Infantile neuroaxonal dystrophy (ORPHA:35069)
Infantile neuroaxonal dystrophy/atypical neuroaxonal dystrophy (INAD/atypical NAD) is a type of neurodegeneration with brain iron accumulation (NBIA; see this term) characterized by psychomotor delay and regression, increasing neurological involvement with symmetrical pyramidal tract signs and spastic tetraplegia. INAD may be classic or atypical and patients present with symptoms anywhere along a continuum between the two.
Epidemiology
Prevalence is unknown, but more than 150 cases have been described, of which the majority are classic INAD.
Clinical description
Classic INAD usually presents between ages six months and three years with psychomotor delay and regression, delayed walking or gait disturbance. It is characterized by early truncal hypotonia progressing to tetraparesis (usually spastic but can be areflexic) and dementia. Visual signs, including strabismus, pendular nystagmus, uncoordinated eye movements, optic atrophy and failing vision are generally early and prominent. Seizures occur in a minority. Onset of atypical NAD is usually in early childhood but can be as late as the late teens and progression is slower. As a result of slower progression patients may present with speech delay and neurobehavioral disturbances including impulsivity, poor attention span and emotional lability. Tetraparesis occurs late in the disease and is not necessarily preceded by truncal hypotonia and patients are more likely to have progressive dystonia and dysarthria. Optic atrophy, nystagmus and seizures occur as in classic INAD.
Etiology
INAD is caused by mutations in the PLA2G6 gene (22q13.1). The mutations alter phospholipid metabolism and often lead to abnormal iron accumulation in the basal ganglia.
Diagnostic methods
The majority of patients with INAD and atypical NAD develop cerebellar atrophy appreciable on MRI at a relatively early age. This, in the presence of high brain iron or optic atrophy, suggests the diagnosis. Genetic testing confirms the diagnosis.
Differential diagnosis
Differential diagnoses include infantile neuronal ceroid-lipofuscinosis, ataxia-telangectasia, and hereditary ataxia (see these terms), although cerebellar atrophy usually presents later for these disorders, other forms of NBIA, including pantothenate kinase-associated neurodegeneration (PKAN; see this term) which is characterized by an ``eye of the tiger'' sign not observed in INAD, infantile GM2 gangliosidosis, Niemann-Pick disease type C, autism and Menkes disease (see these terms).
Antenatal diagnosis
Prenatal diagnosis is possible if the disease causing mutations in the family are known.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Treatment is palliative and includes pharmacologic treatment of spasticity and seizures, oral or intrathecal baclofen for those with significant dystonia, physiotherapeutic treatment of spasticity and measures such as gastric feeding tube or tracheostomy to prevent aspiration pneumonia. Iron chelation therapy is not currently recommended.
Prognosis
The progression of classic INAD is usually rapid and many children never learn to walk. Severe spasticity, progressive cognitive decline and visual impairment can result in a vegetative state. Many affected patients do not survive beyond their first decade, but some survive into their teens or later. The life span of atypical NAD is not known but is expected to be longer than that observed in classic INAD.

                            Last update: 
                            March 2010


                            - Expert reviewer(s): 
                            Dr Allison GREGORY  - Pr Susan HAYFLICK