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Mitochondrial DNA Rearrangements in Young Onset Parkinsonism: Two Case Reports

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Mitochondrial DNA Rearrangements in Young Onset Parkinsonism: Two Case Reports J Neurol Neurosurg Psychiatry 2001;71:685–687 685 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.71.5.685 on 1 November 2001. Downloaded from SHORT REPORT Mitochondrial DNA rearrangements in young onset parkinsonism: two case reports G Siciliano, M Mancuso, R Ceravolo, V Lombardi, A Iudice, U Bonuccelli Abstract Although the precise role of respiratory Parkinson’s disease is a nosological entity chain dysfunction and mtDNA mutations in of unknown origin for which, in some the pathogenesis of Parkinson’s disease re- cases, a possible pathogenetic role for mains to be elucidated, it is worth noting that mitochondrial dysfunction has been pos- in most series of patients with a primary tulated. Two young onset parkinsonian defined defect in mitochondrial activity, aki- 5 patients with mitochondrial DNA netic rigid syndromes are infrequent. (mtDNA) deletions in skeletal muscle are Conversely, recent reports indicate the oc- reported on. Patient 1 also presented with currence of primary pathogenic mtDNA muta- increased blood creatine kinase and lac- tions in Parkinson’s disease, both in the form of 6 tate concentrations and a family history large scale mtDNA rearrangements, and as point mutations in complex I7 and tRNA which included a wide range of pheno- 8 types aVecting multiple systems. Patient 2 genes. presented with multiple symmetric We report here on two unrelated patients in lipomatosis. Histopathological investiga- whom parkinsonism was part of peculiar clini- cal constellations. In these patients molecular tion showed ragged red fibres and COX analysis showed the presence of major mtDNA copyright. negative fibres in muscle biopsies from rearrangements in skeletal muscle, supporting both patients. The data support the hy- the hypothesis that the dopaminergic nigrostri- pothesis that mitochondrial DNA muta- atal system can be a target, at least in some tions may occur in some cases of instances, of mitochondrial involvement. parkinsonism, suggesting that a diagnosis of a mitochondrial disorder should be considered in the presence of consistent Case reports family history and clinical symptoms. CASE 1 (J Neurol Neurosurg Psychiatry 2001;71:685–687) A 40 year old man was referred to us because of young onset (at 30 years) left lateral parkinson- Keywords: Parkinson’s disease; mitochondrial encepha- ism responsive to levodopa. Neurological exam- lomyopathies; mtDNA deletions ination showed bradykinesia and rigidity, pos- http://jnnp.bmj.com/ tural instability, and hypomimia (Hoehn and Yahr stage III). Tremor, pyramidal signs, dysau- Mitochondrial diseases comprise a wide group tonomia, oculomotor dysfunction, cerebellar of disorders which, at their origin, have nuclear impairment, and orthostatic hypotension were or mitochondrial DNA (mtDNA) mutations, absent. Therapy, at that time, was 600 mg/day which are responsible for biochemical defects levodopa/carbidopa and 300 mg/day tolcapone. in respiratory chain function and consequent Motor fluctuations in the form of wearing oV impaired cellular oxidative energy production. were present. General physical examination was on September 29, 2021 by guest. Protected Department of It follows that mitochondrial disorders are normal, and no Kayser-Fleischer rings were Neurosciences, associated with a wide group of clinical present on ophthalmological examination. Rou- Neurology Clinic, manifestations aVecting skeletal muscle, brain, University of Pisa, Via tine laboratory blood chemistry showed abnor- Roma 67, 56126 Pisa, heart, and other highly oxygen dependent mal concentrations of creatine kinase (901 U/l; 1 Italy organs or tissues. normal value<195), glutamic oxaloacetic G Siciliano The hypothesis of pathogenic mitochondrial transaminase (76 U/l; normal value<45), M Mancuso dysfunction in idiopathic Parkinson’s disease glutamic pyruvic transaminase (170 U/l; normal R Ceravolo has become particularly attractive since the V Lombardi value<45), and ã-glutamyltransferase (73 U/l; A Iudice finding by Vyas et al that the parkinsonism normal value<50 U/l), whereas blood cerulo- U Bonuccelli inducing compound N-methyl-4-phenyl- plasmin and urinary copper concentrations were 1,2,3,6-tetrahydropyridine is a mitochondrial normal. Correspondence to: toxin.2 After further reports on deficiency in Abdominal ultrasound scan showed liver cir- Dr G Siciliano [email protected] respiratory chain enzyme complex I in the sub- rhosis and tolcapone was subsequently with- stantia nigra of patients with Parkinson’s drawn. Blood lactate concentration was abnor- Received 14 November 2000 disease,3 other investigators have tried to clarify mally increased during progressive workload and in final form 6 June 2001 the relation between mitochondrial defects and exercise (increment by 120% of the basal value Accepted 27 July 2001 death of nigral dopaminergic neurons.4 at 50% of maximal power output9; normal www.jnnp.com 686 Siciliano, Mancuso, Ceravolo, et al J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.71.5.685 on 1 November 2001. Downloaded from I II III II II IV II § V Figure 1 Pedigree of patient 1, square=male; circle=female; ⁄=dead; diamond=unknown sex. Empty symbols=non-aVected members; black symbols=aVected by diabetes mellitus; point symbols=aVected by liver cirrhosis; II=aVected by Parkinson’s disease; §=proband; *=case 1. value<50%). Brain MRI was normal, as was was normal. Blood lactate concentration at rest neuropsychological evaluation. Liver cirrhosis, was slightly increased above the normal range diabetes mellitus, and a complex pattern of (25 mg/dl; normal value 5.7–22), and brain neurological disorders were disclosed on exam- MRI was normal. Family history was negative ination of family members (fig 1). In particular, for neurological disorders, including symptoms the patient’s 48 year old sister, the proband of and signs more commonly suggestive of this family, had been aVected by bilateral eyelid mitochondriopathy. Muscle biopsy showed ptosis, progressive external ophthalmoplegia, increased variability in fibre size and scattered and sensory ataxia since her early 40s, and ragged red and COX negative fibres. Polymer- increased concentrations of creatine kinase ase chain reaction analysis of mtDNA was (406 U/l) and rest lactate (56.7 mg/dl, normal negative for the above mentioned MERRF and value 5.7–22). Furthermore, family medical MELAS point mutations. Long PCR showed, history disclosed a history of parkinsonism in in addition to wild-type mtDNA, one addi- two maternal uncles, and other maternally tional band, of about 11.6 kb, corresponding to related members were aVected by liver cirrho- a 5000 bp mtDNA deletion (fig 2) located, sis and diabetes mellitus, a clinical association according to the primers used, between nucle- thought to be responsible for the death of three otides 8420 and 13 648 (common deletion). of the patient’s relatives in their 50s. The amount of mutant mtDNA was about Due to the family history a left deltoid mus- 50% of total mtDNA. cle biopsy under local anaesthesia was per- copyright. formed on the patient, after obtaining in- Discussion formed consent. Increased variability in fibre In this study we have described two patients size, scattered (3%) ragged red fibres by with a history of parkinsonism and the trichrome and 10% COX negative fibres were presence of mitochondrial DNA (mtDNA) found on histochemical examination. Whereas mutations in skeletal muscle. These two polymerase chain reaction (PCR) analysis of patients showed some peculiarities in their mtDNA was negative for A8344G and clinical picture—namely, a complex and vari- G8363A MERRF and for A3243G and able occurrence of symptoms suggestive of dis- A3252G MELAS point mutations, Southern eases caused by mtDNA mutations. In particu- blot disclosed, in addition to a wild-type band MPC lar we recorded progressive external of 16.6 kb, at least four additional bands corre- ophthalmoplegia and diabetes mellitus in the http://jnnp.bmj.com/ sponding to multiple species of deleted family of patient 1, and in patient 2, multiple mtDNA. The densitometric amount of mutant symmetric lipomatosis, a disorder often sus- mtDNAs was about 60% of total mtDNA. tained by mitochondrial impairment.10 More- About 8% of ragged red and COX negative over, in family 1 the clinical findings seemed to 5228 bp fibres and a similar pattern of mtDNA be inherited in autosomal dominant fashion rearrangement were found in a muscle biopsy and they were associated with multiple from the patient’s sister. mtDNA deletions in the two analysed mem- 2000 bp bers belonging to a same generation, making it on September 29, 2021 by guest. Protected CASE 2 possible for an autosomal dominant mutation 1500 bp A 52 year old man came to our attention with a to cause such an mtDNA abnormality.11 history of young onset (38 years) parkinsonism Causative factors of selective degeneration of responsive to levodopa. On physical examina- nigrostriatal neurons in Parkinson’s disease tion he showed multiple, symmetric fatty remain largely unknown. However, there is proliferations on his neck, shoulders, and increasing evidence in favour of a significant limbs, with subcutaneous lipomas visible on genetic component in the pathogenesis of this 300 bp ultrasound scan. Neurological examination disease, as recently indicated by the finding of a showed upper limb rest tremor, bradykinesia, point mutation in the á-synuclein gene in some rigidity lateralised on the left side, and postural pedigrees with autosomal dominant Parkin- instability (Hoehn and Yahr stage III). The son’s disease,12 or parkin gene deletions in Figure 2 Long PCR remaining neurological examination was unre- some patients with autosomal recessive Parkin- analysis of mtDNA in 13 patient 2 shows (line P) markable. The patient’s treatment at the time son’s disease. two bands, corresponding to of referral was 400 mg/day levodopa/ Among the possible genetic determinants of wild type (5228 bp) and 5 benserazide and 6 mg/day ropirinole. Motor Parkinson’s disease, the mitochondrial genome kb deleted mtDNA. Line C=control; line fluctuations of the wearing oV type were has also been considered. Although parkinson- M=molecular weights.
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