Diagnosing X-linked Myotubular Myopathy – A German 20-year Follow Up Experience

Abstract

X-linked myotubular myopathy (XLMTM) is a life-threatening rare neuromuscular disease which is caused by pathogenic variants in the MTM1 gene. It has a large phenotypic heterogeneity, ranging from patients who are able to walk independently to immobile patients who are only able to bring hand to mouth and depend on a respirator 24 hours a day every day. This suggests that ventilator requirements may not illustrate the full clinical picture of patients with XLMTM. At present, there is no curative therapy available, despite first promising results from ongoing gene therapy studies. In this study, we evaluated in detail the data from 13 German XLMTM patients, which was collected over a period of up to 20 years in our university hospital. We compared it to the international prospective longitudinal natural history study (NHS) data from 45 patients (containing 11 German patients). To highlight the broad phenotypic spectrum of the disease, we additionally focused on the clinical presentation of three cases at a glance. Comparing our data with the above mentioned natural history study, it appears the patients of the present German cohort seem to be more often severely affected, with higher frequency of non-ambulatory patients and patients on ventilation (and for longer time) and a higher proportion of patients needing a percutaneous endoscopic gastrostomy. Another key finding is a potential gap in time between first clinical presentation and final diagnosis, showing a need for patients to be treated in a specialized center for neuromuscular diseases.

INCEPTUS Natural History, Run-in Study for Gene Replacement Clinical Trial in X-Linked Myotubular Myopathy

“…However, the extent of aminotransferase elevations, as well as the relative elevations of ALT compared to AST, are suggestive of a hepatogenic source. Based on emerging reports of intrahepatic cholestasis complicating XLMTM, [41][42][43][44] in combination with the high frequency of liver-related laboratory abnormalities described in this study, we postulate that monitoring of liver parameters (including potential consultation with a pediatric hepatologist) should be an important aspect of clinical care moving forward. Obtaining liver-related laboratory parameters (ALT, AST, GGT, total and direct bilirubin), plus evaluation of serum bile acid levels, may help identify cholestatic episodes in XLMTM patients, and will also enhance understanding of the incidence of this phenotype in the XLMTM population and the potential triggers for its occurrence.…”

“…Furthermore, a retrospective analysis of hepatic data in a cohort of Italian patients with XLMTM indicates the presence of cholestasis [42]. Additional cases include a child with hypertransaminemia and hyperbilirubinemia (up to 40 times ULN) with hepatopathy and cholestasis [43] and another child with hyperbilirubinemia and elevated urine bile acids consistent with asymptomatic cholestasis leading to severe vitamin K deficiency, coagulopathy and fatal intracranial hemorrhage [44]. One-quarter of INCEPTUS participants had a history of hepatobiliary disease prior to enrollment; during prospective monitoring, 91% experienced hepatobiliary disease or hepatic adverse events or laboratory or ultrasonographic abnormalities (Table 4).…”

Bone Quality in Patients with a Congenital Myopathy: A Scoping Review

“…Low bone mineral density was found in 11 patients (4.5%) (mean age: 10.9±9.7 years; median: 11 years). In more detail, four patients had osteopenia (NM (LMOD3), n = 1, 8 years; NM (TNNC2), n = 1, 27 years; NM (undefined), n = 1, 26 years; CCD (RYR1), n = 1, 4 years) [ 25, 38, 45, 49 ], four patients had osteoporosis (X-linked myopathy (VMA21 mutation), n = 2, 14 years; MTM, n = 1, 11 years; CNM, n = 1, 16 years) [ 31, 33, 44 ], and three patients were reported to have ‘generalized hypomineralization’ without any further specification (undefined NM, n = 3, neonatal) [ 41 ].…”

“…None of the patients with a fracture later at life was reported to have had a fracture of the radius, ulna or tibia. In one patient, fractures of multiple ribs, next to fractures of both femurs, was described at age 1 year without adequate trauma mechanism [ 31 ]. In 17 patients, the localization of the fractures was not described [ 27, 37, 41 ] (See Fig.…”

“…Four patients (MTM, n = 1; NM (LMOD3), n = 1; CNM, n = 1; CCD, n = 1) were reported to receive Vitamin D and/or calcium supplementation or intravenous diphosphonate administration, which were started after low bone mineral density and/or fragility LBFs were noticed [ 31, 38, 44, 49 ]. Detailed clinical information of all affected patients can be found in Supplementary Table 3 .…”