Introducción a la Medicina Genómica

Curso on-line: Introducción a la Medicina Genómica

Módulo 5

Farmacogenética



Caso clínico:

Paciente de 39 años, sexo femenino, fumadora, toma anticonceptivos orales, sin otros antecedentes a destacar. Hace 2 meses episodio de trombosis venosa profunda (TVP) a nivel poplíteo de MID. Anticoagulada primero con heparina y concomitantemente con warfarina a dosis standard de 5 mg/d. Alta domicilio a los 3 días de recibir warfarina. INR al alta: 2.7. A los 7 días de comenzar la warfarina instala hematuria abundante, epístasis y equímosis difusas en zonas de traumatismos mínimos. No requirió transfusión. INR de 9.3. Se suspende warfarina y no hay otras complicaciones hemorrágicas. INR a los 3 días de suspendida la warfarina: 5. A los 5 días de suspendida: 2.7. A los 7 días: 1.34.

De la historia familiar se destaca: madre y hermana que sufrieron TVP a los 50 y 34 años respectivamente. La hermana fue tratada con warfarina, con la cual tuvo una anticoagulación dificultosa, con varios episodios de INR por encima del rango deseado y sangrados menores, pero que no requirieron suspender el tratamiento, que se prolongó por 6 meses. También tuvo eventos adversos durante el tratamiento con Fenitoína por su epilepsia.

Diagnóstico molecular: CYP2C9 *2/*3
Perfil genómico: MTHFR T/T. FV Leiden: N/M, FII: N/N.

Preguntas:

1. ¿El genotipo de la paciente es compatible con la historia referida? ¿Cuál es el efecto de estas dos variantes alélicas sobre la función proteica y sobre los fenotipos farmacocinéticos y clínicos?
2. ¿Estudiaría otros miembros de la familia con este diagnóstico genómico?
3. ¿El evento adverso con Fenitoína puede estar relacionado con el evento adverso frente al tratamiento con warfarina?
4. ¿Se pueden estudiar otros genes además de CYP2C9 para explicar este caso?
5. Comente la observación de la recurrencia familiar de TVP en este caso.
6. Interpretación de los resultados del perfil genómico. Recomendaciones de prevención y tratamiento. Recomendaciones de otros estudios.


Bibliografía:

Sanderson S, Emery J, Higgins J, CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: A HuGEnet™ systematic review and meta-analysis, Genet Med 2005:7(2):97–104.
SELIGSOHN U, LUBETSKY A,, GENETIC SUSCEPTIBILITY TO VENOUS THROMBOSIS, N Engl J Med 2001; 344(16): 1222-1231.


Artículo para analizar:

Berkovic SF, Harkin L, McMahon JM, Pelekanos JT, Zuberi SM, Wirrell EC, Gill DS, Iona X, Mulley JC, Scheffer IE, De-novo mutations of the sodium channel gene SCN1A in alleged vaccine encephalopathy: a retrospective study, Lancet Neurol. 2006; 5(6): 488-92.

BACKGROUND: Vaccination, particularly for pertussis, has been implicated as a direct cause of an encephalopathy with refractory seizures and intellectual impairment. We postulated that cases of so-called vaccine encephalopathy could have mutations in the neuronal sodium channel alpha1 subunit gene (SCN1A) because of a clinical resemblance to severe myoclonic epilepsy of infancy (SMEI) for which such mutations have been identified. METHODS: We retrospectively studied 14 patients with alleged vaccine encephalopathy in whom the first seizure occurred within 72 h of vaccination. We reviewed the relation to vaccination from source records and assessed the specific epilepsy phenotype. Mutations in SCN1A were identified by PCR amplification and denaturing high performance liquid chromatography analysis, with subsequent sequencing. Parental DNA was examined to ascertain the origin of the mutation. FINDINGS: SCN1A mutations were identified in 11 of 14 patients with alleged vaccine encephalopathy; a diagnosis of a specific epilepsy syndrome was made in all 14 cases. Five mutations predicted truncation of the protein and six were missense in conserved regions of the molecule. In all nine cases where parental DNA was available the mutations arose de novo. Clinical-molecular correlation showed mutations in eight of eight cases with phenotypes of SMEI, in three of four cases with borderline SMEI, but not in two cases with Lennox-Gastaut syndrome. INTERPRETATION: Cases of alleged vaccine encephalopathy could in fact be a genetically determined epileptic encephalopathy that arose de novo. These findings have important clinical implications for diagnosis and management of encephalopathy and, if confirmed in other cohorts, major societal implications for the general acceptance of vaccination.

Demystifying vaccination-associated encephalopathy, The Lancet Neurology, Volume 5, Issue 6, June 2006, Pages 465-466 Erick Sell and Berge A Minassian,

Background
Vaccination, particularly for pertussis, has been implicated as a direct cause of an encephalopathy with refractory seizures and intellectual impairment. We postulated that cases of so-called vaccine encephalopathy could have mutations in the neuronal sodium channel α1 subunit gene (SCN1A) because of a clinical resemblance to severe myoclonic epilepsy of infancy (SMEI) for which such mutations have been identified.

Methods
We retrospectively studied 14 patients with alleged vaccine encephalopathy in whom the first seizure occurred within 72 h of vaccination. We reviewed the relation to vaccination from source records and assessed the specific epilepsy phenotype. Mutations in SCN1A were identified by PCR amplification and denaturing high performance liquid chromatography analysis, with subsequent sequencing. Parental DNA was examined to ascertain the origin of the mutation.

Findings
SCN1A mutations were identified in 11 of 14 patients with alleged vaccine encephalopathy; a diagnosis of a specific epilepsy syndrome was made in all 14 cases. Five mutations predicted truncation of the protein and six were missense in conserved regions of the molecule. In all nine cases where parental DNA was available the mutations arose de novo. Clinical-molecular correlation showed mutations in eight of eight cases with phenotypes of SMEI, in three of four cases with borderline SMEI, but not in two cases with Lennox-Gastaut syndrome.

Interpretation
Cases of alleged vaccine encephalopathy could in fact be a genetically determined epileptic encephalopathy that arose de novo. These findings have important clinical implications for diagnosis and management of encephalopathy and, if confirmed in other cohorts, major societal implications for the general acceptance of vaccination.


Links:

PharmGKB
http://www.pharmgkb.org/

CYP2C9 Gene Variants and Clinical Outcomes of Warfarin-Treated Patients
http://www.cdc.gov/genomics/hugenet/reviews_arch.htm