3-Methylglutaconic Aciduria Type VIIB — Rare Hereditary Metabolic Disorder with Antenatal Onset: Clinical Case

Background. 3-methylglutaconic aciduria (3-MGA), type VIIB is a rare hereditary disease with onset in the antenatal period, extremely severe course, and unfavorable outcome. This form of aciduria has not been previously described in Russian Federation. Clinical case description. Severe neonatal 3-MGA caused by pathogenic allele in the CLPB gene manifested in a newborn child with non-epileptic motor disorders (tremor, myoclonus) along with seizures resistant to therapy, and severe neutropenia. Bacterial infection with pneumonia and chylothorax development was observed. The specific feature of this case is the absence of cataract typical for 3-MGA, type VIIB, but presence of hypoparathyroidism, that was not previously described as the manifestations of this disease. Diagnosis 3-MGA, type VIIB, was confirmed by whole-genome sequencing. Two variants of the CLPB gene (NM_001258392.3) were revealed: HG38 variant (chr11-72301838C>CT, c.1293dup) in heterozygous state leading to frameshift and premature stop codon (p.Asp432Argfs*11), and novel HG38 variant (chr11-72294617T>TA, c.1560+2dup) in heterozygous state leading to changes in splice donors. The child died at the age of 1 month and 6 days despite intensive multicomponent management. Conclusion. Pathological motor activity of the intrauterine child combined with neonatal motor impairment and neutropenia are sufficient basis for whole-genome sequencing to establish etiological diagnosis. The types of 3-MGA inheritance correlate with different disease prognosis, thus, it is crucial to examine proband’s parents to evaluate the risks of sick children birth.

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