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Year : 2022  |  Volume : 25  |  Issue : 6  |  Page : 1204-1206

Recurrent rhabdomyolysis, acute kidney injury, and foot drop: A rare case with mitochondrial trifunctional protein (MTP) deficiency

Department of Neurology, Pt. B. D. Sharma University of Health Sciences, Rohtak, Haryana, India

Date of Submission12-Jul-2022
Date of Acceptance31-Aug-2022
Date of Web Publication17-Nov-2022

Correspondence Address:
Surekha Dabla
Department of Neurology, Pt. B. D. Sharma University of Health Sciences, Rohtak, Haryana
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aian.aian_606_22

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How to cite this article:
Dabla S, Wangnoo A, Kumar N, Bala K. Recurrent rhabdomyolysis, acute kidney injury, and foot drop: A rare case with mitochondrial trifunctional protein (MTP) deficiency. Ann Indian Acad Neurol 2022;25:1204-6

How to cite this URL:
Dabla S, Wangnoo A, Kumar N, Bala K. Recurrent rhabdomyolysis, acute kidney injury, and foot drop: A rare case with mitochondrial trifunctional protein (MTP) deficiency. Ann Indian Acad Neurol [serial online] 2022 [cited 2023 Jan 29];25:1204-6. Available from:

Dear Editor,

Mitochondrial trifunctional protein deficiency (MTP deficiency or MTPD) is an autosomal recessive fatty acid oxidation disorder caused by HADHA or HADHB gene mutations. This case illustrates the clinical presentations of a patient with sensorimotor polyneuropathy with recurrent episodes of episodic rhabdomyolysis and foot drop.

A 22-year-old student born out of nonconsanguineous marriage presented with a history of progressive weakness of legs with bilateral foot drop for the past 4–5 years. He had a history of easy fatigability and distal weakness more evident after heavy exertion or prolonged walking (after around 200 m). There is a history of muscle pain and cramps present intermittently and aggravating on prolonged fasting. His parents also complained of difficulty in writing while doing class work during his childhood. There is no history to suggest any fasciculation, grip myotonia, thinning of muscles, and second wind phenomena. His brother has h/o similar illness, which was mild and later improved with time.

There is past history of being operated on for inguinal hernia repair at the age of 3.5 years and bilateral cataract surgery at the age of 10 years. At the age of 12 and 17 years, he had episodes of decreased urine output with red-colored urine following an outdoor activity and prolonged fasting, which required hospitalization. During the work up, hemoglobin was 11.5 g/dL (13–17 g/dL), total leucocyte count (TLC) = 11,400 cells/cumm (4500–11,000 cells/cumm), and platelet count = 2.83 lacs/cumm (1.5–4.1 lacs/cumm). Among liver function test serum glutamic pyruvic transaminase (SGPT) = 88 U/L (8–45 U/L), serum glutamic oxaloacetic transaminase (SGOT) = 318 U/L (7–56 U/L), total bilirubin = 0.35 mg/dL (1–8 mg/dL), serum albumin 3.6 g/dL (3.97–4.94 g/dL), blood urea nitrogen (BUN) = 106 mg/dL (6–20 mg/dL), serum creatinine = 14 mg/dL (0.8–1.2 mg/dL), uric acid 12.4 mg/dL (3.5–7.2 mg/dL), creatine kinase = 3795 U/L (46 to 171 U/L), C-reactive protein (CRP) = 11.3 mg/dL (0–3 mg/dL), serum calcium 7.3 mg/dL (7.6–10.4 mg/dL), serum phosphorus 9.1 mg/dL (2.5–4.5 mg/dL), iPTH = 251.3 pg/mL (15–65 pg/mL), and vitamin D 14.53 ng/mL (30–100 ng/mL). All viral markers were negative. Thyroid function tests were normal. Antinuclear AB–IFA, Hep 2 was homogeneously positive with a speckled pattern. Spot urine examination showed microalbuminuria 301 mg/dL (0–20 mg/dL). Renal biopsy performed was suggestive of acute tubular necrosis. He recovered with sessions of hemodialysis.

Presently on neurological examination, his higher mental functions and cranial nerves were normal. Bulk and tone were normal in all four limbs. There was evident distal muscle weakness in hands and feet with evident clawing and foot deformities [Figure 1] and [Figure 2]. His muscle weakness worsened following prolonged and fast walking in the corridor after 10 min. All the deep tendon reflexes were absent and the bilateral plantar response was flexor. Sensory examination was unremarkable.
Figure 1: Bilateral correctable dystonic posturing of hands

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Figure 2: Showing bilateral high arched feet with clawing of toes

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His routine biochemical tests were normal with mildly raised CPK levels of 361 IU/L. Nerve conduction studies were suggestive of mixed sensorimotor axonal neuropathy involving all four limbs. A genetic study revealed mitochondrial trifunctional protein deficiency with homozygous missense variation in exon 14 of the HADHA gene (chr2:g. 26197752G>T; Depth: 76x) that results in the amino acid substitution of aspartic acid for alanine at codon.

He was advised to avoid precipitating factors like prolonged fasting, and strenuous work along with dietary modifications, which included avoidance of long-chain fatty acids (like olive oil, soybean oil, fish, nuts, avocado, and meat) accounting for less than 10% of total caloric intake with supplementation of vegetable oils for the same to prevent deficiency of omega-3 and omega-6 fatty acid. A daily intake of multivitamins along with antioxidant coenzyme Q10 was prescribed. At the last 3-month follow-up visit, he had no fresh episode of rhabdomyolysis after dietary modifications and an explanation of the disease course.

The present case highlights to consider the possibility of mitochondrial trifunctional protein (MTFP) among patients presenting with progressive motor sensory polyneuropathy with a history to suggest recurrent rhabdomyolysis. MTP is a hetero-octamer multienzyme complex comprising four alpha and four beta subunits residing in the inner mitochondrial membrane. MTP catalyzes three out of the four steps of beta-oxidation of fatty acids involved in breaking down long-chain fatty acids into acyl-CoA chains and ultimately into acetyl-CoA molecules releasing FADH2 and NADH as energy substrates. This pathway is utilized when energy demand is high in prolonged starvation, infection, disease, exercise, or elongated intervals between meals and causes fat to replace carbohydrates as a primary energy source. Deficiency results in symptoms in high metabolic regions like the brain, muscle, liver, and myocardium.[1]

Diagnosis of MTP deficiency can be suspected with the increased 3-OH-acylcarnitine (C14, C16, and C18) levels, especially 16-carbon acyl-CoA in serum or elevated urinary dicarboxylic acids, evident during the episodic symptoms or during the newborn screening of affected parents by tandem mass spectrometry. This can be confirmed by Western blot analysis of enzyme activity in skin fibroblast or white blood cells or by genetic testing to study the mutational analysis involving the HADHA or HADHB gene.

Clinically, MTP deficiency presents with three phenotypic presentations[1]: Neonatal onset: severe disease presenting with lethargy, poor feeding, hypoketotic hypoglycemia, hepatic failure, cardiomyopathy, myopathy with rhabdomyolysis, sensory polyneuropathy, and sudden infant death syndrome.[2] Infant onset: a hepatic phenotype with episodes of hypoketotic hypoglycemia and arrhythmia due to cardiomyopathy and lactic acidosis[3] Adolescent onset: a mild neuromyopathic phenotype comprising sensorimotor axonal neuropathy and skeletal myopathy with recurrent rhabdomyolysis. Our patient presented with adult-onset neuromyopathic phenotype with sensorimotor axonal neuropathy causing bilateral foot drop; myalgias with raised total creatinine phosphokinase levels; elevated transaminases and recurrent myoglobinurias and an episode of rhabdomyolysis precipitated by prolonged starvation or exercise.

Spiekerkoetter et al. studied 15 patients from 13 different families with TFP deficiency and β-subunit mutations with three typical clinical phenotypes: neonatal onset (4 patients), infant onset (2 patients), and adolescent-onset (9 patients). Mutation analysis showed 16 different mutations, missense mutations were the most common (12 patients). The missense mutations were seen associated with the milder myopathic phenotype. The degree of reduction in the enzyme is correlated with the severity of clinical presentation.[2] Liewluck et al.[3] reported HADHA mutation in a 53-year-old man with late adult-onset recurrent rhabdomyolysis and subclinical mild sensorimotor axonal neuropathy and elevated long-chain acylcarnitine levels.

Management of MTP deficiencies is focused primarily on preventing the episodes of severe illness, which include avoiding fasting and frequent feeding. Dietary modifications focussing on a caloric diet restricting the intake of long-chain fatty acids to less than 10% of calorie intake and medium-chain fatty acids to 10%–15% with multivitamins intake to prevent fat-soluble vitamin deficiency may be beneficial. Medium-chain triglyceride supplementation, for example, docosahexaenoic acid can help by suppressing long-chain fatty acid oxidation.

In conclusion, patients with unusual symptoms like recurrent foot drops, positive family history, and episodic rhabdomyolysis of unknown cause, should be evaluated for mitochondrial trifunctional protein deficiency. Dietary modifications may help to lower the frequency of rhabdomyolysis in these cases.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Kompare M, William BR. Mitochondrial fatty-acid oxidation disorders. Semin Pediatr Neurol 2008;15:140-9.  Back to cited text no. 1
Spiekerkoetter U, Sun B, Khuchua Z, Bennett MJ, Strauss AW. Molecular and phenotypic heterogeneity in mitochondrial trifunctional protein deficiency due to b-subunit mutations. Hum Mutat 2003;21:598-607.  Back to cited text no. 2
Liewluck T, Mundi MS, Mauermann ML. Mitochondrial trifunctional protein deficiency: A rare cause of adult-onset rhabdomyolysis. Muscle Nerve 2013;48:989-91.  Back to cited text no. 3


  [Figure 1], [Figure 2]


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