A 5 ½ year old girl had undergone evaluation for hypotonia, cognitive and motor handicap and subependymal nodular heterotopia. She had a muscle biopsy performed on July 19, 2005. Muscle histology and histochemistry were unremarkable. She had oxidative metabolism enzymology performed through Horizon Medical Medicine (now Medical Neurogenetics). There was a mild decrease in Complex IV (cytochrome C oxidase) activity. Dr. John Shoffner’s note indicated, “However, before making a diagnosis of Complex IV (cytochrome C oxidase) deficiency, I would want to see cytochrome C oxidase deficient muscle fibers on histochemistry. If the histochemistry is normal, this result is probably related to freezing of the muscle sample. The report from the muscle biopsy reads ‘cytochrome C oxidase activities are maintained.’” I was in contact with Dr. Shoffner who suggested that she have further studies, likely including a repeat muscle biopsy, done through Medical Neurogenetics in order to reassess this issue. She was then seen by Dr. John Shoffner on March 18, 2009.
Comparative genomic hybridization had shown loss of material involving 5q14.3 to 5q15. This result was deemed to be of uncertain significance. It was deemed possible that this represented a benign inherited copy number variant. The report of the comparative genomic hybridization indicated, “No genes of known clinical significance have been mapped to this region.” The mother had comparative genomic hybridization showing no abnormality. It was not possible to obtain comparative genomic hybridization from the father.
In the March 3, 2009, issue of Neurology, an article appeared reporting periventricular heterotopias, mental retardation, and epilepsy associated with 5q14.3-q15 deletion. (Cardoso C, Boys A, Parrini E, Mignon-Ravix C, McMahon JM, Khantane S, Bertini E, Pallesi E, Missirian C, Zuffardi O, Novara F, Villard L, Giglio S, Chabrol B, Slater HR, Moncla A, Scheffer IE, Guerrini R. Periventricular heterotopia, mentalretardation, and epilepsy associated with 5q14.3-q15 deletion. Neurology. 2009 Mar 3;72(9):784-92.) Accordingly, Dr. John Shoffner then gave a diagnosis of the now recognized syndrome associated with the 5q14.3-q15 deletion. Further studies were unnecessary.
Postscript: Later the patient developed problems with foot pain. An MRI of the spine showed approximately 1 cm Tarlov cysts dorsal to the S2 vertebral body, one on the left and two on the right. These were new since the earlier spine MRI of July 19, 2005. She underwent S2-S3 osteoplastic laminotomies for repair of the bilateral Tarlov cysts of exiting S2 and S3 nerve roots. The “crinkly” foot pain remitted, at least for an extended interval of time. However, her life was rendered miserable by iatrogenic urinary incontinence.
A 20 yo man presented for re-evaluation of an undefined spinocerebellar ataxia. I had previously evaluated him as an adolescent. A cranial MRI showed findings of spinocerebellar atrophy. A vitamin E level was low and vitamin E supplementation was initiated, with poor cooperation. Molecular genetic testing for hereditary ataxias was undertaken with no significant abnormality reported by the laboratory performing the study.
ReplyDeleteWhen the patient was reassessed at 20 years of age, the laboratory data was reviewed. A loose quotation from the note from that evaluation follows: "Additional review of his prior workup including genetic testing identified a mutation at KCNC3. It is on chromosome 19q13.3-q13.4. This was reported erroneously as unknown variant. Upon review of literature with the help of our genetic counselor, this was reported previously as a causative mutation and is found in individuals whose classification falls under spinocerebellar ataxia 13."
So close, but so far away.