BPAN

Beta-propeller-protein-associated neurodegeneration (BPAN) is a disorder that damages the nervous system and has a progressive course. BPAN was first clinically described in 2012. There are currently about 500 known cases worldwide. BPAN is caused by a defect in the WDR45 gene on the X chromosome. The defect, which usually appears to be a spontaneous mutation of the gene, leads to a malfunction of a vital process, autophagy. Iron-containing degradation products can no longer be transported out of the cells and accumulate inside them. For this reason, BPAN is referred to as a disorder that is categorised as neurodegeneration with accumulation of iron in the brain (NBIA), although iron accumulation can only occur late in the course of the disease. Mostly girls are affected. It is assumed that the impairment in boys is so severe that they usually do not survive the embryonic stage.

Many people with BPAN have recurrent epileptic seizures that start in infancy or childhood. Several different types of seizures can appear with this disease, even in the same person. Often the first seizures to occur are those caused by a high fever. However, other causes are also possible, such as incomplete myelination in the brain.

Patients may experience generalized tonic-clonic seizures (also known as grand mal seizures). This type of seizure affects the entire body and causes muscle stiffness, convulsions and unconsciousness. Other types of seizures that can occur with this disease are short gaps in consciousness that can appear as mental absence or daydreaming (absence epilepsy or petit mal seizure), sudden episodes of weak muscle tone (atonic seizures), involuntary muscle twitching (myoclonic seizures), or more pronounced movements called epileptic spasms. Some show seizure patterns similar to epileptic syndromes such as West syndrome or Lennox-Gastaut syndrome.

Children with BPAN also are mentally handicapped, often with delayed motor development or permanent physical disabilities, and have significant problems with vocabulary and speech development. Many children do not develop any language at all. Often difficulties occur in the coordination of movements (ataxia). Ataxia impairs the ability to walk and to develop fine motor skills such as the use of objects. Affected individuals may exhibit behavioural changes that are often compared to Rett syndrome features. These symptoms include repeated hand wrestling or clenching (stereotypical hand movements), teeth grinding (bruxism), sleep disorders, and problems with communication and social interaction characteristic of autism disorders. Often, vision is also impaired.

From late adolescence or early adulthood, people with BPAN suffer a rapid loss of cognitive abilities, which can lead to severe dementia. Movement problems also occur, such as dystonia and Parkinson’s disease. Dystonia is a condition characterised by involuntary, prolonged muscle contractions. In BPAN, dystonia often starts in the arms. Parkinsonism can include unusually slow movements, rigidity, trembling, an inability to keep the body upright and balanced, and a shuffling gait that can cause recurrent falls.

However, the severity of the different symptoms is different in all patients. Therefore, the life expectancy of people with BPAN is also very different. With appropriate treatment of their symptoms, some people can live into mid-age. Premature death can result from complications of epilepsy, dementia or movement problems, such as injuries from falls or difficulty in swallowing, which can lead to bacterial lung infection.

Sources:
US National Library of Medicine – Genetics Home Reference
NBIA Disorders Associaction
NBIAcure