout the body.  The signature ocular manifestation is the whorl-like corneal pattern of lipid (glycosphingolipid) deposits which are present in both hemizygous males and heterozygous females.  These are sometimes referred to as cornea verticillata or Fleischer vortex dystrophy with a pattern similar to that seen in some patients using atabrine or amiodarone.  A general 'haze' throughout the cornea is even more common.  Lens opacities may also be distinctive and generally are one of two types: spoke-like opacities beneath the posterior capsule among males, and wedge-shaped anterior subcapsular deposits, again primarily in males.  The corneal and lens opacities seldom cause significant vision problems.

Involvement of the ocular vessels is present in almost all patients.  A notable increase in tortuosity of conjunctival vessels is present in 97% of hemizygous males and 78% of heterozygous females.  Increased retinal vessel tortuosity is less common but arteriolar involvement significantly increases the risk of central retinal artery occlusions.  An 11 yo Turkish female heterozygote with a cilioretinal artery occlusion and anterior ischemic optic neuropathy in one eye has been reported.

Systemic Features: 

The relatively common occurrence and the protean nature of Fabry disease has lead to its designation by some as the Great Imposter, replacing syphilis to which this term was previously applied.  Compounding the diagnostic difficulties in some individuals is the absence of the complete classical phenotype due to the presence of DNA variants that may modify the expression of some the clinical features.

Most signs present in the first or second decade of life with generally earlier onset in males.  The presence of proteinuria before the age of 20 years in the absence of other primary kidney disease should always raise the possibility of Fabry disease.  However, the diagnosis is often not made until the third decade in males and the fourth decade in females.  Glycosphingolipid inclusion deposits in endothelial cells are responsible for the systemic signs and symptoms including renal and heart disease which are the most common causes of premature death.  Small vessel involvement resulting in cerebrovascular disease and painful peripheral neuropathy can be debilitating. The risk of ischemic strokes is increased.  Cardiac manifestations include hypertrophic cardiomyopathy (60%), mainly involving the left ventricle, and dysfunction of the mitral and aortic valves (10 to 25%).  Dysfunction of renal glomeruli may progress to renal failure by the third to fifth decade in males.  The angiokeratomas and angiomas (most pronounced in a swimming trunk pattern) are secondary to vascular involvement of cutaneous vessels but are non-specific since they also occur in other lysosomal diseases.  The life expectancy of females is reduced by about 5 years and for males about 16 years compared with the general US population.

Involvment of the autonomic system manifests as intermittent fever, hypohidrosis, and poor temperature control.  Some patients have periodic crises of severe pain in the extremities as well as intermittent epigastric pain. Hearing loss and episodic tinnitus are common complaints.

Genetics

This is an X-linked disorder and generally assumed to be recessive although some have suggested dominance since most heterozygous females have significant manifestations that can be life-threatening.  The mutations in the responsible gene (GLA), located at Xq22, involve a variety of deletions, rearrangements and single base pair changes.  Defects in the GLA gene lead to dysfunction of the enzyme alpha-galactosidase A resulting in lysosomal deposition of glycosphingolipids throughout the body, especially in vascular endothelial cells.   

The milder disease and increase in the range of clinical manifestations among females is likely a reflection of variable patterns of X-inactivation.

Increased tortuosity of retinal arterioles is also seen in fucidosis (230000), Williams syndrome (194050), and in a condition known as retinal arteriolar tortuosity (611773, 180000).

Pedigree: 
X-linked dominant, father affected
X-linked dominant, mother affected
Treatment
Treatment Options: 

Enzyme replacement therapy using agalsidase alfa (commercially available as Febrazyme (tm)) have shown promise as measured by renal function, pain intensity, left ventricular size, and general quality of life.  However, the impact on longevity remains to be determined.  Evidence suggests that early treatment is associated with improved outcomes. The corneal and lenticular opacities generally do not require treatment.

Continuous release of cardiac troponin I (cTNI) with elevated serum levels may be a clue to the severity of heart involvement.

References
Article Title: 

Favourable effect of early versus late start of enzyme replacement therapy on plasma globotriaosylsphingosine levels in men with classical Fabry disease

Arends M, Wijburg FA, Wanner C, Vaz FM, van Kuilenburg ABP, Hughes DA, Biegstraaten M, Mehta A, Hollak CEM, Langeveld M. Favourable effect of early versus late start of enzyme replacement therapy on plasma globotriaosylsphingosine levels in men with classical Fabry disease. Mol Genet Metab. 2017 May 4. pii: S1096-7192(17)30156-7.

PubMed ID: 
28495078

Continuous cardiac troponin I release in fabry disease

Feustel A, Hahn A, Schneider C, Sieweke N, Franzen W, Gunduz D, Rolfs A, Tanislav C. Continuous cardiac troponin I release in fabry disease. PLoS One. 2014 Mar 13;9(3):e91757. doi: 10.1371/journal.pone.0091757. eCollection 2014.

PubMed ID: 
24626231

Fabry disease: overall effects of agalsidase alfa treatment

Beck M, Ricci R, Widmer U, Dehout F, de Lorenzo AG, Kampmann C, Linhart A,
Sunder-Plassmann G, Houge G, Ramaswami U, Gal A, Mehta A. Fabry disease: overall effects of agalsidase alfa treatment. Eur J Clin Invest. 2004 Dec;34(12):838-44.

PubMed ID: 
15606727
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