Search

Variants of the C19ORF12-gene have been described in patients with spastic paraplegia type 43 and in patients with mitochondrial membrane protein-associated neurodegeneration (MPAN), a subtype of neurodegeneration associated with brain iron accumulation (NBIA). In both subtypes optic atrophy and neuropathy have been frequently described. This case report describes a patient with bilateral optic atrophy and severe distal muscle weakness based on motor neuropathy without involvement of the central nervous system. Exome sequencing revealed a homozygous pathogenic missense variant (c.187G>C;p.Ala63Pro) of the C19ORF12-gene while iron deposits were absent on repeat MR-imaging of the brain, thus showing that peripheral neuropathy and optic neuropathy can be the sole manifestations of the C19ORF12-related disease spectrum whereby iron accumulation in the brain may be absent.

Heterozygous familial hypercholesterolaemia (FH) is a common autosomal dominant inherited metabolic disease with a prevalence of 1 in 500 in most Western countries. 1– 3 People with FH experience an increased risk for coronary artery disease (CAD) and excess mortality especially at a young age. 4, 5 Until recently the diagnosis of FH was based on clinical signs and symptoms alone. These included increased cholesterol concentrations, in particular of LDL-cholesterol, in combination with the presence of tendon xanthoma, corneal arcus, xanthelasmata and a history of early CAD. Frequently FH was diagnosed after a first cardiac event.

Systematic testing for genetically mediated risk factors has emerged recently, including genetic testing of apparently healthy people. The testing will often be organised within screening programmes.1 Although the empirical evidence of the health benefits of such screening can be convincing, the broader consequences of family screening demand guided implementation strategies, including considerations of the effects on quality of life (QoL) and psychological well being.2,3 Familial hypercholesterolaemia (FH) is a genetic disorder, predisposing to coronary artery disease. The estimated frequency of the genetic factor in western countries is 1 in 500 persons.4–6 In about 90%, the associated metabolic defect results in an accumulation of plasma cholesterol and consequent excess CAD mortality.4–8 The availability of DNA diagnosis at an asymptomatic stage and of effective lipid lowering therapy have called for cascade screening.9–14 In 1994, an FH screening programme was started in The Netherlands on a provisional basis, including a parallel, independent evaluation study. The evaluation study addressed not only the uptake and diagnostic procedure, but also the short and long term impact on QoL and psychological well being of the participants of the screening programme. Some evidence on QoL effects of non-genetic screening programmes is available. Early studies on hypertension screening showed adverse effects, which were contradicted later, both on hypertension and cholesterol screening.15–23 In non-genetic cancer screening programmes, participants showed a temporary decline in the psychological domain of QoL.24–26 For example, in breast cancer screening, anxiety and depression following screening were raised but to a subclinical level,27 without lasting adverse psychological effects.28–30 The psychological disturbance of prostate cancer screening was even less.31 In genetic testing, carriers of an autosomal recessive disorder sometimes grow pessimistic about themselves and could grow less optimistic about their future …

The aim of this article is threefold. First, we describe the accuracy of people's risk perception who have been screened on familial hypercholesterolemia (FH) in a family-based screening program. Second, we identify factors that modify risk perception. Finally, we show the influence of risk perception on subsequent preventive behavior. The risk perception of 556 screenees (677 participants, overall response = 82%) was measured by postal questionnaires on three occasions: at screening and 3 days and 7 months after the test result was reported to the patient. Presentation of the risk was precategorized and given both as numerical (1 in x) and as verbal probability. In addition, medication use and attitudes toward gene therapy were determined 7 months after screening. On average, the screenees underestimated their numeric risk of having FH and getting a myocardial infarction (MI). Furthermore, FH-positive screenees perceived that they were at greater risk of MI than FH negatives, and screenees with the highest actual risk used medication more, perceived a greater risk, and opted more often for future gene therapy. Risk perception of having FH was influenced by cholesterol level, while MI risk perception was affected by age, education, cholesterol level, and cardiovascular disease (CVD) in the family. We conclude that FH-positive screenees correctly perceive a higher risk of getting a heart attack than do FH-negative screenees. Screenees did not believe that MI was inevitable, and risk perception was associated with both medication use and the intention to opt for gene therapy, but not with other preventive measures. Thus, genetic risk notification seems to be acceptable and does not lead to aversion to preventive behavior. (C) 2003 Wiley-Liss, Inc