Neurology -- Correspondence for Casali et al., 56 (6) 802-805

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Correspondence published:

Reply to Dr. Chalmers' letter: Carlos Casali, Filippo Maria Santorelli (6 November 2001)

Mitochondrial myopathy, parkinsonism, and multiple mtDNA deletions in a Sephardic Jewish family: R M Chalmers (6 November 2001)

Reply to Dr. Chalmers' letter 6 November 2001

Carlos Casali
Universita di Roma "La Sapienza Roma Italy,
Filippo Maria Santorelli
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Re: Reply to Dr. Chalmers' letter

Casali{at}uniroma1.it Carlos Casali, et al.

We thank Dr. Chalmers for calling our attention to two additional families with the syndrome of progressive external ophthalmoplegia, mitochondrial myopathy and parkinsonism associated with multiple mitochondrial DNA (mtDNA) deletions. [1]
Contrary to our report on a large Sephardic-Jewish family, the pattern of inheritance was clearly autosomal dominant in the British families. At this time, we cannot speculate on the possibility of a similar genetic condition, though allelism seems likely.
We agree that parkinsonism, even when L-dopa responds, in the context of a mtDNA-related disorder are quite different from idiopathic Parkinson's disease. As shown in one of the British families, lewy bodies were absent. However, this seems quite common in other genetic forms of parkinsonism, such as that related to mutations in the parkin gene. [4]
The growing evidence that parkinsonism occurs in mtDNA-related disorders should suggest investigating carefully affected patients to unmask subtle, subclinical parkinsonian features. [2, 3, 5] In our family, for instance, only two elderly patients were presented with a full-blown syndrome, while younger relatives only presented mild rigidity and akinesia. Such signs could easily have escaped clinical attention, if not carefully searched for.
Therefore, we believe that both our report and the British report might equally contribute to a better understanding of the different pathogenic mechanisms underlying neurodegeneration in mtDNA-related syndromes.
References:
1) Casali C, Bonifati V, Santorelli FM, et al. Mitochondrial myhopathy, parkinsonism and multiple mitochondrial DNA deletions in a Sephardic Jewish family. Neurology 2001:56:802-805.
2) Chalmers RM, Brockington M, Howard RS, Lecky BRF, Morgan-Hughes JA, Harding AE. Mitochondrial encephalopathy with multiple mitochondrial DNA deletions: a report of two families and two sporadic cases with unusual clinical and neuropathological. J Neuro Sci 1999:143:41-45.
3) Checcarelli N, Prelle A, Moggio M, et al. Multiple deletions of mitochondrial DNA in sporadic and atypical cases of encephalomyopathy. J Neurol Sci 1994;123(1-2):74-79.
4) Takahashi H, Ohama E, Suzuki S, et al. Familial juvenile parkinsonism: Clinical and pathologic study in a family. Neurology 1994;44:437-441.
5) Simon DK, Pulst SM, Sutton JP, Browne SE, Beal MF, Johns DR. Familial multisystem degeneration with parkinsonism associated with the 11778 mitochondrial DNA mutation Neurology 1999;53:1787-1793.

Mitochondrial myopathy, parkinsonism, and multiple mtDNA deletions in a Sephardic Jewish family 6 November 2001

R M Chalmers
Worthing Hospital Worthing, West Sussex UK
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Re: Mitochondrial myopathy, parkinsonism, and multiple mtDNA deletions in a Sephardic Jewish family

rmchalmers{at}talk21.com R M Chalmers

Casali et al. describes a family of Sephardic Jews with progressive external ophthalmolpegia, skeletal muscle weakness and parkinsonism with autosomal dominant or pseudodominant inheritance. [1] Southern blot analysis of DNA extracted from muscle demonstrated multiple mitochondrial DNA (mtDNA) delections.
We have reported a British family with almost an identical phenotype. [2] Our family also had progressive external ophthalmoplegia, skeletal muscle weakness and parkinsonism (which responded to levodopa). In addition, our family had cataracts and a mild sensorimotor neuropathy. The inheritance in this family was autosomal dominant.
In the same report, we described the post mortem findings in a member of a second British family with autosomal dominant inheritance of multiple mtDNA deletions. Sections of the substantia nigra showed marked neuronal loss with gliosis and scanty pigmented neurones. No lewy bodies were seen on ubiquitin staining.
It is clear that parkinsonism can be present in some families with multiple mtDNA deletions. A number of autosomal loci have been identified in families with multiple mtDNA mutations [3] but no linkage has been associated with our families (unpublished data) or the family reported by Casali et al. The correlation between genotype and phenotype in families with multiple mtDNA deletions has not been well characterized, but it is clearly possible that our family with parkinsonism and the family described by Casali et al. could harbor mutations in the same, as yet unidentified, autosomal locus. Casali et al. speculates on the relationship between the parkinsonism seen in their family and that in idiopathic Parkinson�s disease. The absence of lewy bodies in the pathological study of our case may suggest differences in the mechanisms of nigral degeneration observed in idiopathic Parkinson�s disease and in families with multiple mtDNA deletions.
References:
1) Casali C, Bonifati V, Santorelli FM, et al. Mitochondrial myhopathy, parkinsonism and multiple mitochondrial DNA deletions in a Sephardic Jewish family. Neurology 2001:56:802-805.
2) Chalmers RM, Brockington M, Howard RS, Lecky BRF, Morgan-Hughes JA, Harding AE. Mitochondrial encephalopathy with multiple mitochondrial DNA deletions: a report of two families and two sporadic cases with unusual clinical and neuropathological. J Neuro Sci 1999:143:41-45.
3) Kaukonen J, Zeviani M, Comi GP, et al. A third locus predisposing to multiple deletions of mtDNA in autosomal dominant progressive external ophthalmoplegia. Am J Hum Genet 1999;65:256-261.