FTL

Hyperferritinemia-Cataract Syndrome

Clinical Characteristics
Ocular Features: 

Lens opacification is the only ocular sign of this disorder.  These may be congenital and nuclear in location but this is variable.  Pulverulent and ‘sunflower’ light-diffracting opacities have also been described and are likely responsible for the glare that many patients experience.  In some patients cataracts may not be diagnosed until adult life.  Ferritin levels in surgically removed lenses are 1,500 times higher than controls and histochemical studies demonstrate that the crystalline lens opacities consist of intracellular L-ferritin.

Systemic Features: 

Serum levels of iron and transferrin saturation are normal but ferritin levels are high.  Most patients are asymptomatic but blood loss may lead to iron deficiency anemia.

Genetics

This is an autosomal dominant disorder resulting from mutations in the FTL gene located at 19q33.33.  Phenotypic variability is common as expressed by serum ferritin levels and the characteristics of the lens opacities.

A patient with homozygosity of the FTL mutation has been reported but the phenotype resembled that of heterozygous patients.

Cataracts may also be present among other disorders of iron metabolism.  For example, mutations in the gene HFE (6p21.3) that is responsible for a form of hemachromotosis (235200), can also be associated with lens opacities consisting of both general nuclear sclerosis and discrete opacities.  Epilepsy may be part of the phenotype as well. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No systemic treatment is necessary in most patients but cataracts can be removed if visually significant.

References
Article Title: 

Neurodegeneration with Brain Iron Accumulation

Clinical Characteristics
Ocular Features: 

Optic atrophy is a major ocular feature and the primary cause of visual impairment.  A minority (25%) of patients also have a diffuse fleck retinopathy with a bull’s eye maculopathy.  Later the retinopathy may resemble retinitis pigmentosa with a bone spicule pattern. Nystagmus is often present.  These signs usually follow systemic signs such as difficulties in locomotion.  An apraxia of eyelid opening has been noted and some patients have blepharospasm. 

Systemic Features: 

This is a progressive disorder of the basal ganglia with prominent symptoms of extrapyramidal dysfunction.  Onset is in early childhood or in the neonatal period with delayed development and sometimes mental retardation.  Choreoathetoid writhing movements, stuttering, dysphagia, muscle rigidity, and intermittent dystonia are prominent features.  Seizures are uncommon.  Older individuals may exhibit dementia and ambulation is eventually impaired.  The MRI usually shows an area of hyperintensity in the medial globus pallidus that has been called the ‘eye of the tiger’ sign but this is not pathognomonic.  Axonal degeneration with accumulation of spheroidal inclusions can be seen histologically. 

Genetics

The title of this disorder ‘neurodegeneration with brain iron accumulation’ actually refers to a group of disorders with somewhat common characteristics.  Pentothenate kinase-associated neurodegeneration or NB1A1 (234200) is  the most common of these. 

Types  NBIA2A (256600) and NBIA2B (610217) are caused by mutations in the PLA2G6 gene (22q13.1).  The former can be seen neonatally but usually has its onset in the first two years of life and is sometimes called infantile neuroaxonal dystrophy or Seitelberger disease.  Death may occur before the age of 10 years.  Signs of motor neuron and cerebellar disease are more prominent than in NB1A1. 

NBIA2B has a later onset (4-5 years) and profound sensorimotor impairment but there are many overlapping features and the nosology is confusing.  Mutations in the FTL gene cause yet another form designated NBIA3 (606159) but ocular signs seem to be absent. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is evidence that treatment with deferiprone reduces the amount of iron accumulation in the globus pallidus with motor improvement in at least some patients.  Most patients require supportive care.

References
Article Title: 
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