Transcript MERRF

Myoclonic Epilepsy with Ragged Red
Fibers (MERRF)
A mutation of the mitochondria
Katarina Mendoza and Kaytee Smith
Introduction
 MERRF is a rare mitochondrial disorder with juvenile onset that includes
symptoms of:


Stroke-like episodes (Pathognomonic sign) and generalized myoclonic epilepsy, ataxia, and
ragged-red fibers (RRF) in muscle biopsies (Lorenzoni et al., 2011)
Dementia, cardiomyopathy, lipomatosis, neuropathy, and optic atrophy are more rare
symptoms that may occur (Lorenzoni et al., 2011)
 Histopathological finding of ragged red fibers in skeletal muscle tissue
(Brackmann et al., 2012)

Causes: The two most frequent MERRF mutations are A to G transition at nucleotide 8344
and T to C transition at nucleotide 8356 in the mitochondrial tRNALys gene.

The A8344G tRNALys mutation causes poor aminoacylation of the mutant tRNA (Du et al., 2009)
 Maternal lineage family members are found to have significant phenotypic
heterogeneities of MERRF pedigrees (Lorenzoni et al., 2011)

(only the egg passes on the mitochondria)
Mitochondrial Mutation
 The T8356C tRNALys mutation shows severe reduction in protein synthesis,
synthesis of aberrant translation products and defective aminoacylation of the
tRNA
 This A to G transition affects structure stabilization, methylation, aminoacylation
and codon recognition (Du et al., 2009)
History and Discovery
 The disease was first named 1982, and was called “Fukuhara disease” by Rowland.
 The first reported patient had been diagnosed with Ramsay Hunt syndrome
associated with Friedreich's ataxia

BUT the patients seemed to have a different disease altogether, later named MERRF.
Diagnostic Tests
 Patients can only be diagnosed with MERRF by undergoing muscle biopsies or
molecular studies (Lorenzoni et al., 2011)
 Muscle biopsies often confirm the diagnosis of MERRF by revealing the presence of
RRF (Ragged Red Fibers) with MGT and SDH staining and deficiencies in COX activity
 A large proportion of muscle fibers (RRF and non-RRF) with deficient COX activity and
reduced presence of SSV, can help distinguish MERRF from other mitochondrial
myopathies (Lorenzoni et al., 2011).
 An elevated serum lactate level is an important MERRF indicator because it may
indicate mitochondrial dysfunction (DiMauro et al., 2002; Ozawa et al., 1995)
 Creatine kinase levels in muscles may also indicate the presence of the disease
because of possible correlation between myoclonic epilepsy and the kinases
(Brackmann et al., 2012)
 Recommended first molecular test when MERRF is suspected: PCR/RFLP for the
A8344G (Lorenzoni et al., 2011)

it is a simple test for this genetic defect

tRNALys mutations are frequently involved in the MERRF phenotype
 Second recommended diagnostic test: the molecular analysis of the tRNALys gene by
direct sequencing (Lorenzoni et al., 2011)
Treatments
 Symptomatic treatment of MERRF includes management of myoclonus with
antiepileptic drugs (Lorenzoni et al., 2011).

Valproate is the first-line antiepileptic drug for generalized seizures and epileptic form abnormalities
(spike, polyspike, and spike–wave complex)
 Myoclonus is often refractory to conventional treatment, but Clonazepam has
been shown to be beneficial in many patients (Lorenzoni et al, 2011)
 New biochip that could help in diagnosing the disease
Clinical Consequences if MERRF is
untreated
 Patients with MERRF show neuronal loss and gliosis of the brain, including the
basal ganglia, cerebellum and spinal cord (Lorenzoni et al., 2011)
 The accumulation of mitochondria in muscle fibers has been found in up to 92%
of MERRF patients (Lorenzoni et al., 2011).
 A large proportion of muscle fibers (RRF and non-RRF) with deficient COX
activity and reduced presence of SSV, can help distinguish MERRF from other
mitochondrial myopathies (Lorenzoni et al. 2011)
 There is an association between cerebellar ataxia and weakness and the A8344G
mutation.
RECENT RESEARCH:
Detection of known base substitution mutations in human
mitochondrial DNA of
MERRF and MELAS by biochip technology (Du et al., 2009)
 Development of a novel biochip format for efficient discriminating of
single base substitution in a panel of 31 known mtDNA mutations of
MELAS and MERRF
 This biochip would be beneficial in:
1.
2.
improving quality of life
prognosis of the often neglected or overlooked entities of the disease
 Biochip format, when modified, would also be applicable to expand the
screening spectrum of any potential mutations identified in the
mitochondrial diseases
 allows for better diagnosis
References
 Brackmann, F., Abicht, A., Ahting, U., Schröder, R., Trollmann, R. (2012). Classical
MERRF phenotype associated with mitochondrial tRNALeu (m.3243A>G)
mutation. Eur J Pediatr, 171, 859–862. doi: 10.1007/s00431-011-1662-8
 Du, W., Li, W., Chen, G., Cao, H., Tang, H., Tang, X., Jin, Q., Sun, Z., Zhao, H., Zhou,
W., He, S., Lv, Y., Zhao, J., Zhang, X. (2009). Detection of known base substitution
mutations in human mitochondrial DNA of MERRF and MELAS by biochip
technology.. Biosensors and Bioelectronics 24, 2371–2376.
doi:10.1016/j.bios.2008.12.008
 Fukuhara, N. (2008). Fukuhara Disease. Brain Nerve 60, 53-58.
 Lorenzoni, P. J., Scola, R. H., Kay, C. S. K., Arndt, R. C., Silvado, C. E., Werneck, L.
C. (2011). MERRF: Clinical features, muscle biopsy and molecular genetics in
Brazilian patients. Mitochondrion 11, 528–532. doi:10.1016/j.mito.2011.01.003