MERRF Classification: Implications for Diagnosis and Clinical Trials.

BACKGROUND: Given the etiologic heterogeneity of disease classification using clinical phenomenology, we employed contemporary criteria to classify variants associated with myoclonic epilepsy with ragged-red fibers (MERRF) syndrome and to assess the strength of evidence of gene-disease associations. Standardized approaches are used to clarify the definition of MERRF, which is essential for patient diagnosis, patient classification, and clinical trial design. METHODS: Systematic literature and database search with application of standardized assessment of gene-disease relationships using modified Smith criteria and of variants reported to be associated with MERRF using modified Yarham criteria. RESULTS: Review of available evidence supports a gene-disease association for two MT-tRNAs and for POLG. Using modified Smith criteria, definitive evidence of a MERRF gene-disease association is identified for MT-TK. Strong gene-disease evidence is present for MT-TL1 and POLG. Functional assays that directly associate variants with oxidative phosphorylation impairment were critical to mtDNA variant classification. In silico analysis was of limited utility to the assessment of individual MT-tRNA variants. With the use of contemporary classification criteria, several mtDNA variants previously reported as pathogenic or possibly pathogenic are reclassified as neutral variants. CONCLUSIONS: MERRF is primarily an MT-TK disease, with pathogenic variants in this gene accounting for ~90% of MERRF patients. Although MERRF is phenotypically and genotypically heterogeneous, myoclonic epilepsy is the clinical feature that distinguishes MERRF from other categories of mitochondrial disorders. Given its low frequency in mitochondrial disorders, myoclonic epilepsy is not explained simply by an impairment of cellular energetics. Although MERRF phenocopies can occur in other genes, additional data are needed to establish a MERRF disease-gene association. This approach to MERRF emphasizes standardized classification rather than clinical phenomenology, thus improving patient diagnosis and clinical trial design.

Rolandic mitochondrial encephalomyelopathy and MT-ND3 mutations.

Mitochondrial encephalopathies may be caused by mutations in the respiratory chain complex I subunit genes. Described here are the cases of two pediatric patients who presented with MELAS-like calcarine lesions in addition to novel, bilateral rolandic lesions and epilepsia partialis continua, secondary to MT-ND3 mutations. Data were collected included neurologic symptoms, serial brain imaging, metabolic evaluations, skeletal muscle biopsies, mitochondrial biochemical and molecular testing. Permission for publication was given by the families. Muscle histology revealed nonspecific changes, with no ragged red or blue or COX-negative fibers. Sequencing of the mitochondrial DNA indicated patient 2 to be homoplasmic in muscle for the mt.10158T>C mutation in the ND3 subunit and Patient 1 to be 75% heteroplasmic for the mt.10191T>C mutation, also in ND3. Bilateral rolandic lesions and epilepsia partialis continua accompanied by suspicion of mitochondrial disease are indications to search for an underlying mutation in the MT-ND3 gene.

Abnormalities in gastrointestinal motility are associated with diseases of oxidative phosphorylation in children.

OBJECTIVE: Disorders of the mitochondrial electron transport chain enzymes of oxidative phosphorylation (OXPHOS) have neurologic, musculoskeletal, ophthalmologic, cardiac, and GI manifestations. Many adult and pediatric patients with disorders of OXPHOS have abnormalities in intestinal motility. The purpose of this study was to describe pediatric patients who initially presented with signs of GI dysmotility and were later evaluated and found to have a disorder of OXPHOS. METHODS: Data were collected on six patients, including initial GI and neurologic symptoms, histology of skeletal muscle biopsies, mitochondrial DNA mutational analysis, OXPHOS enzyme assay, upper GI barium imaging, technetium-99M liquid gastric emptying scan, upper GI endoscopy, esophageal manometry, and antroduodenal manometry. RESULTS: All six children presented with symptoms of GI dysmotility within 2 wk of life. Patients later developed symptoms of neurologic disorders. All patients had abnormalities in OXPHOS enzyme analysis. Muscle histology showed nonspecific changes with no ragged red fibers. Sequencing of the mitochondrial DNA showed no recognized mutations. No patient had any evidence of intestinal obstruction or malrotation by upper GI barium imaging. Four patients had delayed gastric emptying. Three patients had endoscopic and histologic evidence of esophagitis. All six had demonstrable neuropathic abnormalities by antroduodenal manometry, including the following: nonpropagated antral bursts, absent migrating motor complexes, postprandial antral hypomotility, retrograde migrating motor complexes, and tonic contractions with the migrating motor complex. CONCLUSIONS: Abnormalities in GI motility may be an early presenting sign of disorders of OXPHOS in children.

Rod photoreceptor function in children with mitochondrial disorders.

OBJECTIVE: To test the hypothesis that function of the rod photoreceptors is abnormal in pediatric patients with mitochondrial disorders. METHODS: Patients (n = 22; median age, 5 years) with a deficiency of 1 or more of the mitochondrial enzyme complexes, or a mutation in mitochondrial DNA, were studied by means of scotopic, full-field electroretinography (ERG). The conditions of ERG testing allowed derivation of the parameters of the activation of rod phototransduction from the ERG a-wave, and postreceptoral function from b-wave and P(2) stimulus-response functions. The deactivation of phototransduction was studied in 5 patients. The patients' ERG responses were compared with those of healthy control subjects (n = 25). RESULTS: Responses from 19 patients were sufficient for analysis of rod photoreceptor and postreceptoral function. Saturated amplitudes of the rod photoresponse and b-wave sensitivity were significantly depressed in the patients. Saturated amplitudes of rod cell and P(2) responses were correlated. The kinetics of deactivation of phototransduction were slowed even if the kinetics of activation were normal. CONCLUSIONS: In patients with mitochondrial disorders, some abnormalities of the scotopic ERG responses originate in the rod photoreceptors, but postreceptoral processes may also be abnormal. From a practical perspective, ERG testing can contribute to diagnosis of mitochondrial disorders.