Clin Genet 2004: 65: 64–65
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Copyright # Blackwell Munksgaard 2004

CLINICAL GENETICS

Letter to the Editor

Cerebellar ataxia as atypical manifestation of
the 3243A>G MELAS mutation
To the Editor:
The mitochondrial encephalomyopathy, lactic
acidosis, and stroke-like episode syndrome
(MELAS) is defined by the presence of strokelike episodes due to focal brain lesions often
localized in the parieto-occipital lobes and lactic
acidosis, and ragged red fibers (1). Ataxia can be
observed in some patients. The 3243A>G
substitution in the mitochondrial (mt) DNA
tRNALeu (UUR) gene is by far the most frequent
molecular etiology of MELAS. The genotype–
phenotype correlation of the 3243A>G mutation
is rather loose because the associated clinical manifestations are not restricted to cases with the fullblown MELAS syndrome. For instance, the
3243A>G mutation has been detected in patients
with maternally inherited progressive external
ophthalmoplegia, isolated myopathy, cardiomyopathy, or even in maternally inherited diabetes
mellitus and deafness. We report on an Italian
man with severe sporadic cerebellar ataxia as the
presenting symptom of a MELAS mutation.
A 55-year-old man, who denied a positive family
history of neurological diseases, presented a 10-year
history of progressive speech and balance disturbances. The IQ of the patient was within the normal
range. Neurologic examination revealed ataxic gait,
dysarthric speech, and bilateral dysmetry on fingerto-nose. There was also mild proximal muscle
weakness (4.5–5 using the Muscular Rating Scale)
and hypotrophy in the upper limb girdle muscles.
Proprioception and all sensory modalities were
preserved. Blood routine examination, including
lactate and creatine kinase content were normal.
Electromyography was consistent with myopathic
features in proximal upper and lower limb muscles.
Brain MRI showed cortical and cerebellar atrophy
(Fig. 1). Succinate dehydrogenase histochemical
stain in a skeletal muscle biopsy showed numerous
ragged blue fibers (RBF), of which the vast
majority showed intense staining of cytochrome
c oxidase (COX). Few muscle fibers were RBF/
COX negative. Screening of the most common
mtDNA alterations revealed the presence of the
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3243A>G mutation. Using a described polymerase
chain reaction-restriction fragment length polymorphism quantitative analysis and the endonuclease HaeIII, we estimated mutant genomes at
40% in muscle and 8% in blood. No maternal
relatives were studied.
Idiopathic late onset cerebellar ataxia represents
about 50% of all forms of neurodegenerative
ataxias in Italy (2). Using traditional clinical criteria
(3), the diagnosis can be made after exclusion of
other neurological conditions, such as tumors and
multiple sclerosis, in the absence of family history.
Recently, ataxia has been observed in several mitochondrial encephalomyopathies (coenzyme Q10
deficiency syndrome, neuropathy, ataxia, retinitis
pigmentosa, myoclonus epilepsy and ragged red
fibers, and Kearns–Sayre syndrome) (4). Furthermore, mitochondrial dysfunction as a primary
cause of neuronal cell death for the vast majority
of neurodegenerative diseases, including cerebellar
ataxia, has been hypothesized (5).

Fig. 1. Sagittal T1-weighted magnetic resonance imaging of
the brain shows marked cortical and cerebellar atrophy.

Letter to the Editor

The patient herein reported had long complained of symptoms related to his cerebellar disorder, but he did not manifest classical signs of
the MELAS syndrome. The concurrence of muscle
weakness and atrophy raised the suspect of
mitochondrial involvement in the pathogenesis
of cerebellar ataxia. MtDNA analysis in blood
and muscle samples detected the 3243A>G mutation in relatively low abundance. It is tempting to
hypothesize higher proportions segregating in the
cerebellum or even locally in individual Purkinje
cells. Single-fiber studies have showed that the
pattern of intra-tissue segregation of mutant
genomes may be more important than the absolute
amount for the expression of the clinical phenotype (6, 7). Recent neuropathological studies in
MELAS cases revealed diffuse atrophy of the
cerebellar cortex, gliosis of cerebellar white matter,
and cactus formation in Purkinje cells with mitochondria accumulation (8). Two extensive studies
have assessed the relative frequency of the
3243A>G substitution in patients with sporadic
ataxia (9, 10). Only one of 83 patients harboured
about 8% of the mutation, but this was measured
only in blood (10). Our findings emphasize the
necessity to consider mtDNA alterations in the
diagnostic ascertainment of cerebellar ataxia, after
the exclusion of more obvious genetic causes.
Acknowledgements

References
1. Hirano M, Ricci E, Koenigsberger R et al. MELAS: an
original case and clinical criteria for diagnosis. Neuromuscul Disord 1992: 2: 125–135.
2. Cellini E, Forleo P, Nacmias B et al. Clinical and genetic
analysis of hereditary and sporadic ataxia in central Italy.
Brain Res Bull 2001: 56 (3/4): 363–366.
3. Harding AE. Clinical features and classification of inherited
ataxias. Brain Res Bull 1993: 61: 1–14.
4. Bertini E, Dionisi-Vici C, Zeviani M. Metabolic and
mitochondrial ataxias. In: Genetic of movement disorders.
USA: Elsevier Science, 2003, 24: 231–252.
5. Schon EA, Manfredi G. Neuronal degeneration and mitochondrial dysfunction. J Clin Invest 2003: 111: 303–312.
6. Petruzzella V, Moraes CT, Dano MC, Bonilla E, Di Mauro S,
Schon EA. Extremely high levels of mutant mtDNAs colocalize with cytochrome c oxidase-negative ragged-red fibers
in patient harboring a point mutation at nt. 3243. Hum Mol
Genet 1994: 3: 449–454.
7. Silvestri G, Rana M, Odoardi F et al. Single fibre PCR in
MELAS (3243) patients: correlations between intratissue
distribution and phenotypic expression of the mtDNA
(A3243G) genotype. Am J Med Genet 2000: 94 (3): 201–206.
8. Tanahashi C, Nakayama A, Yoshida M, Ito M, Mori N,
Hashizume Y. MELAS with the mitochondrial DNA 3243
point mutation: a neuropathological study. Acta Neuropathol 2000: 99: 31–38.
9. Majamaa K, Moilanen JS, Uimonen S et al. Epidemiology
of A 3243 G, the mutation for mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes:
prevalence of the mutation in an adult population. Am J
Hum Genet 1998: 63: 447–454.
10. Chinnery PF, Brown DT, Archibald K, Curtis A, Turnball DM.
Spinocerebellar ataxia and the A3243G and A8344G mtDNA
mutations. J Med Genet 2002, 39: e22.

This work was financially supported by grants from the National
Project on ‘Bioenergetics and Biomembranes’ and the Project on
‘Molecular, Cellular, Diagnostic and Epidemiological Analysis of
Pediatric and Neurological Diseases’ (Cluster 04) of the Italian
Ministry for the University (MIUR) and the Center of Excellence on ‘Comparative Genomics’, University of Bari.

V Petruzzella
S Zoccolella
A Amati
A Torraco
P Lamberti
F Carnicella
L Serlenga
S Papa

Correspondence:
Dr. Vittoria Petruzzella,
Department of Medical Biochemistry & Medical Biology,
University of Bari
P.zza Giulio Cesare 11,70124 Bari,
Italy.
Tel.: þ390 80 5478112.
e-mail: v.petruzzella@biochem.uniba.it

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