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Janet Hoenicka, PhD; Lídice Vidal, BS; Blas Morales, MD, PhD; Israel Ampuero, BS; F. Javier Jiménez-Jiménez, MD, PhD; Jose Berciano, MD, PhD; Teodoro del Ser, MD, PhD; Adriano Jiménez, MD, PhD; Pedro G. Ruíz, MD, PhD; Justo G. de Yébenes, MD, PhD

Arch Neurol. 2002;59:966-970.

Background  Several genetic errors in -synuclein (Park1) and ubiquitin carboxyl-terminal–hydrolase L1(Park5) genes cause autosomal dominant familial Parkinson disease. Mutations in the parkin gene (Park2) are the major cause of autosomal recessive Parkinson disease.

Objective  To analyze the clinical and molecular data of 19 Spanish kindreds (13 with recessive, 4 with dominant, and 2 with uncertain inheritance) who have familial Parkinson disease.

Methods  We searched for the previously described mutations in Park1 and Park5 genes and for new or described mutations in Park2. We used single-strand conformation polymorphism, direct sequencing, and restriction digestion of polymerase chain reaction (PCR)–amplified genomic DNA for this study.

Results  None of these families have either Park1 or Park5 mutations. We found 5 different mutations in Park2 gene in 5 of the families with recessive inheritance. To our knowledge, 2 of these mutations, V56E and C212Y, have not been previously reported. The other mutations found (deletion of exons 3 and 5 and 225delA) have been described in other ethnic groups. Heterozygous carriers of a single Park2 mutation either were asymptomatic or developed clinical symptoms in late adulthood or after brief exposure to haloperidol therapy.

Conclusions  Mutations in Park2 gene account for 38% of the families with recessive parkinsonism in Spain. We found 2 cases of simple heterozygous Park2 mutation carriers that developed clinical symptoms, either in late adulthood or after brief exposure to parkinsonizing agents. Thus, hereditary Parkinson disease has more variable clinical phenotype and molecular defects than previously thought since heterozygous mutations could be a risk factor for parkinsonism.

From the Unidad de Diagnóstico Molecular, Banco de Tejidos para Investigaciones Neurológicas, Madrid (Drs Hoenicka and de Yébenes, Ms Vidal, and Mr Ampuero), Servicios de Neurología, Hospital Universitario S Cecilio, Granada (Dr Morales), Hospital Príncipe de Asturias, Alcalá de Henares (Dr Jiménez-Jiménez), Hospital Severo Ochoa, Leganés (Dr del Ser), Hospital Ramón y Cajal, Madrid, and Hospital Marqués de Valdecilla, Cantabria (Dr Jiménez), and Fundación Jiménez Díaz, Madrid (Drs Berciano, Ruíz, and de Yébenes), Spain.

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