Pregunta 11. Cuál es el diagnóstico?


A 57-year-old man has a 20-year history of gradual weakness in the arms and legs that has become worse over the past 2 years. He reports poor concentration, word finding difficulties, and a hand tremor. He also states he was forced to retire a year ago due to his progressive disability. History reveals episodes suggesting transient ischemic attacks or seizures, recurrent headaches, and frequent falls. A muscle biopsy was done by another neurologist 7 years ago, but the patient did not follow up due to loss of insurance. Family history is significant for diabetes mellitus, migraines in his mother, and hypertension in his father. Examination reveals proximal moderate weakness, distal axonal neuropathy, bilateral intention tremor, and inability to tandem walk. The biopsy slides are obtained and reviewed. Which of the following diagnostic studies is most indicated for this patient?

A. Limb girdle muscular dystrophy gene panel
B. Nonischemic exercise muscle testing
C. EMG/nerve conduction studies and single-fiber EMG
D. Mitochondria DNA sequencing **
E. Serum NT5C1a antibody test
** = Your answer

Mitochondrial myopathies are a heterogeneous group of disorders that result from a dysfunction of the mitochondrial respiratory chain and are caused by mutation of genes encoded by either nuclear or mitochondrial DNA. Some mitochondrial disorders affect only a single organ (e.g., the eye in Leber hereditary optic neuropathy), whereas others involve multiple organs systems and have prominent neurologic and myopathic features. These include, but are not limited to, Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO), myoclonic epilepsy with ragged red fibers (MERRF), myoclonic epilepsy myopathy sensory ataxia (MEMSA), and mitochondrial encephalomyopathy, lactic-acidosis, and stroke-like episodes (MELAS), mitochondrial neurogastro encephalopathy (MNGIE), autosomal recessive cardiomyopathy and ophthalmoplegia (ARCO), and Leigh syndrome.
The wide clinical diversity of mitochondrial myopathies provides diagnostic challenges for even the most knowledgeable and experienced neurologists. It is important to recognize the common mitochondrial syndromes described above; however, patients often present with disorders that do not fit within one of these classical phenotypes. Therefore, it is important to consider the diagnosis of mitochondrial disease when patients have red flag manifestations characteristic of mitochondrial disease. Thus, in obtaining the medical history of patients believed to have a mitochondrial encephalomyopathy, clinicians should inquire about exercise intolerance, migraines, diabetes mellitus, short stature, and hearing loss. Family history is important, but evidence of maternal inheritance may be subtle with an mtDNA point mutation. For example, in families with a history of MELAS syndrome, relatives in the maternal lineage may have migraine-like headaches or diabetes mellitus as the only manifestations of the genetic defect. Careful physical examination may reveal subtle clues to the correct diagnosis. Patients are often short statured and thin. Cognitive dysfunction is common, varies in severity, and usually becomes progressively worse. Cranial nerve dysfunction includes ptosis, ophthalmoparesis, and hearing loss. Fundoscopy may reveal pigmentary retinopathy.
Myopathy typically causes bulbar dysfunction, proximal limb muscle weakness, or both. Peripheral neuropathy is usually axonal sensorimotor but may be demyelinating as in MNGIE.
Aside from the red flags in the clinical presentation and history, the diagnosis is based on laboratory, electrodiagnostic, and pathology findings. In KSS, MELAS, and MERRF, ragged red fibers with ultrastructurally abnormal mitochondria are almost always identified in skeletal muscle with Gomori trichrome stain. SDH histochemistry reveals ragged blue fibers with darker-than-normal staining in the subsarcolemmal regions of the muscle fibers. In patients with MELAS, there often is excessive SDH staining within blood vessel walls, so-called strongly SDH-reactive vessels (SSVs). Another peculiar characteristic of skeletal muscle from MELAS patients is the relative preservation of COX staining in ragged red fibers, in contrast to muscle from KSS and MERRF patients, in which there are abundant COX-negative ragged red fibers on serial or double-stained (SDH and COX) sections.
The identification of numerous mtDNA mutations, including duplications, depletions, multiple deletions, and over 270 pathogenic point mutations as well as over 100 nuclear genes for mitochondrial diseases have revolutionized the understanding and classification of these disorders. For busy clinicians, it is impossible to keep up to date with the rapid progress of mitochondrial genetics; therefore, it may be necessary to consult specialists with expertise in these complex and diverse disorders. Nevertheless, it is important for clinicians to guide the molecular geneticists in the selection of the appropriate DNA tests from the increasingly complex and costly menus now available. Whole mtDNA sequencing of blood samples is now commercially available and is a useful screening test for patients with evidence of a maternal inheritance. Panels of nuclear DNA genes are also commercially available, but must be applied judiciously in patients who show clinical hallmarks of mitochondrial disease with supportive laboratory evidence such as lactic acidosis, respiratory chain defects, mtDNA rearrangements/depletion, or mitochondrial histopathologic changes in muscle.
The progressive nature and duration of the patient’s history, as well as the involvement of multiple organs and supportive pathologic findings, suggest a mitochondrial disease. Results of genetic testing revealed 64% heteroplasmy for an A-to-G mutation at nucleotide 8344 (m.8344A>G) of the mtDNA tRNALys gene, consistent with MERRF.

* Goyal N. The genetics of inherited and acquired myopathy. Advances in Neurogenetics. C28 AAN Annual Meeting 2017.
* Hirano M. Mitochondrial diseases in neurology. Mitochondrial Biology C187. AAN Annual Meeting 2017.

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