A review of published studies to improve our understanding
by Amanda Hill, Highlands Ranch, Colorado
As many as 20 percent of patients with FSHD have an “infantile” or “early-onset” form, which is generally understood to be more severe and more quickly progressing than typical FSHD. Historically, the criteria that have been used to define early-onset FSHD include facial weakness by the age of five and shoulder weakness by the age of 10. These criteria contrast with the more typical form of FSHD, which is defined by slowly progressing facial and shoulder muscle weakness starting in adolescence or young adulthood, though onset of symptoms may occur as late as 70 years of age.
Despite the fact that up to one in five FSHD patients may have the early-onset form of FSHD (estimates range from 3 to 21 percent), our understanding of the clinical features and prognosis of early-onset FSHD is limited. No large-scale studies have been done to systemically evaluate the features of early-onset FSHD or follow individuals over a period of time to understand how quickly these features change and progress.
A collaborative group of researchers from across the world recently performed a comprehensive review of every single scientific article published about one or more patients with early-onset FSHD since 1970 (see Goselink, et al., 2017).
This massive undertaking is a valuable step forward in improving our understanding of the presentation and progression of early-onset FSHD. It is the first effort to compile all the published data about early-onset FSHD and compare characteristics across all patients.
To do this, the researchers searched scientific publication databases for articles that included observations or data about early-onset FSHD patients. They found usable reports for 227 patients.
Next, they extracted from the publications the same data for all 227 patients, including demographics, clinical severity of disease, wheelchair dependency, pattern of muscle involvement, developmental abnormalities, and other systemic features such as hearing loss, vision problems, respiratory issues, etc.
Then the researchers used statistical methods to look for relationships among all these variables, asking questions such as, Does wheelchair dependency associate with respiratory issues? Spoiler alert: It does.
The researchers put together a larger picture, backed up by data and statistics, of how early-onset FSHD presents. The 227 reports evaluated were 55 percent female, 45 percent male, 74 percent Caucasian, 25 percent Asian, and 1 percent African.
From these data, the researchers described early-onset FSHD as having an average age of onset of 2.8 years, with about a quarter of cases showing symptoms in the first year of life, usually facial weakness that resulted in feeding issues and sometimes inadequate eye closure.
The pattern of muscle involvement was similar to typical FSHD but more severe, and 40 percent of the patients were wheelchair dependent, a much higher figure than for FSHD patients overall, among which 20 to 25 percent become dependent on a mobility device by age 50. A majority of the early-onset patients had spinal deformities (70 percent), with lumbar hyperlordosis (aka swayback) being by far the most common (51 percent).
Also interesting was the finding that half of early-onset FSHD patients had one or more systemic features, meaning the FSHD was affecting other bodily systems outside the skeletal muscles. These systemic features included hearing loss (40 percent); retinal damage (37 percent); decreased capacity to exhale forcefully, indicating restricted breathing (31 percent); delayed development (15 percent); abnormal electrocardiogram, which measures electrical activity of the heart (9 percent); epilepsy (8 percent); the need for assisted ventilation (8 percent); and vision loss (6 percent).
About one-third of the patients who had systemic involvement have more than one of these symptoms, indicating that it is not uncommon for early-onset FSHD patients to have multiple systemic issues.
Next, the researchers performed statistical analyses to determine if each of these disease features associated with any others and, if so, whether that observation was likely due to the FSHD and not random chance.
This exercise resulted in several interesting and, as scientists say, “statistically significant” relationships. For example, in this group of patients, being female was associated with an earlier age of onset, wheelchair dependency, developmental delays, and ECG abnormalities. These observations are intriguing because they deviate from typical FSHD, in which it is generally accepted that males tend to be more affected than females.
Another new and fascinating observation was that ECG abnormalities, epilepsy, and cognitive impairment were all more prevalent in Asian than in Caucasian patients. On the flipside, spinal deformities were more prevalent in Caucasian patients. These geographical differences have not been reported before and will be important for researchers to pursue with additional studies.
Other associations the researchers found confirmed results of previous studies. For instance, a lower number of D4Z4 repeats was associated with higher clinical severity, wheelchair dependency, hearing loss, and epilepsy. Furthermore, an earlier age of onset was associated with higher clinical severity, earlier loss of ambulation, hearing loss, and developmental delays.
Two of the strongest associations were that patients with epilepsy had a very high prevalence of cognitive impairment, and that patients with ECG abnormalities had a high prevalence of assisted ventilation. Other clinically significant associations included: wheelchair dependency with spinal deformities, wheelchair dependency with assisted ventilation, hearing loss with vision loss, and developmental delay with cognitive impairment.
For all of these relationships and associations, it is important to note that the presence of one feature (e.g., developmental delay) does not guarantee that an individual will have or develop the second feature (e.g., cognitive impairment). Instead, based on the data extracted from these 227 cases, we can say, for example, that having developmental delay increases the odds of having cognitive impairment.
Unfortunately, the researchers who compiled these data did not calculate the relative risk in each of these scenarios, so it is difficult to put a quantitative value on the associations.
While incredibly informative and important, this review does have its limitations. For instance, the researchers were only able to look at one point in time for each of the 227 patients. Therefore, these data do not reflect changes in disease progression over time. In addition, the ages of the 227 patients are skewed, with a majority (~70 percent) being between seven and 31 years old. Hence, the observations made here may not as accurately reflect older patients living with early-onset FSHD.
The researchers who authored this report also note that there are many possible selection biases in the scientific articles that they compiled to start with. For example, one article focused on patients in northern Italy because that’s where the scientists were from, and in another article, scientists were specifically looking at patients with hearing loss.
Taken all together, the 227 patients reported in this study probably do not represent a truly normal distribution or random sampling of all early-onset FSHD patients. Consequently, the need for larger, well-designed studies that make observations over a length of time are still desperately needed to improve our understanding of early-onset FSHD.
Thankfully, two such studies are already underway at multiple sites throughout the world, including one supported by the FSH Society in the United States. In fact, just a few months after this review was published, another group of researchers followed up on nine of these early-onset patients who were originally evaluated in 1994 and 1995 as children (see Goselink, et al., 2018). After 22 years of disease progression, the key finding the researchers noted was the variable long-term prognosis and high degree of variability of disease severity. Other findings they noted supported and mirrored the findings explained here by the comprehensive review.
All of this tells us we live in an exciting and fast-paced time for FSHD research. So stay tuned, eager readers; we’ll have more results soon!
Early onset facioscapulohumeral dystrophy – a systematic review using individual patient data. Goselink RJM, Voermans NC, Okkersen K, Brouwer OF, Padberg GW, Nikolic A, Tupler R, Dorobek M, Mah JK, van Engelen BGM, Schreuder THA, Erasmus CE. Neuromuscul Disord. 2017 Dec;27(12):1077-1083. doi: 10.1016/j.nmd.2017.09.007. Epub 2017 Sep 21.
A 22-year follow-up reveals a variable disease severity in early-onset facioscapulohumeral dystrophy. Goselink RJM, van Kernebeek CR, Mul K, Lemmers RJLF, van der Maarel SM, Brouwer OF, Voermans N, Padberg GW, Erasmus CE, van Engelen BGM. Eur J Paediatr Neurol. 2018 May 3. pii: S1090-3798(18)30019-9.