First discription of a Kearns-Sayre-like-syndrome with ragged red fibres and cerebral folate deficiency

Aims: The female is the first child of healthy, non-consanguineous German parents. From the age of two years failure to thrive and a pre-disposition for infections was observed. At the age of six years sensorineural hearing loss and hypoparathyreoidis occurred. The patient was referred to us at the age of 7.4 years for psychosomatic therapy, having been diagnosed with interaction problems within the family, refusal to eat and vomiting. Upon admission significant dystrophy was noted. Elektrolyte imbalance, hypoglycemia and lactic acidemia occured upon nasogastral tube feeding with a high-caloric diet. Neurological examination revealed a myopathic facies, mild ptosis, external ophtalmoplegia, generalized muscular hypotonia, ataxia, dysmetria and intermittent tremor. ECG and echocardiography were unremarkable.

Methods: Cerebral MRI showed hyperintensities in bilateral basal ganglia and white matter alterations (Leigh syndrome) with global atrophy, spectroscopy revealed lactate peaks. CSF analysis showed elevated lactate (30mg/dl), protein (298mg/dl) and low folate (5-MTHF 6 nmol/l, n:42–98nmol/l), with normal levels of serum folate. Fundoscopy showed pigmentary retinopathy. We also found renal tubular dysfunction.

Results: The muscle biopsy revealed cox-negative ragged red fibres. Evaluation of the oxidative phosphorylation showed a severe mitochondrial dysfunction with an ATP-production of 6.7 (n: 15.4–30.2) nmolCOS/h.mUCS, with diminished substrate oxidation rates and deficiency of the respiratory chain complexes I, III, II+III, and IV. Sequencing of the entire mitochondrial mtDNA did not reveal any mutations nor deletions. 250kbSNP array revealed a 300kb gain at 1q43.

Conclusion: The case shows phenotypical overlap with Kearns-Sayre-syndrome. An mitochondrial DNA alteration was ruled out. To further evaluate the possibility of a mitochondrial DNA depletion syndrome exome-sequencing is planned. A folate transport problem at the blood-brain-barrier is probably underlying the cerebral folate deficiency. In literature cases with positive response to folate substitution are described.

mitochondrial encepahlomyopathy - cerebral folate deficiency