Published on in Children's Doctor
Patients with mitochondrial disease often undergo a diagnostic odyssey and require multiple specialists to treat their multisystemic disease. During my clinical fellowship with the Mitochondrial Medicine Frontier Program (MMFP), I encountered various patients that could not have been diagnosed or managed without a collaborative team.
One case is that of a 6-year-old boy who first presented to his pediatrician with mild speech delay at 4 1/2 years of age. Multiple evaluations revealed motor delays, and he was prescribed physical therapy for his proximal lower extremity weakness. He was also having difficulty gaining weight and needed nasogastric tube feeds under the guidance of a nutritionist and a gastroenterologist. His metabolic evaluation noted an elevated lactate and an elevated alanine on plasma amino acids, which is a sign of long-standing lactic acidosis. Given his multisystemic symptoms and labs, there was a concern for mitochondrial disease and prompted testing of his mitochondrial DNA (mtDNA) via MitoGenome.
He first presented to the CHOP at 6 years old as a transfer of care for management of status epilepticus, and the ICU and Neurology teams aided in stabilizing him. During his admission, additional Neuroradiology diagnostic testing further confirmed the suspicion of mitochondrial disease. His brain MRI showed multifocal gray matter hyperintensities and basal ganglia calcifications, and MR spectroscopy revealed an inverted lactate doublet. His MitoGenome in blood was reported during his admission and noted 2 mtDNA variants of uncertain significance (VOUS) in MT-ND3 and MT-TR genes at 46% level heteroplasmy each. It is important to note that multiple mitochondria exist per cell, with multiple mitochondrial genome copies in each mitochondrion. A pathogenic mtDNA variant may be present only in a proportion of all mtDNA genomes within a cell or tissue, a phenomenon called heteroplasmy. Many mtDNA pathogenic variants only cause clinical manifestations when present in a given tissue at a certain level of heteroplasmy. It is less common for 2 mtDNA variants to be present at the exact same heteroplasmy level.
Given his presentation, further evaluation was pursued through a muscle biopsy during his g-tube placement with General Surgery. The Pathology report of his muscle tissue was classic for mitochondrial myopathy with ragged red fibers, ragged blue fibers, COX-negative fibers, and abnormal mitochondria seen on electron microscopy. MitoGenome testing of his muscle tissue in the Division of Genomic Diagnostics (DGD) lab revealed both VOUS at over 90% heteroplasmy. A maternal saliva sample was also obtained for comparison. His mother harbored the MT-ND3 variant at over 90%, but the MT-TR variant at only 3% heteroplasmy level. Since mom was healthy, asymptomatic, and had a low heteroplasmic load for the MT-TR variant, it is assumed pathogenic and causing his disease.
The effects of this variant are being studied through research on cytoplasmic hybrid (cybrid) cell lines to prove its pathogenicity. He is currently being managed as a patient with mitochondrial disease. His comprehensive care was only made possible by multidisciplinary team with contributions from ICU, Neurology, Neuroradiology, Gastroenterology, General Surgery, General Pediatrics, Mitochondrial Medicine, Physical Therapy, DGD, Pathology, and Rehabilitation and the ability to perform the most advanced diagnostic testing at CHOP.