Dear Editor,
Inflammatory myositis (IMM) is an autoimmune disease that predomintanely involves
proximal limb muscles. Several conditions could “mimic” the clinical pictures of IMM
presenting with myalgia, increase of serum muscle enzymes. In this letter,we share
a rare case that mimic IMM: Late-onset glutaric acidaemia type II.
A 21-year-old woman visited the emergency department because of muscle weakness and
hypoglycaemic coma. She had a 1-year history of exercise intolerance, myalgia and
muscle weakness. Her body weight decreased from 65 to 40 kg. Physical examination
at admission revealed neck and proximal limb muscle weakness (manual muscle testing
8 [MMT8] score, 26 points) accompanied by severe muscle atrophy. Her serum creatine
kinase (CK) and lactate dehydrogenase (LDH) levels were 15514 U/L (reference interval
[RI]: 40–200 U/L) and 1438 U/L (RI: 120–250 U/L), respectively, and serum myoglobin
(Mb) level was 758.5 ng/mL. Abdominal ultrasonography showed severe hepatic steatosis
and electromyography revealed features of myopathy. Magnetic resonance imaging (MRI)
of her thigh muscles was normal. The patient was diagnosed with idiopathic inflammatory
myositis (IIM), and she was treated with 60 mg/day methylprednisolone (MP) and coenzyme
Q10 (10 mg, 3 times/day).
Her myalgia and muscle weakness began to improve, and her serum CK level retured to
normal range. However, her dysphagia and shortness of breath remained unimproved.
Her blood gas test showed higher than normal carbon dioxide partial pressure. Biopsy
of the vastus lateralis muscle revealed vacuolar-degenerated myofibres and excess
lipid storage (Figure 1A-C). Urine organic acids pyruvate and 3-hydroxybutyrate were
detected by Gas chromatographymass spectrometry (GC/MS) which indicated the presence
of acetonuria. Inherited metabolic disease tandem mass spectrometry detection was
performed and revealed reductions in free carnitine and various acylcarnitines.
Figure 1
Pathological findings from left quadriceps muscle biopsy in this patient. (A) Varying
sizes lipid vacuoles within muscle fibres (HE staining, × 400). (B) Lipid particle
deposition within muscle fibres (ORO staining, × 400). (C) Electron microscopy showing
lipid droplet deposition within muscle fibres.
Gene analysis was performed thereafter. Homozygous c.250G>A (chr4.159603421) mutation
in ETFDH (Figure 2A) was identified. Her parents were both heterozygous for c.250G>A
mutation (Figure 2B, C). Thus, the diagnosis of late-onset glutaric acidaemia type
II (GAII) was confirmed. Her clinical and biochemical conditions was significantly
improved after administration of riboflavin (20 mg three times daily) and L-carnitine
(10 mL three times daily).
Figure 2
Sequencing of the electron transfer flavoprotein dehydrogenase gene of the patient
(A), her father (B), and her mother (C), showed the same missense mutation of c.250G>A
(p.Ala84Thr ) in chr4-159603421. The mutation was homozygous, while in her parents
it was heterozygous.
GAII is an autosomal recessive disorder caused by mutations in genes encoding electron
transfer flavoprotein A, B (ETFA, ETFB) or electron transfer flavoprotein dehydrogenase
(ETFDH), also known as multiple acyl-coenzyme A dehydrogenase deficiency (MADD), A
wide spectrum of different ETFDH mutations has been reported worldwide, of which c.250G
> A (p.Ala84Thr) is the most common, being found predominantly in southern China,
while c.770A > G (p.Try257Cys) and c.1227A > C (p.Leu409Phe) are more common in northern
China. ETFDH mutations often present as late-onset forms. The classical clinical manifestations
of late-onset GAII include recurrent or progressive proximal muscle weakness and myalgia
accomapined with recurrent episodes of hypoglycaemia with hypoketosis, gastrointestinal
dysfunction and hepatic dysfunction. Cold, infection, and nutrient deprivation that
increase metabolic stress can exacerbate muscle weakness and rhabdomyolysis.[1,2]
However, the symptoms of late-onset GAII are usually atypical, this makes the differential
diagnosis difficult. The important hint to differentiate late onset GAII from IMM
is that the myositis specific autoantibodies were generally negative in the former
condition.[3]
The diagnosis of GAII could be made based on the presence of urinary organic acid
profiles which is characterized by elevated amounts of glutaric acid, ethylmalonic
acid, isovaleric acid, a-methylbutyrate, isobutyrate, aliphatic dicarboxylic acids,
and their derivatives, acylcarnitine profiling by tandem mass spectrometry screening
of serum or dried blood spot samples characteristically shows increased concentrations
of short-, medium-, and long-chain acylcarnitines (C4-C12).[4]
In this case, anuria showed by urine analysis and reduced serum acylcarnitine levels
were incompatible with the GAII, however, these presentations were consistent with
primary systemic carnitine deficiency (CDSP). This may due to fasting before sample
collection, malnutrition and residual enzyme activity in the body.[5] Therefore, although
acylcarnitine spectrum and gas chromatography-mass spectrometry analysis of organic
acids can provide clues for genetic metabolic diseases, the sensitivity and specificity
for the diagnosis is low.
Patients with late-onset GAII usually respond to riboflavin, with a response rate
as high as 98.4%.[6] However, the dose and course of treatment are controversial,
and no systematic evaluation has yet been reported. High-dose and long-term riboflavin
treatment is commonly recommended.[7] Furthermore, carnitine supplementation has also
been suggested in view of the low carnitine levels in these patients.[8] Glucocorticoids
can promote treatment effects to a certain extent in some patients with GAII, but
cannot achieve the same efficacy as that of riboflavin.[9]
In conclusion, the clinical manifestations of late-onset GAII are generally non-specific
and are easily being misdiagnosed especially in the early stage. GAII should be suspected
in cases of rapid progression of myopathy, especially in patients with metabolic abnormalities,
such as liver damage, hyperammonaemia, and hypoglycaemia. Blood amino acid and acylcarnitine
profile analysis, urine organic acid analysis, muscle biopsy, and genetic test should
be performed to ensure early diagnosis. Riboflavin supplementation is the first line
medication.