Dear editor,
Limb-girdle muscular dystrophies (LGMDs) are a heterogenous group of genetic diseases generally characterized by proximal muscle weakness (1). Among them, LGMD-R18 is an autosomal recessive form caused by a mutation on the 4q35 locus of the gene encoding transport protein particle complex 11 (TRAPPC11). The available clinical data is limited to case reports and series of Syrian, Hispanic, Chinese, and Turkish origin (1,2,3,4,5,6). Our aim was to contribute to the existing data by presenting a LGMD-R18 case, to the best of our knowledge, the first reported from Türkiye.
A 25-year-old, consanguineous male patient visited our clinic due to difficulty in walking and frequent falls. He began to walk at a normal age, but suffered a developmental delay following a single non-febrile epileptic seizure at age three. While his seizures did not recur, he started to fall behind his peers in terms of physical and intellectual development, and from the age of eight, had difficulty in climbing stairs and experienced frequent falls. He was the third of four siblings, but neither his siblings nor his parents reported similar complaints. His muscle strength was 4/5 in the bilateral forearm flexors and extensors and the wrist extensors, 4/5 in the neck flexors, 3/5 in the neck extensors, 2/5 in the hip flexors, 2/5 in the hip extensors, 2/5 in the thigh adductors, and +4/5 in the knee flexors and extensors. His deep tendon reflexes were normal and his Gower’s sign was positive.
The findings indicated limb-girdle myopathy, which was supported by the electromyography findings. The cranial magnetic resonance imaging (MRI) and electroencephalography examinations returned normal results. The computed tomography (CT) (Figure 1c) imaging in the soft tissue window and the MRI (Figure 1a, b, d) indicated advanced fatty replacement in the bilateral paravertebral, periscapular, paracostal, gluteal, and proximal thigh muscles, while the bilateral posterior parascapular, trapezius, and vastus lateralis muscles were comparatively preserved. The liver ultrasonography, electroencephalography, eye, and heart examinations returned normal results. His total score was 22/30 in the mini mental state examination, with impaired time orientation and attention, and his IQ test score was consistent with borderline mental capacity. Due to the age of symptom onset and the history of parental consanguinity, a genetic examination was performed, which revealed TRAPPC11 homozygous c.2938G>A (p.Gly980Arg) missense mutation. In the subsequent family screening, a heterozygous c.2938G>A (p.Gly980Arg) mutation in one allele and a c.2944T>C (p.Tyr982His) mutation in another allele was detected in the mother, and a single allele c.2938G>A (p.Gly980Arg) mutation in the father, while the neurological examinations were normal for both parents and they had no LGMD-related complaints. In light of these findings, the diagnosis was LGMD-R18 with syndromic features, including musculoskeletal deformities, neurodevelopmental, and cognitive problems.
We hereby report this case to emphasize that, while LGMD-R18 is a rare disease, it has variable clinical features due to dysfunction of TRAPPC11 encoding. More than 30 pathogenic mutations were identified, and 23 of these including TRAPPC11 are related to LGMD-R (2). The TRAPPC11 gene encodes TRAPPC, which is a cell membrane trafficking protein involved in the transport between the endoplasmic reticulum and the Golgi apparatus (1). The structural defects in TRAPPC11 mainly cause disruption of the secretory cell functions along with muscle-, brain-, liver-, and eye-related pathologies (1), with, according to a recent study, the type and severity of these pathological changes differing according to the tissue (6). Thus, TRAPPC gene-associated pathological diversity appears to be one of the greatest challenges to phenotyping LGMD.
After the first LGMD-R18 cases were published in 2013 (5), a growing number of case reports has increased our insight into the disease phenotype. Table 1 presents all the previously reported pathological features along with the differences among the individuals, and it is clear that these patients had a number of common clinical features, such as early disease onset, high creatine kinase levels, and developmental delay (7). Conversely, only two patients were born from a consanguineous marriage, while a minority of the patients, including ours, had epileptic seizures (3,4).
When compared with others, our patient displays somewhat different clinical features, which may lead to clinical findings that are limited in scope, but nonetheless, valuable. The coexistence of LGMD and epileptic seizures is known to be common with LGMD-R23, but in most LGMD types, conditions stemming from the underlying pathological metabolic processes, such as encephalopathy and structural brain abnormalities, may predispose the individual to seizure development (6). While our patient’s seizure issue is unrelated to his myopathy, it should always be borne in mind that a patient with LGMD is vulnerable to epileptic seizure.
Recent publications have noted patterns of muscle involvement and their correlation with MRI; however, differences in the localization of the affected muscles are expressed only in terms of lower or upper extremity dominance (6). The pattern of muscle group involvement detected in our patient has never been previously discussed, and is valuable in terms of illustrating the importance of imaging in phenotyping. In addition, the correlation between the CT and MRI findings confirms the sensitivity of CT in patients unable to undergo MRI.
Finally, unlike many genetic diseases, thus far, LGMD-R18 appears to exhibit no homogeneous geographical distribution pattern, which may be related to the lack of newly reported cases. However, some cases are members of ethnoreligious communities (5), suggesting that LGMD-R18 may be more common in closed societies.
In summary, the detection of TRAPPC11 gene mutation and the related clinical syndromes not only provides a better understanding of the clinical features but is also informative in terms of inheritance characteristics and geographical distribution characteristics. Comprehensive genetic analysis is essential for accurate diagnosis, as well as for raising awareness among future generations. While disease-modifying treatment studies on LGMD currently exist, for syndromic patients, the accurate determination of treatment targets will only be possible with appropriate phenotyping.