Overview

Phosphate diabetes is defined by urinary phosphate wasting due to impaired tubular reabsorption. It can be classified based on either a genetic or acquired origin. Chronic hypophosphatemia causes rickets in children, leading to growth disorders, bone deformities, and bone pain. In adults, it results in osteomalacia, pseudofractures, as well as muscle fatigue and weakness during exertion.

X-linked hypophosphatemia (XLH) is a common cause of hereditary rickets linked to renal phosphate loss due to elevated FGF23 levels, most often caused by mutations in the PHEX (Phosphate Regulating Endopeptidase X-Linked) gene. Clinical trials have already demonstrated significant improvements in the quality of life of patients with XLH following the approval of the anti-FGF23 antibody, Burosumab.

However, there are other causes of phosphate diabetes, such as tumor-induced osteomalacia (TIO), proximal tubulopathies (Dent disease, cystinosis), or mutations in Npt2a/C.

As described above, patients with phosphate diabetes report bone pain and variable muscle fatigue depending on the underlying cause. These symptoms can significantly impact quality of life by limiting physical activities early on. However, standard quality-of-life questionnaires often lack the specificity to accurately assess these symptom-related impairments. At present, the investigators lack objective biomarkers that can quantitatively assess subclinical metabolic abnormalities at the muscular level in these patients.

Various data from animal models and preclinical studies suggest direct links between serum phosphate levels, intracellular phosphate (Pi), ATP production, and altered muscle metabolism. Muscle tissue requires energy, primarily derived from ATP hydrolysis. ATP is synthesized via mitochondrial oxidative phosphorylation, which is regulated by intracellular phosphate levels.

In five XLH patients, older studies compared intracellular Pi levels to those of five healthy controls and showed a decrease in Pi without a change in intracellular ATP. Smith et al. found ATP concentrations within the lower limit of normal at rest, while Pesta et al. reported a decrease in muscle ATP concentration in hypophosphatemic mice, which normalized after correcting serum phosphate levels.

Two recent studies using 31-phosphorus magnetic resonance spectroscopy (31P-MRS) showed no change in intracellular ATP levels in XLH patients, both before muscle activity and after burosumab treatment. However, these studies were conducted at rest. Yet, the main issue for patients lies in physical activity, as quality-of-life impairments often begin with limitations in daily physical tasks. Moreover, no current data are available on intracellular Pi or ATP levels in other forms of phosphate diabetes.

These parameters can be measured in vivo, non-invasively, using 31P-MRS. This technique employs a standard 3T MRI scanner equipped with a multinuclear coil to detect phosphorus instead of protons. It allows for ATP, Pi, and phosphocreatine concentrations to be measured every 2 minutes and 45 seconds. The procedure is non-irradiating, requires no contrast injection, and focuses on the patient's leg, meaning the whole body does not need to be inside the MRI scanner.

Additionally, in FGF23-mediated phosphate diabetes, calcitriol suppression leads to renin-angiotensin-aldosterone system (RAAS) activation and hypertension. In contrast, proximal tubulopathies cause salt wasting. The third sodium compartment (non-osmotically active sodium stored in subcutaneous and muscle tissue) can be assessed non-invasively using 23Na-MRI (sodium-23 MRI), which also uses a 3T (3 tesla) MRI scanner and a multinuclear coil to detect sodium signals under the same conditions as 31P-MRS.

Patients with XLH also exhibit a distinct metabolic profile, with an increased risk of obesity, hypertension, left ventricular hypertrophy, and elevated uric acid levels.

The goal of the study is to quantitatively measure intramuscular ATP, intracellular phosphate (Pi), intracellular pH, and phosphocreatine both before and during exercise in patients with phosphate diabetes. The study also aims to characterize the mitochondrial and metabolic profile of these patients and assess the non-osmotically active third sodium compartment in these disorders.

Eligibility

Inclusion Criteria:

• Inclusion Criteria for Patients:
• Patient ≥ 10 years old with phosphate diabetes, i.e., genetically confirmed XLH or phosphate diabetes of another origin characterized by hypophosphatemia with a decreased Tm/GFR.
• Patient has given consent to participate in the study.
• Signed consent (by both legal representatives for minor patients).
• Patient regularly followed up within the pediatric nephrology services at the Femme Mère Enfant hospital and the nephrology-functional exploration services at the Edouard Herriot hospital.

Inclusion Criteria for Pediatric Controls:

• Patient aged 10 to 17 years, without chronic kidney disease, without hypophosphatemia, without muscular abnormalities, and without growth disorders.
• Patient has given consent to participate in the study.
• Signed consent (by both legal representatives for minor patients).
• Patient regularly followed up within the pediatric nephrology services at the Femme Mère Enfant hospital.

Inclusion Criteria for Adult Controls:

• Patient without chronic kidney disease, without hypophosphatemia, without muscular abnormalities, and without malnutrition.
• Patient has given consent to participate in the study.
• Signed consent.
• Patient regularly followed up within the renal functional exploration services at the Edouard Herriot hospital.

Exclusion Criteria:

• Pregnant, parturient, or breastfeeding women
• Individuals deprived of liberty by a judicial or administrative decision
• Individuals receiving psychiatric care
• Individuals admitted to a healthcare or social institution for purposes other than research
• Adults under legal protection (guardianship, curators)
• Individuals not affiliated with a social security system or benefiting from a similar scheme
• Subjects participating in another interventional study with an exclusion period still in effect at pre-inclusion
• General contraindications for MRI: wearing a pacemaker/ICD (implantable cardiac device) or mechanical heart valves not MRI-compatible, presence of non-MRI-compatible equipment, presence of metallic objects.