A rhabdomyolysis tale

On 11/1/11, I posted "my personal best".

CK 1,142,740. 10 yo boy with history of chronic mild fatigue and exercise intolerance with accelerating difficulties this past summer.

Eventually became quite weak and fatigued. Found to have rhabdomyolysis.

Treated with hemodialysis. Additional lab results from presentation:

Lactate 19 mmol/L. Plasma AA nl. Acylcarnitines increased C5OH (plasma and urine). Carnitine total 69, esterified 58, free 11. Acylglycines nl.

Generalized aminoaciduria. Urine organic acids reflective of lactic acidosis and ketosis, also increased p-OHphenyllactic. CRP, ESR and uric acid increased. Convalescent CK 185. Persisting lactate elevation (-3).Etiology being pursued, but undetermined at the present time.

11/21/11  Interim report: Muscle biopsy shows evidence for chronic myopathy, fiber type II atrophy, and mitochondriopathy. There is fiber size variation, muscle atrophy, limited necrosis, inward migration of muscle nuclei, and fibrosis. EM shows increased non-membrane bound glycogen, abnormal mitochondria, and fibrosis.

11/21/11 A correspondent wrote:  A conceivable but unlikely aetiology [I love this spelling, also haemolysis below,  probably says "enkephalopathy also"]  is phosphoglycerate kinase deficiency (x linked). Some families have been described lacking the other usual manifestations ( encephalopathies, chronic /acute haemolysis). I presume family history is negative?

11/20/13  Succinate cytochrome reductase activity was 38% of the normal mean. "The tissue was fatty with connective tissue present and most assays had to be repeated. It is relatively common for this particular enzyme to be reduced in such circumstances likely due to its lability." The patient was identified as a heterozygous carrier for p.Asp118Gly (c.353A>G) in exon 4 of the CPT2 gene. Otherwise, a variety of molecular genetic testing, including whole exome sequencing, has been negative. There has been doubt expressed that the mutation identified is sufficent to explain the patient's presentation. In September of this year, there was another episode of rhabdomyolysis with CK >50,000.

11/21/13 No family history. My metabolism colleague writes: Ambry indicated PGK was on the tier one list of genes, had good coverage by Next Gene and can be excluded as no mutations were identified. It is a good thought and I was amazed that it is not on the Baylor Rhabdomyolysis Panel.
 

11/22/13 Another correspondent wrote:  Dr. Breningstall's patient is very likely to have CPT2 deficiency. I am curious as to whether enzyme testing was done in tissue since genetic testing could not confirm 2 mutations. There are heterozygous carriers with reduced enzyme activity that can become symptomatic; alternatively, the second mutation was not covered well on exome or is intronic.
 

11/22/13 Further information regarding CPT2 in this patient:

"All we seem to have so far in this case is a single class 5 pathogenic mutation in CPT2 corroborated by 2 labs. It is very unlikely that the presence of a single pathogenic mutation for a recessive disorder is adequate to cause severe rhabdomyolysis. CPT activity in muscle was 89% of the normal mean and should have been in the 40-60% range for a carrier. If mitochondria! content is elevated, this could account for the apparent increased activity. That is why we always normalize CPT data in a ratio relationship with citrate synthase. In this case, the ratio was normal. As for condition, the tissue was labeled as 'fatty'. That could have all sorts of implications on specific activity which we measure as 'per gram of tissue'. It could be that the finding of a mutation in CPT2 was just happenstance distracting us from the true cause."
 

This brings us to the present when whole exome sequencing has been done.  The patient was identified as having a mutation in the FDX1L gene, c.3G>T (p.M1?) {as of 11/15, altered to c.12G>T (p.M.41)},which is homozygous.
 

Spiegel R, Saada A, Halvardson J, Soiferman D, Shaag A, Edvardson S, Horovitz
Y, Khayat M, Shalev SA, Feuk L, Elpeleg O. Deleterious mutation in FDX1L gene is
associated with a novel mitochondrial muscle myopathy. Eur J Hum Genet. 2014
Jul;22(7):902-6.

Abstract

Isolated metabolic myopathies encompass a heterogeneous group of disorders, with mitochondrial myopathies being a subgroup, with depleted skeletal muscle energy production manifesting either by recurrent episodes of myoglobinuria or progressive muscle weakness. In this study, we investigated the genetic cause of a patient from a consanguineous family who presented with adolescent onset autosomal recessive mitochondrial myopathy. Analysis of enzyme activities of the five respiratory chain complexes in our patients' skeletal muscle showed severely impaired activities of iron sulfur (Fe-S)-dependent complexes I, II and III and mitochondrial aconitase. We employed exome sequencing combined with homozygosity mapping to identify a homozygous mutation, c.1A>T, in the FDX1L gene, which encodes the mitochondrial ferredoxin 2 (Fdx2) protein. The mutation disrupts the ATG initiation translation site resulting in severe reduction of Fdx2 content in the patient muscle and fibroblasts mitochondria. Fdx2 is the second component of the Fe-S cluster biogenesis machinery, the first being IscU that is associated with isolated mitochondrial myopathy. We suggest adding genetic analysis of FDX1L in cases of mitochondrial myopathy especially when associated with reduced activity of the respiratory chain complexes I, II and III.

A colleague's effors in this investigation are appreciated.