Very-long-chain acyl-coenzyme A dehydrogenase deficiency— a new cause of myoglobinuric acute renal failure

Andrew P. Cairns1, Paula M. O'Donoghue1, Victor H. Patterson2 and J. Henry Brown1,

1 The Renal Unit, Antrim Area Hospital, and 2 The Department of Neurology, Belfast City Hospital, Northern Ireland

Keywords: acute renal failure; acylcarnitines; myoglobinuria; rhabdomyolysis; very-long-chain acyl coenzyme A dehydrogenase deficiency



   Introduction
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 Introduction
 Case
 Discussion
 References
 
Skeletal muscle uses two principal sources of energy: fatty acids and glucose. Fatty acids are particularly important when fasting, or during prolonged exercise. Very-long-chain acyl-CoA dehydrogenase (VLCAD) is an enzyme catalysing the dehydrogenation of long-chain fatty acids in the first step of mitochondrial fatty acid oxidation [1]. VLCAD deficiency normally presents in infancy or early childhood with cardiomyopathy or episodes of hypoglycaemia [1].

We describe the case of a man with VLCAD deficiency who presented for the first time at the age of 41 with muscle pains, dark urine, and renal failure. We believe this to be only the second published case of VLCAD deficiency presenting in adult life as acute renal failure requiring dialysis.



   Case
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 Introduction
 Case
 Discussion
 References
 
A 41-year-old man was referred complaining of passing dark brown urine for 3 days, associated with a feeling of extreme tiredness, pain and heaviness in the legs. The symptoms had been present since performing an unusually large amount of heavy lifting while moving house during the preceding week.

The patient gave a history of developing marked muscle pains after moderate exercise over the past 20 years, often followed by the presence of dark urine. On this occasion the muscle pains were more severe and the dark urine slower to clear than usual. Past medical history included only two episodes of acute gout. He took no medications, was an ex-smoker of 5 years, and drank 10 units of alcohol per week.

On examination he was apyrexic and clinically euvolaemic. Blood pressure was 160/82 mmHg; pulse 80 b.p.m., regular. Full power was present in all muscle groups, with normal tone, reflexes and sensation.

Dipstick urinalysis revealed large amounts of proteinuria and haematuria. Laboratory values were as follows: sodium 139 mmol/l (normal range 136–146), potassium 4.5 mmol/l (3.5–5.2), chloride 92 mmol/l (95–108), bicarbonate 29 mmol/l (22–30), urea 29.9 mmol/l (2.3–6.6), creatinine 776 µmol/l (70–180), glucose 6.9 mmol/l (4–6). Haemoglobin 13.3 g/dl (12–17), leukocytes 10.5x109/l (4–11), platelets 238x109/l (150–400), creatine kinase 177 600 U/l (25–180), creatine kinase (MB fraction) 540 U/l (=0.03%), aldolase 22.2 U/l (1.2–7.6), Lactate dehydrogenase 5084 U/l (240–525), aspartate transaminase 4520 U/l (5–40), alanine aminotransferase 1200 U/l (5–40). Other liver function tests were within normal limits. Arterial blood gases, chest X-ray, and ECG showed no abnormalities.

Total urinary protein excretion was 0.3 g/24 h (<0.15). Urine microscopy revealed two red cells per mm3 with 50 white cells per mm3. There was no growth on repeat urine cultures. The presence of urinary myoglobin was confirmed by spectroscopy and precipitation.

A diagnosis of acute renal failure secondary to rhabdomyolysis and myoglobinuria was made. He remained oliguric and 2 days after admission blood urea had risen to 45.1 mmol/l and serum creatinine to 1039 µmol/l. A subclavian catheter was inserted and haemodialysis commenced. Six haemodialysis sessions over a 2-week period were required. Urine output began to increase after 11 days and had increased to 3 l/day at 2 weeks.

The patient was discharged after 17 days, dialysis independent, with a blood urea of 19.2 mmol/l, and creatinine of 838 µmol/l. Renal function steadily improved and at 3 months blood urea was 6.5 mmol/l, and creatinine 145 µmol/l.

Further investigations were undertaken to determine the precise cause of this patient's rhabdomyolysis. Fasting resting lactate was normal at 1.9 mmol/l. Blood ammonia was normal at 25 µmol/l. DNA analysis for dystrophin gene deletion was negative. Muscle biopsy was not diagnostic, showing non-specific minor myopathic features. Immunocytochemical staining for both dystrophin I and II and spectrin was positive in all fibres. There were no inclusions or mitochondrial abnormalities, and myofibrils were intact. Endomysial collagen was not increased.

Blood acylcarnitine levels were measured by mass spectrometry (a) and the following abnormal results obtained:

(001)

(002)
This pattern is strongly in keeping with the diagnosis of VLCAD deficiency [1].

Fibroblasts were cultured from a skin biopsy and tritium release assays of fatty acid ß-oxidation performed using [9,10-3H]myristate and [9,10-3H]palmitate and [9,10-3H]bleate (b). Results are expressed as nmol per mg protein per hour followed by mean percentage of controls:

(003)
These results strongly support the diagnosis of a mild VLCAD deficiency [1].

The patient has been advised to avoid excessive exercise particularly when fasting, stop exercise if he develops muscle cramps or pain, and maintain a high fluid intake when exercising. He has been advised to take a high-carbohydrate, low-fat diet. He has had no recurrences in the subsequent 2 years. If he continues to follow this advice we would expect a good prognosis.



   Discussion
 Top
 Introduction
 Case
 Discussion
 References
 
Rhabdomyolysis is an important cause of acute renal failure (10–15% of cases) [2]. Recognized causes include muscle injury, sepsis, drugs, toxins, inflammatory myopathies, metabolic disorders, and hereditary defects of glycogenolysis and of fatty acid metabolism. The cause of rhabdomyolysis in a significant proportion of cases remains undefined.

Fatty acids are important muscle substrates, especially when fasting or during prolonged exercise. VLCAD is an enzyme catalysing the dehydrogenation of long-chain fatty acids in the first step of mitochondrial fatty acid oxidation [1]. VLCAD was first identified in 1992 [3]. The human VLCAD gene has been identified and located on the short arm of chromosome 17 between bands p11.2 and p11.13105 [4]. The gene is 5.4 kb long and contains 20 exons [5].

A number of patients with VLCAD deficiency have now been identified. A large study by Vianey-Saban et al. [1] looked at 30 such patients in 27 unrelated families. Two main clinical phenotypes of VLCAD deficiency were described:

(i) A severe or ‘cardiomyopathic’ phenotype characterized by the early onset of symptoms before 8 months of age, 30% before 2 days of age. Most patients die in the course of the first metabolic decompensation with hypertrophic cardiomyopathy and pericardial effusion.
(ii) A mild phenotype without cardiac symptoms (30% of patients) have a clinical course characterized by episodes of hypoglycaemia, beginning in infancy or early childhood.
There has been one patient reported as presenting in adult life, with acute renal failure requiring dialysis [6]. Two other patients with VLCAD deficiency presenting in adult life have been described: a 21-year-old man presented with a 5-year history of muscle pains after prolonged exercise or fasting, occasionally associated with myoglobinuria [7], and a 42-year-old woman presenting with a 2-year history of muscle pains and sweating associated with myoglobinuria after exercise or upper respiratory tract infections [8]. Neither of these two patients developed renal failure.

The adult presentation of VLCAD deficiency has a milder phenotype presumably because of the presence of some residual enzyme activity. This is only the second report of VLCAD deficiency presenting with acute renal failure requiring dialysis. A greater than usual level of exercise in the fasting state caused excessive rhabdomyolysis and the failure to maintain an adequate fluid intake resulted in acute renal failure in this patient. It is possible that a significant number of cases of rhabdomyolysis which do not have any established aetiology may have discoverable metabolic defects similar to those in this patient. Therefore we would suggest that in such cases enzymatic defects are looked for, so that appropriate advice can be given.



   Acknowledgments
 
The authors wish to thank Dr M. Pourfarzam (a), Spence Biochemical Genetics Unit, Royal Victoria Infirmary, Newcastle upon Tyne, for blood acylcarnitine level analysis, and Dr S. Olpin (b), Department of Chemical Pathology, Sheffield Children's Hospital, for tritium release assays of fatty acid ß-oxidation in cultured fibroblasts.



   Notes
 
Correspondence and offprint requests to: Dr J.H. Brown, Consultant Nephrologist, The Renal Unit, Antrim Area Hospital, Bush Road, Antrim BT41 2RL, Northern Ireland, UK. Back



   References
 Top
 Introduction
 Case
 Discussion
 References
 

  1. Vianey-Saban C, Divry P, Brivet M et al. Mitochondrial very-long-chain acyl coenzyme A dehydrogenase deficiency: clinical characteristics and diagnostic considerations in 30 patients. Clin Chim Acta1998; 269: 43–62[ISI][Medline]
  2. Zager RA. Rhabdomyolysis and myohemoglobinuric acute renal failure. Kidney Int1996; 49: 314–326[ISI][Medline]
  3. Izai K, Uchida Y, Orii T, Yamamoto S, Hashimoto T. Novel fatty acid B-oxidation enzymes in rat liver mitochondria. I. Purification and properties of very-long-chain acyl-coenzyme A dehydrogenase. J Biol Chem1992; 267: 1027–1033[Abstract/Free Full Text]
  4. Andresen BS, Bross P, Vianey-Saban C et al. Cloning and characterization of human very-long-chain acyl-CoA dehydrogenase cDNA, chromosomal assignment of the gene and identification in four patients of nine different mutations within the VLCAD gene. Hum Mol Genet1996; 5: 461–472[Abstract/Free Full Text]
  5. Orii KO, Aoyama T, Souri M et al. Genomic DNA organisation of human mitochondrial very-long-chain acyl-CoA dehydrogenase and mutation analysis. Biochim Biophys Res Commun1995; 217: 987–992[ISI][Medline]
  6. Gillett GT, Krywawych S, Brivet M et al. VLCAD Deficiency presenting with recurrent rhabdomyolysis in an adult. J Inher Metab Dis1996; 19 [Suppl. 54]: 108 [abstract]
  7. Ogilvie I, Pourfarzam M, Jackson S, Stockdale C, Bartlett K, Turnbull DM. Very long-chain acyl coenzyme A dehydrogenase deficiency presenting with exercise-induced myoglobinuria. Neurology1994; 44: 467–473[Abstract]
  8. Smelt AHM, Poorthuis BJHM, Okenhout W et al. Very long chain acyl-coenzyme A dehydrogenase deficiency with adult onset. Ann Neurol1998; 43: 540–544[ISI][Medline]
Received for publication: 15. 2.00
Revision received 24. 3.00.



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