Sensory neuropathy as a manifestation of multiple acyl-coenzyme A dehydrogenase deficiency

Abstract

Multiple acyl-coenzyme A dehydrogenase deficiency (MADD) is a rare metabolic disorder which typically manifests with muscle weakness. However, despite late-onset MADD being treatable, it is often misdiagnosed, due in part to the heterogeneity of presentations. We report a case of late-onset MADD manifesting first as a sensory neuropathy before progressing to myopathic symptoms and acute metabolic decompensation. Early diagnostic workup with acylcarnitine profiling and organic acid analysis was critical in patient outcome; metabolic decompensation and myopathic symptoms were completely reversed with riboflavin supplementation and dietary modification, although sensory neuropathy persisted. Clinical consideration of MADD as part of the differential diagnosis of neuropathy with myopathy is crucial for a timely diagnosis and treatment of MADD.

Background

Multiple acyl-coenzyme A dehydrogenase deficiency (MADD) is an autosomal recessive disorder of β-oxidation, resulting from a deficiency of electron transfer flavoprotein (ETF) or electron transfer flavoprotein dehydrogenase (ETFDH).¹ The metabolic consequence is impaired adenosine triphosphate synthesis, excessive lipid accumulation and insufficient gluconeogenesis. This results in a clinically heterogenous disorder which can present in the neonatal period (types 1 and 2) but can also be late-onset (type 3).¹ MADD has been associated with a homozygous deficit in the ETFDH gene (less commonly ETFA and ETFB). While MADD is a rare disorder, it is important to identify and diagnose, because early initiation of treatment with riboflavin may lead to complete symptom resolution. We describe a case of MADD in a patient presenting initially with a sensory neuropathy prior to myopathy, of which only the latter was responsive to riboflavin supplementation and dietary changes.

Case presentation

A woman in her 40s presented following 5 days of deteriorating proximal weakness and recurrent falls. She had a background of 6 months of progressive exercise intolerance, lethargy and fatigue, being restricted to her bed for 2 days preceding admission. She denied diplopia, dysphagia or dysarthria, and there were no fatigable elements to the weakness in the history.

She had a medical history of hypercholesterolaemia, treated with 20 mg of atorvastatin. She had also consulted a neurologist 2 years prior with gradually progressive ascending numbness to the level of both knees. Electrophysiology at that time revealed a sensory large fibre axonal neuropathy. Screening blood tests (including, but not limited to, HIV serology, vitamin B12, folate, HbA1c and serum protein electrophoresis, although serum creatine kinase (CK) was not tested at this time) had been unremarkable, but she had no further investigations and this presentation had been labelled as an idiopathic sensory neuropathy. For personal reasons, she had not attended follow-up. She was a current smoker of 27 pack years, with no history of alcohol misuse and unremarkable family history.

Physical examination was significant for bilateral facial weakness and proximal muscle weakness (2/5) in the upper and lower extremities, although distal strength was largely preserved. Deep tendon reflexes were present in the upper limbs and present at the knees with reinforcement, but ankle jerks were absent and her plantar flexor. There was no sensory loss in the upper limbs, but joint position sense was symmetrically impaired to the level of the ankles, and light touch and vibration sense was impaired to the knees. Pin-prick sensation was preserved and there was no ataxia.

During the first 12 hours post-admission, the patient deteriorated markedly becoming tachycardic (110 beats per minute), hypotensive (59/36 mm Hg), hypoglycaemic (1.8 mmol/L) and obtunded with GCS 10. She was treated with intramuscular glucagon and intravenous dextrose and hydrocortisone, before being taken to intensive care for haemofiltration, vasopressor support and (eventually) intubation.

Investigations

Initial investigations were significant for white cell count 15.2×10⁹/L (neutrophilia), C reactive protein 160 mg/L, calcium 2.91 mmol/L, CK 12 073 IU/L (figure 1), alanine aminotransferase (ALT) 259 U/L and ammonia 277 µmol/L. HIV and hepatitis serology were both negative. Immunology showed normal antinuclear antibody, antineutrophil cytoplasmic antibody, anti-Ro/La, anti-Mi-2, antineuronal, anti-Hu, anti-AChR, anti-MUSK and anti-HMGCR.

Figure 1.

The levels of serum CK (red) and ammonia (blue) during the first days of the admission; different treatments are displayed in green. The dietary modification was initially a low-fat feed and quickly refined to a medium-chain triglyceride-free feed. She was in the intensive care unit from days 2–24 and discharged 1 month later, continuing on riboflavin and a low-fat, high-carbohydrate diet life-long. Figure created by NC. CK, creatine kinase.

At the time of deterioration, investigations revealed a metabolic acidosis (pH 7.04, pCO2 4.1 kPa, HCO3 8.0 mmol/L) with an anion gap of 35, an acute kidney injury (creatinine 186 µmol/L) and worsening transaminitis (ALT 477 U/L), with her urine dipstick positive for blood but negative for protein and ketones. These results (hypoketotic hypoglycaemia, hyperammonaemia and rhabdomyolysis), and the exacerbation several days into a recent illness, raised clinical suspicion of a fatty acid oxidation disorder.

Therefore, we arranged investigations to include urine/plasma amino and organic acids, a blood spot acylcarnitine profile and a deltoid muscle biopsy. The biopsy, illustrated in figure 2 (A and B), revealed coarse vacuolation with excess lipid within the muscle fibres. The acylcarnitine profile showed increases in butyryl-acylcarnitine, isovaleryl-acylcarnitine, hexanoyl-acylcarnitine, octanoyl-acylcarnitine and decanoyl-acylcarnitine species (C4-10).

Figure 2.

(A) A muscle biopsy taken from the deltoid. H and E ×200 showing coarse vacuolation of muscle fibres. (B) Oil red stain confirming the significant excess of lipid deposition within fibres.

Differential diagnosis

While there is a wide differential for a gradually progressive peripheral neuropathy centred on large-fibre sensory nerves, the shorter history of progressive exercise intolerance, with proximal weakness on examination, indicates disorders of the neuromuscular junction or muscle. Given the lack of ocular involvement or demonstrable fatigability at examination, a myopathy seemed the most likely. The combination of neuropathy and myopathy, with an acute metabolic crisis, biased our differential to mitochondrial and metabolic deficits. The wider differential diagnosis included drug-induced, inflammatory and infectious myopathies. Additionally, given the prolonged statin use, a necrotising autoimmune myositis featured high on our initial differential diagnosis.

The results of the investigations performed as the patient deteriorated on admission were strongly suggestive of glycogen storage or fatty acid oxidation disorders (or potentially mitochondrial disease or a urea cycle disorder).² Fatty acid oxidation disorders became our top differential when the patient’s history was considered: there were no suggestive clues to a glycogen storage disorder or to multisystem involvement, such as in mitochondrial illness.

The biopsy results narrowed our differential still further; evidence of lipid storage myopathy meant that at the top of the histological differential were primary carnitine deficiency, MADD and neutral lipid storage disease. However, it was the acyl-carnitine profile that clarified the final diagnosis of MADD (glutaric aciduria type 2).

Treatment

On admission to intensive care following her deterioration in hospital, the patient’s statin was discontinued and she was commenced on sodium benzoate 250 mg/kg and L-carnitine 50 mg/kg six hourly, in line with our clinical suspicion of fatty acid oxidation disorder and while further investigations were arranged.

After the muscle biopsy and acyl-carnitine profile confirmed the diagnosis of MADD, our patient was placed on 400 mg riboflavin supplementation once daily – the precursor to flavin adenine dinucleotide which enhances function of the mutant ETF in MADD¹, and to which, the majority of MADD patients are sensitive.³ We also collaborated with the regional centre for metabolic medicine, who recommended she be placed on L-carnitine 3 g two times per day, and co-enzyme Q10 be added at 200 mg daily. Meanwhile, dieticians recommended a nasogastric regimen consisting of medium-chain triglyceride-free feed and a subsequent life-long low-fat, high-carbohydrate diet.

Outcome and follow-up

The patient’s lab results after starting treatment showed normalisation of ammonia levels within 4 days, CK within 1 week and ALT within 3 weeks, indicating biochemical improvement on treatment. The patient was extubated and rehabilitated over a couple of months and has returned to independent living. She has normal power in her limbs and continues riboflavin supplementation, the modified diet and avoidance of fasting. Unfortunately, her sensory symptoms attributed to peripheral neuropathy have persisted.

Discussion

Our patient was diagnosed with type 3 (late onset) MADD. The vast majority of patients in this group present with chronic myopathic symptoms, such as weakness and exercise intolerance. Less commonly, acute metabolic decompensation can occur, characterised by acidosis, hypoketotic hypoglycaemia and rhabdomyolysis, often in the context of a recent illness or period of fasting.⁴

This case is especially interesting because it first presented with a sensory neuropathy, which has previously been reported to occur in people with MADD, although it is unusual.⁵ A recent retrospective study of 10 unrelated patients with adult-onset MADD (all identified by serum acylcarnitine profile) reported sensory neuropathy in only two patients, and even in these patients, the complaint at onset was of myalgia rather than sensory neuropathy.⁶ While all patients in this study improved after riboflavin administration, the sensory neuropathy experienced by these two patients persisted.

The diagnosis in this case was made on acylcarnitine profiling and organic acid analysis which, alongside skin biopsies for fatty acid flux studies, are the specialist investigations of choice to confirm the metabolic deficit.² While muscle MRI was not performed in this case, it can be used as a helpful adjunct to assess the pattern of muscle involvement and to better select a target for muscle biopsy.⁷ On next-generation sequencing using the illumine TruSight One sequencing panel of the EFTA, ETFB and EFTDH genes, we only identified one heterozygous pathogenic ETFDH allele, but the patient’s clinical, biochemical and histological findings were all consistent with MADD. Furthermore, reports indicate that patients can harbour undetectable pathogenic mutations in this gene,^{1 3} meaning that MADD can be diagnosed without a homozygous deficit if the clinical picture and investigations fit sufficiently well.

There are no consensus guidelines in the management and treatment of MADD, in part due to the heterogeneity of presentation, so routine daily treatment is highly variable based on the manifestations experienced by the individual,⁸ and current treatment recommendations are primarily based on expert opinion. Riboflavin supplementation and dietary modifications (to high-carbohydrate low-fat diets) are generally used first-line to address the metabolic disturbance in fatty acid metabolism (figure 3). In addition, patients are advised to avoid fasting, and L-carnitine 50–100 mg/kg/day in three divided doses can be used to address carnitine deficiency.⁸

Figure 3.

Simplified representation of fatty acid metabolism showing the metabolic disturbance in our patient. Failure of ETF or ETFDH to pass electrons generated during fatty acid β-oxidation to the mitochondrial electron transport chain results in accumulation of upstream acylcarnitine C4-C10 species, sometimes a secondary reduction in carnitine and a build-up of organic acids (from other convergent pathways). Impaired β-oxidation limits ketogenesis so fasting or prolonged vomiting results in metabolic decompensation. Supplementation with riboflavin increases the FAD pool to support residual ETF/ETFDH function; coQ10 (a coenzyme required for the electron recipient complex III) has a similar role. Avoidance of fasting and a low-fat high-carbohydrate diet help bypass the metabolic defect to avoid acute decompensation. Figure created by ZG. CPTI, carnitine palmitoyl transferase I; CPTII, carnitine palmitoyl transferase II; CACT, carnitine acylcarnitine translocase; co-Q10, coenzyme Q10 (ubiquinone); FAD, flavin adenine dinucleotide; FADH, reduced FAD; ETF, electron transfer flavoprotein; ETFA and ETFB, electron transfer flavoprotein subunits A and B; ETFDH, electron transfer flavoprotein dehydrogenase; e, transfer of electrons; III, complex III of the electron transport chain.

While the early-onset forms of MADD carry a high mortality, the prognosis of late-onset MADD is good if diagnosed promptly. The 5% of patients who die from MADD typically do so during metabolic crises and so early diagnosis and treatment reduce the chance of this occurring.¹ While, in our case, the unusual initial presentation with sensory neuropathy before the myopathy made early diagnosis more difficult, the patient was young to have acquired neuropathy, so we suggest that early-onset neuropathy with myopathic symptoms should result in MADD as a differential.

Learning points.

• Multiple acyl-coenzyme A dehydrogenase deficiency is a rare but treatable metabolic disorder that should form part of a differential diagnosis for patients with myopathy alongside neuropathy.

• If left untreated, it may lead to severe metabolic derangements that can be life-threatening.

• Early identification with muscle biopsy and serum acyl-carnitine profile increases the chance of a good recovery, although sensory neuropathy is largely irreversible by current treatment options.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).