Global FKRP Registry: observations in more than 300 patients with Limb Girdle Muscular Dystrophy R9

Abstract

Objective: The Global FKRP Registry is a database for individuals with conditions caused by mutations in the Fukutin-Related Protein (FKRP) gene: limb girdle muscular dystrophy R9 (LGMDR9, formerly LGMD2I) and congenital muscular dystrophies MDC1C, Muscle-Eye-Brain Disease and Walker-Warburg Syndrome. The registry seeks to further understand the natural history and prevalence of FKRP-related conditions; aid the rapid identification of eligible patients for clinical studies; and provide a source of information to clinical and academic communities.

Methods: Registration is patient-initiated through a secure online portal. Data, reported by both patients and their clinicians, include: age of onset, presenting symptoms, family history, motor function and muscle strength, respiratory and cardiac function, medication, quality of life and pain.

Results: Of 663 registered participants, 305 were genetically confirmed LGMDR9 patients from 23 countries. A majority of LGMDR9 patients carried the common mutation c.826C > A on one or both alleles; 67.9% were homozygous and 28.5% were compound heterozygous for this mutation. The mean ages of symptom onset and disease diagnosis were higher in individuals homozygous for c.826C > A compared with individuals heterozygous for c.826C > A. This divergence was replicated in ages of loss of running ability, wheelchair-dependence and ventilation assistance; consistent with the milder phenotype associated with individuals homozygous for c.826C > A. In LGMDR9 patients, 75.1% were currently ambulant and 24.6%, nonambulant (unreported in 0.3%). Cardiac impairment was reported in 23.2% (30/129).

Interpretation: The Global FKRP Registry enables the collection of patient natural history data, which informs academics, healthcare professionals and industry. It represents a trial-ready cohort of individuals and is centrally placed to facilitate recruitment to clinical studies.

Figure 1

Registration process and data flow in the Global FKRP Registry.

Figure 2

The current age of all genetically confirmed Global FKRP Registry participants (n = 320). The number of male and female patients within each 10‐year age range, from 1 to 9 through to 70–79 years, is presented. Male (black); female (gray).

Figure 3

The current age of LGMDR9 patients with the common FKRP gene mutation (c.826C > A, n = 294). Patient number within each 10‐year age range is further stratified by zygosity of the common FKRP gene mutation and by sex. The difference between homozygous c.826C > A and heterozygous c.826C > A mean ages is significant (P < 0.0001). Homozygous c.826C > A, male (black); Homozygous c.826C > A, female (gray); Heterozygous c.826C > A, male (white); Heterozygous c.826C > A, female (dots).

Figure 4

The age of LGMDR9 patients with the common FKRP gene mutation associated with specific motor functions: (A) the age of LGMDR9 patients at which running ability was lost (n = 171). The difference between homozygous c.826C > A and heterozygous c.826C > A mean ages is significant (P < 0.0001); (B) the current age of ambulant LGMDR9 patients (n = 222); and (C) the current age of LGMDR9 patients who use a wheelchair, either part‐time or full‐time (n = 148). For each graph, patient number within each 10‐year age range is further stratified by zygosity of the common FKRP gene mutation and by sex. Homozygous c.826C > A, male (black); Homozygous c.826C > A, female (gray); Heterozygous c.826C > A, male (white); Heterozygous c.826C > A, female (dots).