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Gomori trichrome staining (Figure 1A). Histochemistry showed abnormal subsarcolemmal activity of succinate dehydrogenase (Figure 1B) and on electron ...

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Hyperventilation due to mitochondrial myopathy Peter Moosmann MD PhD Sebastian Brandner MD 1 2 Stephanie Kleinle PhD Beat Frauchiger MD J R Soc Med 2000;93:25-26

Mitochondrial diseases are rare, and diagnosis is frequently delayed by their uncharacteristic presentation.

CASE HISTORY

A 35-year-old man was admitted in a `desolate psychophysical state' with stomach-ache, loss of appetite and general fatigue. He complained of dry mouth, gradual decrease in muscle strength, and dyspnoea and trembling after mild exercise, followed by muscle pain. Previously, airway hyperresponsiveness had been diagnosed. His mother, a person of short stature, had died at the age of 21, only months after the birth of a daughter who herself died in infancy. On examination the patient was of asthenic build with slightly decreased muscle bulk, generally subnormal strength (score 4, active movement against resistance), symmetrical tendon re¯exes and intact sensation. His gait was unaffected. Findings on ophthalmoscopy, radiography of chest and nasal sinuses, electrocardiography, and lung function testing were normal, as were blood gases and the results of other routine laboratory tests. Gastroscopy revealed chronic gastritis and Helicobacter pylori was eradicated with triple therapy. The patient performed normally on exercise testing, apart from a rapid heart rate and prolonged recovery, during which he hyperventilated and nearly collapsed. He seemed depressed (a feature mentioned in previous medical records) but psychiatric examination did not con®rm this impression. Recurring hyperventilation and general weakness were interpreted as functional disease and the patient was discharged. Nevertheless, a neurological evaluation was planned. Ten days later he returned with massive hyperventilation after strenuous work. Blood pH was 7.08, base excess was 22.4 mmol/L and lactate was raised at 14.1 mmol/L. Department of Medicine, Thurgauisches Kantonsspital, CH-8501 Frauenfeld; 1

Department of Neuropathology, University Hospital, CH-8091 Zurich

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Departments of Pediatrics and Clinical Research, University Hospital, CH-3010

Berne, Switzerland Correspondence to: Dr B Frauchiger

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Serum creatine kinase was normal, and of a series of organic acids assayed in urine, only lactate was excreted at a abnormally high rate. Cerebrospinal ¯uid had a normal cell count, glucose and protein, and a raised lactate at 3.5 mmol/L. An oxidative phosphorylation disease was presumed. Ultrastructural and histochemical analyses of muscle tissue revealed subsarcolemmal accumulation of compensatory hyperplastic, structurally and functionally abnormal, mitochondria leading to the ragged-red appearance of the muscle ®bres on haematoxylin±eosin and Gomori trichrome staining (Figure 1A). Histochemistry showed abnormal subsarcolemmal activity of succinate dehydrogenase (Figure 1B) and on electron microscopy typical paracrystalline inclusions were seen in altered mitochondria (Figure 1C). Finally, the biochemical activities of oxidative phosphorylation complexes I and III were decreased, and a heteroplasmic point mutation (T618C) was identi®ed that, disrupting a conserved base pair in the anticodon stem, supposedly impairs formation of the mitochondrial tRNAPhe1. Although maternal inheritance might have been suggested by the family history, the mitochondrial mutation was not present in the patient's second sister.

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COMMENT

What initially seemed to be a functional disease turned out to be a rare mitochondrial myopathy. The `other human genome' was brought to common awareness a decade ago when mitochondrial DNA (mtDNA) mutations underlying mitochondrial myopathies and Leber's hereditary optic neuropathy were identi®ed2. Since then, more than a hundred mtDNA defects have been identi®ed that cause diseases of bewildering diversity. Moreover, a single molecular and biochemical lesion may manifest itself in different ways, with variable onset and time course of the clinically apparent disease3,4. Chinnery and Turnbull5 distinguish between three groups of patients with suspected mitochondrial diseasesÐ(1) patients with a clearly recognizable syndrome; (2) patients with a cluster of features suggesting a mitochondrial defect; and (3) patients with unusual clinical presentation. For instance, stroke before the age of 40, seizures and lactic acidosis suggest a MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes), but most of the new cases of mtDNA disease present uncharacteristically5. In this respect, observations in the case reported here are not unusual. For years, the slowly evolving muscle weakness, the exercise intolerance, the hyperventilation and the chronic fatigue were mistaken for a functional disease, and only when a massive metabolic acidosis was detected was an abnormality of oxidative phosphorylation taken into

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Figure 1 Muscle biopsy. Ragged red ®bres as seen with the Gomori trichrome stain (A); enzyme histochemistry shows increased succinate dehydrogenase activity in these ®bres (B) and electron microscopy shows characteristic paracrystalline inclusions (C).

consideration and a mitochondrial disease identi®ed. The presence of a heteroplasmic mutation of a mitochondrial tRNA gene con®rms the diagnosis. The actual myopathy was mild and the central nervous system was unaffected (in particular, there was no stroke-like episode). The diagnostic approach to a suspected mitochondrial disease has to be adapted to the clinical presentation and to incorporate histochemical, biochemical and molecular genetic information5. Precise diagnosis aids management (e.g. by avoiding unnecessary treatments), genetic counselling and, to a certain extent, prognosis (e.g. there are data6 suggesting a relationship between mutation load in muscle biopsy and clinical phenotype, at least in some mutations). No speci®c treatment can at present be offered to affected individuals.

REFERENCES

Cadaveric renal transplantation with simultaneous iliac bypass

CASE HISTORY

M R Mustafa FRCS M H Wise MD FRCS

P J Gibbs FRCS

J R Soc Med 2000;93:26±27

Vascular atheromatous disease is common in patients with end-stage renal failure and when worse than expected can pose considerable technical dif®culties during transplantation. Wessex Renal & Transplant Unit, St Mary's Hospital, Milton Road, Portsmouth

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PO3 6AD, UK Correspondence to: Mr M H Wise

1 Kleinle S, Schneider V, Moosmann P, Brandner S, KraÈhenbuÈhl S, Liechti-Gallati S. A novel mitochondrial tRNAPhe mutation inhibiting anticodon stem formation associated with a muscle disease. Biochem Biophys Res Comm 1998;247:112±15 2 Johns DR. The other human genome: mitochondrial DNA and disease. Nature Med 1996;2:1065±8 3 Chinnery PF, Turnbull DM. Mitochondrial medicine. Q J Med 1997;90:657±67 4 Wallace DC. Mitochondrial diseases in man and mouse. Science 1999;283:1482±8 5 Chinnery PF, Turnbull DM. Clinical features, investigation, and management of patients with defects of mitochondrial DNA. J Neurol Neurosurg Psychiatry 1997;63:559±63 6 Chinnery PF, Howell N, Lightowlers RN, Turnbull DM. Molecular pathology of MELAS and MERRF. The relationship between mutation load and clinical phenotypes. Brain 1997;120:1713±21

A woman aged 54 with end-stage renal failure secondary to chronic pyelonephritis was admitted for cadaveric renal transplantation. She had kept generally well on continuous ambulatory peritoneal dialysis, was a non-smoker and had never had chest pain or intermittent claudication. On examination she seemed ®t, her femoral pulses were palpable and the peripheries were warm. The donor organ was a good-quality left kidney from a 40-year-old male, cold ischaemic time 23 hours. At operation, a left-sided extraperitoneal approach was made to the iliac vessels, the perivascular lymphatics being carefully cauterized while the arteries were mobilized. Unfortunately, the internal and external iliac arteries proved too heavily diseased and calci®ed to sustain a renal transplant. Endarterectomy was attempted, but resulted in complete disruption of the common iliac artery. We therefore had to perform a simultaneous vascular reconstruction and renal transplantation. The proximal end of a 13 mm/6.5 mm soft woven Dacron (Vascutek) bifurcated prosthesis was anastomosed to the common iliac

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artery, with one distal limb anastomosed end-to-end with the donor renal artery and the other to the distal external iliac artery (see Figure 1). The internal iliac artery was ligated. The kidney perfused well on unclamping, as did the patient's leg. Postoperative recovery was complicated by delayed graft function requiring eight days of peritoneal dialysis, and by development of a haematoma (resulting from a protocol renal transplant biopsy on the sixth postoperative day) which required open evacuation. On day 40 an ispilateral lymphocele was treated by open drainage and fenestration; the development of this collection was no surprise in view of the disruption to the lymphatics that must have occurred during the ®rst operation. For the operative procedures she received prophylactic broadspectrum antibiotics. At one year after transplantation the patient is well with excellent renal function (serum creatinine about 120 mmol/L). Interestingly, intermittent claudication did develop on the left six months postoperatively and duplex doppler revealed a common femoral stenosis on the left. Her symptoms and her ankle/brachial pressure index improved with a strict exercise regimen. COMMENT

At renal transplantation, mild or moderate atherosclerosis of the iliac vessels can usually be dealt with by careful positioning of the arterial anastomosis and accurate placement of sutures. When it is severe, endarterectomy is sometimes successful; but, as in our case, this procedure may irreparably damage the native vessel. The donor iliac vessel has been used as an arterial homograft in atherosclerotic transplant recipients with good results1,2, but this option was not open to us. Published data suggest that vascular reconstruction with prosthetic material is associated with a high incidence of graft loss as a result of vascular complications3.

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Figure 1 Arterial reconstruction

In theory, the risk of prosthesis infection is also higher than in a non-immunosuppressed patient. If the bypass were to become infected in our patient, we would almost certainly remove it, reimplant the kidney at an alternative site and construct an extra-anatomical bypass to the lower limb. This is the second patient in our unit to undergo renal transplantation with the aid of a bifurcated Dacron prosthesis when severe atherosclerosis was found at operation. Both have done well, with no complications attributable to the Dacron implant.

REFERENCES 1 Benedetti E, Baraniewski HM, Asolati M, Pollak R, Schuler JJ. Iliac reconstruction with arterial allograft during pancreas±kidney transplantation. Clin Transplantation 1997;11:459±62 2 Ames SA, Bower VD, Corry RJ. Arterial homograft use in an atherosclerotic renal allograft recipient. Transplant Proc 1989;21:3853±5 3 Van der Vliet JA, Naaf DBJ, van Bockel JH, et al. Fate of renal allografts connected to vascular prosthesis. Clin Transplantation 1996;10:199±2

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