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
Inheritance
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
In order for autosomal recessive disorders to be expressed, offspring generally must inherit two mutations, one from each carrier parent. Carriers with only one mutation, such as the parents, do not have clinical disease. Note that carrier parents can expect that 1 in 4 children (25%) will inherit both mutations and have the disorder, 2 in 4 children (50%) will be carriers like their parents, while 1 in 4 children (25%) inherit neither mutation.
In order for autosomal recessive disorders to be expressed, offspring generally must inherit two mutations, one from each carrier parent. Carriers with only one mutation, such as the parents, do not have clinical disease. Note that carrier parents can expect that 1 in 4 children (25%) will inherit both mutations and have the disorder, 2 in 4 children (50%) will be carriers like their parents, while 1 in 4 children (25%) inherit neither mutation.