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.
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.
No comments:
Post a Comment