With advances seen in diagnostic methodologies, Next Generation Sequencing (NGS) is increasingly available and applicable in relevant clinical settings. When inborn errors of metabolism (IEMs) are suspected and routine metabolic workup fails to establish a diagnosis, NGS may prove beneficial.
Family 1: Three sisters, born to consanguineous parents of Brazilian descent, were referred due to developmental delay, hypotonia, and ataxia. Brain MRI/MRS, EEG, NCV/EMG, optholmological exam, muscle biopsies and thorough metabolic screening were all normal, however CSF-neurotransmitter levels showed non-specific decreases of HVA, 5HIAA and BH4.
Whole Exome Sequencing (WES) was pursued, and found the patients to harbor the previously-described Arg228Ter mutation in the B4GALNT1 gene, thus establishing the diagnosis of Spastic paraplegia 26.
Family 2: A 5 months old female infant, first-born to consanguineous parents of Arab-Muslim descent, was referred due to a combination of microcephaly, dysmorphism, FTT, developmental delay, jaundice, metabolic acidosis, hypoglycemia, hepatomegaly and brain atrophy. An exhaustive diagnostic evaluation ensued, however failed to confirm a diagnosis. Mitochondrial DNA depletion was suspected. Unfortunately, the patient died within several months.
In order to establish a molecular diagnosis, WES was performed and revealed the patient to harbor a L398P mutation in the GFM1 gene, which encodes the mitochondrial elongation factor EFG1. The mutation was previously reported to disrupt mitochondrial translation with subsequent hepatoencephalomyopathy.
To conclude, we report of two families for whom NGS techniques brought to molecular diagnoses of rare IEMs, where regular laboratory workups failed. Subsequently, genetic counseling and prenatal diagnosis for future pregnancies can now be offered.
