Almost half a million people in Sweden currently live with a rare diagnosis – as many as those who live with cancer. The majority of rare conditions are congenital and some cause chronic and progressive symptoms leading to considerable functional impairment. Extensive genetic analysis is performed in search of a diagnosis, but more than half of these patients are today left without one.
“Spinocerebellar ataxias, known collectively as SCA diseases, are a large group of rare hereditary diseases in which ataxia – difficulties in coordinating movements – is a common denominator. Today there are more than 100 different known ataxia diseases, and the number is constantly growing”, says Andreas Puschmann, researcher and associate professor of neurology at Lund University and consultant at Skåne University Hospital.
Spinocerebellar ataxia type 4 (SCA4) is one such type of hereditary ataxia. It affects the cerebellum and nervous system, which leads to progressive difficulties with walking, balance and coordination, fine motor skills, as well as severe falls in blood pressure when in upright position. SCA4 was originally identified in 1996 in a big US family whose ancestors originated from Skåne (the Region in southernmost Sweden where the city of Lund is located), but the genetic cause could not be found until recently. Now, a research team in Lund has finally pinpointed a mutation in the ZFHX3 gene as the cause of the disease. The mutation leads to a protein with an abnormally long repetition of the amino acid glycine, which likely is the reason for an accumulation of proteins in nerve cells, causing imbalance in the nervous system.
“It has taken us over 12 years to solve the mystery of this disease. Detecting mutations like this one require specific analyses that were developed fairly recently. It can be combined with the latest type of DNA sequencing, long-read sequencing, which, as its name suggests, yields unbroken DNA segments more than a hundred times longer than standard short-read sequencing. With this improved data, we can study large mutations in a more reliable way,” says Joel Wallenius, bioinformatician.
Now that the genetic mutation has been discovered, doctors can use a simple blood test to diagnose a person who shows symptoms of the disease. Even though SCA4, like many other of these rare neurological conditions do not yet have a curative treatment, it can be a relief for families with rare diseases that the cause is becoming understood.
“Identifying the causative genes creates conditions for the development of treatments. There are already effective gene therapies for other genetic neurological diseases, which gives hope to patients with SCA4 and many other uncommon genetic diseases,” concludes Andreas Puschmann.
