Pilot Program of Newborn Screening for 5q Spinal Muscular Atrophy in the Russian Federation.

5q spinal muscular atrophy (5q SMA) is one of the most common autosomal recessive disorders in the Russian Federation. The first medication to treat 5q SMA was registered in the Russian Federation for treatment of all 5q SMA types in 2019, and the last of the three currently available in December 2021. We launched the pilot newborn screening (NBS) program for 5q SMA in Moscow, the Russian Federation, starting in 2019. During the pilot program, 23,405 neonates were tested for the deletion of exon 7 of the SMN1 gene, the most common cause of 5q SMA. We used the SALSA® MC002 SMA Newborn Screen Kit (MRC Holland) to specifically detect homozygous deletions of SMN1 exon 7. We used the restriction fragment length polymorphism (RFLP) approach to validate detected homozygous deletions and the SALSA MLPA Probemix P060 SMA Carrier Kit (MRC Holland) to determine the SMN2 exon 7 copy number to prescribe gene therapy for 5q SMA. Three newborns with a homozygous deletion of the SMN1 gene were detected. The calculated birth prevalence of 1:7801 appears to be similar to the results in other European countries. The children did not show any signs of respiratory involvement or bulbar weakness immediately after birth. Until now, no 5q SMA case missed by NBS has been detected.

Plasma FGF-21 and GDF-15 are elevated in different inherited metabolic diseases and are not diagnostic for mitochondrial disorders.

Recently, the plasma cytokines FGF-21 and GDF-15 were described as cellular metabolic regulators. They share an endocrine function and are highly expressed in the liver under stress and during starvation. Several studies found that these markers have high sensitivity and specificity for the diagnosis of mitochondrial diseases, especially those with prominent muscular involvement. In our study, we aimed to determine whether these markers could help distinguish mitochondrial diseases from other groups of inherited diseases. We measured plasma FGF-21 and GDF-15 concentrations in 122 patients with genetically confirmed primary mitochondrial disease and 127 patients with non-mitochondrial inherited diseases. Although GDF-15 showed better analytical characteristics (sensitivity = 0.66, specificity = 0.64, area under the curve [AUC] = 0.88) compared to FGF-21 (sensitivity = 0.51, specificity = 0.76, AUC = 0.78) in the pediatric group of mitochondrial diseases, both markers were also elevated in a variety of non-mitochondrial diseases, especially those with liver involvement (Gaucher disease, galactosemia, glycogenosis types 1a, 1b, 9), organic acidurias and some leukodystrophies. Thus, the overall positive and negative predictive values were not acceptable for these measurements to be used as diagnostic tests for mitochondrial diseases (FGF-21 positive predictive value [PPV] = 34%, negative predictive value [NPV] = 73%; GDF-15 PPV = 47%, NPV = 28%). We suggest that FGF-21 and GDF-15 increase in patients with metabolic diseases with metabolic or oxidative stress and inflammation.