OBJECTIVES: Homozygous mutations in the HAX1 gene were recently identified in severe congenital neutropenia patients belonging to the original Kostmann family in northern Sweden. Our observations suggested that these patients also develop neurological and neuropsychological symptoms. METHODS: Detailed clinical studies and mutation analyses were performed in the surviving patients belonging to the Kostmann kindred and in two patients not related to this family, along with studies of HAX1 splice variant expression in normal human tissues. RESULTS: Five of six Kostmann family patients and one other patient from northern Sweden harboured homozygous HAX1 mutations (568C-->T, Q190X) and one carried a heterozygous ELA2 gene mutation. One Swedish patient of Kurdish extraction carried alternative homozygous HAX1 mutations (131G-->A, W44X). All the three patients with Q190X mutations who were alive and available for evaluation developed neurological disease with decreased cognitive function, and three of four patients who reached 10 years developed epilepsy. In contrast, the patients with the ELA2 and W44X HAX1 mutations, respectively, showed no obvious neurological abnormalities. Moreover, two alternative HAX1 splice variants were identified in normal human tissues, including the brain. Both transcripts contained exon 5, harbouring the Q190X mutation, whereas the 5' end of exon 2 containing the W44X mutation was spliced out from the second transcript. CONCLUSIONS: We describe neurological and neuropsychological abnormalities for the first time in Kostmann disease patients. These central nervous system symptoms appear to be associated with specific HAX1 mutations.
OBJECTIVES: Homozygous mutations in the HAX1 gene were recently identified in severe congenital neutropeniapatients belonging to the original Kostmann family in northern Sweden. Our observations suggested that these patients also develop neurological and neuropsychological symptoms. METHODS: Detailed clinical studies and mutation analyses were performed in the surviving patients belonging to the Kostmann kindred and in two patients not related to this family, along with studies of HAX1 splice variant expression in normal human tissues. RESULTS: Five of six Kostmann family patients and one other patient from northern Sweden harboured homozygous HAX1 mutations (568C-->T, Q190X) and one carried a heterozygous ELA2 gene mutation. One Swedish patient of Kurdish extraction carried alternative homozygous HAX1 mutations (131G-->A, W44X). All the three patients with Q190X mutations who were alive and available for evaluation developed neurological disease with decreased cognitive function, and three of four patients who reached 10 years developed epilepsy. In contrast, the patients with the ELA2 and W44XHAX1 mutations, respectively, showed no obvious neurological abnormalities. Moreover, two alternative HAX1 splice variants were identified in normal human tissues, including the brain. Both transcripts contained exon 5, harbouring the Q190X mutation, whereas the 5' end of exon 2 containing the W44X mutation was spliced out from the second transcript. CONCLUSIONS: We describe neurological and neuropsychological abnormalities for the first time in Kostmann diseasepatients. These central nervous system symptoms appear to be associated with specific HAX1 mutations.
Authors: Muhammad Faiyaz-Ul-Haque; Abdullah Al-Jefri; Fouad Al-Dayel; Jalaluddin A K M Bhuiyan; Hala A Abalkhail; Randa Al-Nounou; Ahmed Al-Abdullatif; Monogaran S Pulicat; Ameera Gaafar; Ayodele A Alaiya; Iskra Peltekova; Syed H E Zaidi Journal: Eur J Pediatr Date: 2010-02-25 Impact factor: 3.183
Authors: Jun Xia; Audrey A Bolyard; Elin Rodger; Steve Stein; Andrew A Aprikyan; David C Dale; Daniel C Link Journal: Br J Haematol Date: 2009-09-22 Impact factor: 6.998
Authors: Alicja Trebinska; Alina Rembiszewska; Karolina Ciosek; Konrad Ptaszynski; Sebastian Rowinski; Jolanta Kupryjanczyk; Janusz A Siedlecki; Ewa A Grzybowska Journal: BMC Cancer Date: 2010-03-02 Impact factor: 4.430