Novel KRIT1 mutation and no molecular evidence of anticipation in a family with cerebral and spinal cavernous malformations.

TY - JOUR

T1 - Novel KRIT1 mutation and no molecular evidence of anticipation in a family with cerebral and spinal cavernous malformations.

AU - Kuhn, Jens

AU - Brümmendorf, Tim

AU - Brassat, Ute

AU - Lehnhardt, Fritz G

AU - Chung, Boi-Dinh

AU - Harnier, Simon

AU - Bewermeyer, Heiko

AU - Harzheim, Andreas

AU - Assheuer, Josef

AU - Netzer, Christian

PY - 2009

Y1 - 2009

N2 - BACKGROUND: Cerebral cavernous malformations (CCM) are vascular brain anomalies which can result in a variety of neurological symptoms. Familial CCM is inherited as an autosomal-dominant trait. There is one study in the literature which reports statistical evidence for anticipation in familial CCM. METHODS: We reevaluated the clinical course of the disease and performed molecular analyses in a previously described three-generation CCM family with apparent anticipation. RESULTS: Disease started at a younger age in each generation, strongly suggesting anticipation. The patient in generation I showed no clinical symptoms by the age of 68, whereas his son became wheelchair-bound at the age of 43 due to an intramedullary cavernous malformation at the thoracolumbar transition of the spinal cord. The patient in generation III had a pons hemorrhage at the age of 11 due to a large brainstem cavernoma. The hemorrhage caused facial palsy and hemiparesis, persisting as Millard-Gubler syndrome. Sequencing of KRIT1 identified a novel frameshift mutation in exon 15 (c.1561delC or p.Leu551X) which cosegregated with the phenotype. Flow-FISH analysis of granulocyte and lymphocyte telomere length showed that telomeres were longest in the youngest affected family member. CONCLUSIONS: We could not find any evidence for either of the two currently known molecular mechanisms for genetic anticipation (i.e., expansion of repetitive DNA elements or progressive telomere shortening) in this family. However, the family presented here raises the important question whether surveillance of CCM families with gradient-echo MRI should not only include the cerebrum, but the spinal cord as well.

AB - BACKGROUND: Cerebral cavernous malformations (CCM) are vascular brain anomalies which can result in a variety of neurological symptoms. Familial CCM is inherited as an autosomal-dominant trait. There is one study in the literature which reports statistical evidence for anticipation in familial CCM. METHODS: We reevaluated the clinical course of the disease and performed molecular analyses in a previously described three-generation CCM family with apparent anticipation. RESULTS: Disease started at a younger age in each generation, strongly suggesting anticipation. The patient in generation I showed no clinical symptoms by the age of 68, whereas his son became wheelchair-bound at the age of 43 due to an intramedullary cavernous malformation at the thoracolumbar transition of the spinal cord. The patient in generation III had a pons hemorrhage at the age of 11 due to a large brainstem cavernoma. The hemorrhage caused facial palsy and hemiparesis, persisting as Millard-Gubler syndrome. Sequencing of KRIT1 identified a novel frameshift mutation in exon 15 (c.1561delC or p.Leu551X) which cosegregated with the phenotype. Flow-FISH analysis of granulocyte and lymphocyte telomere length showed that telomeres were longest in the youngest affected family member. CONCLUSIONS: We could not find any evidence for either of the two currently known molecular mechanisms for genetic anticipation (i.e., expansion of repetitive DNA elements or progressive telomere shortening) in this family. However, the family presented here raises the important question whether surveillance of CCM families with gradient-echo MRI should not only include the cerebrum, but the spinal cord as well.

M3 - SCORING: Zeitschriftenaufsatz

VL - 61

SP - 154

EP - 158

JO - EUR NEUROL

JF - EUR NEUROL

SN - 0014-3022

IS - 3

M1 - 3

ER -