Overlapping Phenotype of Adult-Onset ALPK3-Cardiomyopathy in the Setting of Two Novel Variants.

Inherited cardiomyopathies (CMPs) are fairly common causes of morbidity and mortality, particularly, in young individuals. In substantial number of cases, only morphological diagnostic criteria cannot distinguish one CMP from another because of incomplete penetrance, advanced stage of the disease, or overlapping phenotypes. Genetic testing has become a mandatory tool for definite diagnosis that is required for family screening, individual prognosis, and personalized treatment strategy in routine practice. In parallel, accumulation of genotype-phenotype correlations, especially for rare genes, promotes the deciphering of underling molecular mechanisms and the development of targeting treatment of CMPs. Here we present an adult-onset case comprised morphological features of several CMPs: asymmetric left ventricle (LV) hypertrophy, severe systolic dysfunction, LV hypertrabeculation and restrictive physiology. Using next-generation sequencing, two novel variants (NM_020778.5:c.1958C>G:p.Ser653* and c.3491G>A:p.Arg1164Gln) in alpha-protein kinase 3 (ALPK3) gene were identified and confirmed with Sanger sequencing. The trans-position (location on different alleles) of identified ALPK3 variants was established by plasmid cloning method. The ALPK3 gene, encoding nuclear alpha-protein kinase 3, has only recently been associated with CMPs and there are still few clinical data on ALPK3 variant carriers. To date, only five affected individuals with adult-onset CMPs in the setting of biallelic variants of ALPK3 gene have been reported.

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.