SNP Shot: Genomic Insights

Facioscapulohumeral muscular dystrophy (FSHD) is a condition marked by muscle weakness and muscle wasting (atrophy). Its name reflects the muscles most commonly affected: those of the face (facio-), around the shoulder blades (scapulo-), and in the upper arms (humeral). The onset of FSHD symptoms typically occurs during adolescence, although the age of onset and the severity of symptoms can vary significantly. Some individuals may not experience noticeable symptoms until later in life, while others may exhibit severe symptoms as early as infancy or childhood.

The initial symptom is often weakness in the facial or shoulder muscles. Facial weakness can make activities like drinking from a straw, whistling, or smiling difficult. Weakness around the eyes can prevent complete closure during sleep, potentially leading to dry eyes and related complications. Notably, facial weakness may be more pronounced on one side. Shoulder muscle weakness commonly results in the shoulder blades protruding from the back, a condition known as scapular winging. Weakness in the shoulder and upper arm muscles can impair the ability to raise the arms overhead or throw a ball.

The muscle weakness associated with FSHD progresses gradually over many years and can spread to other areas of the body. Weakness in the lower leg muscles can cause foot drop, affecting gait and increasing the risk of falls. Hip and pelvic muscle weakness can make climbing stairs or walking long distances challenging. Furthermore, individuals with FSHD may develop an exaggerated lower back curve (lordosis) due to weakness in the abdominal muscles. Approximately 20% of those affected may eventually require wheelchair assistance.

Other possible signs and symptoms of FSHD include mild high-frequency hearing loss and abnormalities of the retina, the light-sensitive tissue at the back of the eye. These findings are often subtle and may only be detected through medical testing. In rare cases, FSHD can affect the heart (cardiac) muscle or the muscles required for breathing.

Researchers have identified two types of FSHD: type 1 (FSHD1) and type 2 (FSHD2). Both types present with the same symptoms and are distinguished by their underlying genetic causes.

Inheritance:

FSHD1 follows an autosomal dominant inheritance pattern. This means that having just one copy of a shortened D4Z4 region on a "permissive" chromosome 4 is enough to cause the condition. In most instances, an affected individual inherits the altered chromosome from a parent who also has FSHD. However, some individuals with FSHD1 have no family history of the condition. These cases are considered sporadic and result from a new (de novo) D4Z4 contraction on one copy of a "permissive" chromosome 4. FSHD2 is inherited in a digenic manner, requiring two separate genetic changes for the disorder to develop. To have FSHD2, a person must inherit a mutation in the SMCHD1 gene (located on chromosome 18) and, independently, inherit one copy of a "permissive" chromosome 4. Typically, affected individuals inherit the SMCHD1 gene mutation from one parent and the "permissive" chromosome 4 from the other. Because neither parent usually carries both genetic changes, they are typically unaffected.