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Diagnosis of Mitochondrial Diseases: Clinical and Histological Study of Sixty Patients with Ragged Red Fibers

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Diagnosis of Mitochondrial Diseases: Clinical and Histological Study of Sixty Patients with Ragged Red Fibers Original Article Diagnosis of mitochondrial diseases: Clinical and histological study of sixty patients with ragged red fibers Sundaram Challa, Meena A. Kanikannan*, Murthy M. K. Jagarlapudi**, Venkateswar R. Bhoompally***, Mohandas Surath*** Departmetns of Pathology and *Neurology, Nizam’s Institute of Medical Sciences, Hyderabad. **Institute of Neurological Sciences, Care Hospital, ***L.V. Prasad Eye Institute, Hyderabad, India. Background: Mitochondrial diseases are caused by muta- group of patients. tions in mitochondrial or nuclear genes, or both and most Key Words: Mitochondrial disease, Ragged-red fiber, Pro- patients do not present with easily recognizable disorders. gressive external ophthalmoplegia, Kearns-Sayre syndrome, The characteristic morphologic change in muscle biopsy, Myoclonus epilepsy with ragged-red fibers, Heart block. ragged-red fibers (RRFs) provides an important clue to the diagnosis. Materials and Methods: Demographic data, pre- senting symptoms, neurological features, and investigative findings in 60 patients with ragged-red fibers (RRFs) on muscle biopsy, seen between January 1990 and December Introduction 2002, were analyzed. The authors applied the modified res- piratory chain (RC) diagnostic criteria retrospectively to de- Mitochondrial diseases with ragged-red muscle fibers (RRF) termine the number of cases fulfilling the diagnostic criteria as well as some without RRF, are caused by mutations in mi- of mitochondrial disease. Results: The most common clini- tochondrial or nuclear genes, or both, which are normally in- cal syndrome associated with RRFs on muscle biopsy was volved in the formation and maintenance of a functionally in- progressive external ophthalmoplegia (PEO) with or with- tact oxidative phosphorylation system in the mitochondrial out other signs, in 38 (63%) patients. Twenty-six patients inner membrane.1 These disorders present, with bewildering (43%) had only external ophthalmoplegia, 5 (8%) patients array of clinical presentations and are usually dominated by presented with encephalomyopathy. Specific syndromes the involvement of the nervous system and the skeletal mus- were the presenting feature in 8 (13%), Kearns-Sayre syn- cle (hence the term “mitochondrial encephalomyopathies”). drome (KSS) in 4 and myoclonus epilepsy with ragged-red In most cases, myopathy is associated with a cluster of cen- fibers (MERRF) in 4. Myopathy was the presenting feature tral nervous system (CNS) symptoms, suggesting one of the in 5 (8%) and 4 presented with infantile myopathy. Of the 60 well-defined mitochondrial encephalomyopathies. However, the patients, 18 (30%) had proximal muscle weakness. Two encephalomyopathies may be less specific, consisting of one patients with KSS and one patient with myopathy had com- 2- plete heart block necessitating pace making. When the modi- of the CNS symptoms typical of mitochondrial dysfunction. 15 fied RC diagnostic criteria were applied, only 26 (43%) pa- Most of the recent proposed criteria for the diagnosis of tients had one other major criterion in addition to RRFs for mitochondrial diseases include biochemical and molecular ge- 16,17 the diagnosis of mitochondrial diseases. The remaining 34 netic testing. Often these tests are expensive and may not (57%) patients with RRFs on muscle biopsy had only some be available in most medical centers in the developing world. clinical features suggestive of RC disorder but did not fulfill However mitochondrial diseases associated with RRFs can the clinical criteria (of the modified diagnostic criteria) for be diagnosed on muscle biopsy. RRFs are characterized by the diagnosis of mitochondrial diseases. Conclusion: In large proliferations of subsarcolemmal mitochondria and re- patients with clinical features suggestive of RC disorder, placement of some of the contractile elements with demonstration of RRFs on muscle biopsy helps in confirm- intermyofibrillar accumulations of mitochondria. These ap- ing the diagnosis of mitochondrial disease in only a sub- pear red as detected by Gomori-Trichrome staining and can C. Sundaram Professor of Pathology, Nizam’s Institute of Medical Sciences, Panjagutta, Hyderabad - 500 82, India. E-mail: [email protected] Neurology India September 2004 Vol 52 Issue 3 353 CMYK 353 Challa S, et al: Mitochondrial Diseases also be seen using a stain for succinate dehydrogenase. They Table 1b: Minor diagnostic criteria 18 have a moth-eaten appearance. They may be isolated, infre- Clinical quent or numerous and may involve type 1 fibers often.19 Only Symptoms compatible with a RC defect a few small case series have been reported from India and all Histology 20,21,22 1% - 2% ragged-red fibers if aged 30 – 50 years the case series were based on muscle biopsy. This paper Any ragged-red fibers if < 30 years of age presents the clinical data of 60 patients with RRFs on muscle > 2% subsarcolemmal mitochondrial accumulations in a patient biopsy and discusses the diagnosis of mitochondrial diseases. < 16 years of age Widespread electron microscopic abnormalities in any tissue Enzymology Materials and Methods Antibody based demonstration of a defect in RC complex expression Case files of patients with RRF on muscle biopsy seen between 20% - 30% activity of any RC complex in a tissue 30% - 40% activity of any RC complex in a cell line January 1990 and December 2002 were retrieved from the neuropa- 30% - 40% activity of the same RC complex activity in more thology files, Department of Pathology, of our center. The clinical than two tissues data noted included age, gender, family history, presenting symp- Functional toms and neurological features. Investigative findings included se- Fibroblast ATP synthesis rates 2 – 3 SD below mean rum creatine phosphokinase (CK), electromyoneurographic (EMNG) Fibroblasts unable to grow on media with glucose replaced by findings, and CT and/or MRI features. One patient had muscle analy- galactose sis for mitochondrial respiratory chain studies. None of the patients Molecular Identification of nuclear or mtDNA mutation of probable had molecular genetic testing. The diagnostic criteria applied for the pathogenicity diagnosis of mitochondrial diseases were those proposed by Bernie Metabolic et al17 (Table 1a & b). For categorizing patients into various clinical One or more metabolic indicators of impaired RC function 1 syndromes, the classification proposed by Nordin and Johns, 2001 *Diagnostic criteria proposed by Bernier et al (2002) was adopted. Muscle biopsy was done by open biopsy from left vastus lateralis in also done on cryo-sections. Electron microscopic studies could not be all patients. The biopsy was divided into three parts: one part was done due to its unavailability at our center. snap frozen in isopentane precooled in liquid nitrogen for cryo-sec- tions; one part was fixed in 3% cacodylate buffered glutaraldehyde Results for election microscopy; and one part was fixed in 10% buffered for- malin for routine paraffin embedding sections. Cryo-sections were stained with haematoxyclin and eosin, modified Gomori trichrome Clinical Features stain (MGT), Masson’s trichrome stain, oil red O, periodic acid Schiff The mean age at the time of diagnosis was 29.3 years (range with and without diastase. Enzyme histochemistry with adenosine 1 – 71 years) and there were 35 males and 25 females. The triphosphatase (ATP) at pH 9.4, 4.6 and 4.3, succinic dehydroge- mean age at the onset of the disease was 19.7 years (range: nase (SDH) and NADH-Tetrazolium reductase (NADH-TR) were birth to 59.7 yrs) and the age of the onset in each diagnostic criteria is given in table 1. The disease had a progressive course Table 1a: Proposed major diagnostic criteria for mitochondrial in all the patients. The mean delay between the onset of the * disease diagnosis disease and the diagnosis was 6.7 years (range 2 months to I. Clinical: Clinically complete mitochondrial encephalomyopathy or 30 yrs). Based on the clinical features, patients could be mitochondrial cytopaty defined as fulfilling all three of the following 1 conditions grouped into one of the clinical syndromes proposed. (a) Unexplained combination of multisystemic symptoms that is (Table 2). The most common clinical syndrome associated with essentially pathognomonic for a respiratory chain (RC) RRFs on muscle biopsy was progressive external ophthalmo- disorder (b) Symptoms must include at least three of the organ system plegia (PEO) with or without other signs in 38 (63%) pa- presentations, namely neurologic, muscular, cardiac, renal, tients. Twenty-six patients (43%) had only external ophthal- nutritional, hepatic, endocrine, hematological, otologic, moplegia and 6 had oculopharyngeal weakness. Six patients ophthalmologic, dermatologic or dysmorphic. (c) A progressive clinical course with episodes of with PEO had associated myoclonus. Five (8%) patients pre- exacerbations OR a family history that is strongly indicative sented with cerebellar ataxia, 3 had associated myopathy and of mtDNA mutation (at least one maternal relative other than 2 had diffuse muscle wasting. Specific syndromes were the the probands whose presentation predicts a probable or presenting feature in 8 (13%), Kearns-Sayre syndrome (KSS) definite RC disorder) (d) Exclusion of other metabolic or non-metabolic disorders in 4 and myoclonus epilepsy with ragged-red fibers (MERRF) Histology in 4. Myopathy was the presenting feature in 5 (8%) and 4 (a) > 2% ragged-red fibers in skeletal muscle presented with infantile myopathy. Of the 60 patients,
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