Postmortem molecular screening for mutations in ryanodine receptor type 1 (RYR1) gene in psychiatric patients suspected of having died of neuroleptic malignant syndrome.

Postmortem diagnosis of neuroleptic malignant syndrome (NMS) is difficult to perform, because the clinical symptoms just before death are not usually available. Malignant hyperthermia (MH) is a catastrophic, life-threatening hypermetabolic syndrome triggered by certain anesthetics. Ryanodine receptor type 1 (RYR1) gene mutations are known to be involved in susceptibility to MH. Similarities in clinical features, such as elevated body temperature, between NMS and MH have led to the suggestion that NMS is a neurogenic form of MH. In this study, we analyzed possible mutations of the RYR1 gene in 11 psychiatric patients suspected at autopsy to have died of NMS. All cases were suspected of having elevated body temperature at death, and their causes of death could not be determined by autopsy examinations. Two mutations (R4645Q and A612T) in the RYR1 gene were identified. The R4645Q mutation has previously been reported in MH patients, but five heterozygous mutations were also found in 400 Japanese control alleles. The other mutation was novel, and was not found in the same control alleles. The results of this study provide the first successful identification of RYR1 mutations in psychiatric patients suspected at autopsy of having died of NMS. However, the association between RYR1 gene mutations and cause of death in psychiatric patients suspected of dying of NMS remains unclear.

Identification of a novel mutation V2321M of the cardiac ryanodine receptor gene of sudden unexplained death and a phenotypic study of the gene mutations.

Mutations of the cardiac ryanodine receptor (RyR2) gene cause catecholaminergic polymorphic ventricular tachycardia, which sometimes results in a finding of sudden unexplained death (SUD) at autopsy. We found a novel mutation (V2321M) in exon 46 of the RyR2 gene in a SUD case. V2321M was localized in a highly conservative site of the RyR2 gene, but was not found in 400 reference alleles. We previously reported two SUD cases with R420W mutations in exon 14 of the RyR2 gene. We examined possible phenotypic characteristics of all three of these cases of SUD with the RyR2 gene mutations. All cases displayed mesenteric lymph node hypertrophy as well as tendencies for aortic narrowing. By contrast, only one of the 14 SUD cases without RyR2 mutations displayed these phenotypes. This study supports the concept that postmortem genetic testing of RyR2 mutations should be considered in autopsy examinations of SUD cases. It also raises the possibility that some cases with RyR2 mutations may display phenotypic changes in lymphoid and cardiovascular organs.

Analysis of two types of novel alleles in the DXS10011 locus.

A population study of the short tandem repeat locus DXS10011 was carried out in a sample of 104 unrelated Japanese individuals (56 males, 48 females). Thirty-six different alleles were distinguished. The power of discrimination was 0.933 (male) and 0.997 (female). Sequence analysis of alleles was examined for 34 samples. The sequence structures of the alleles were classified into three types: A, B and C. Type A had a regular repeat structure of the repeat region: (GAAA)(n). Types A and B differed in the base sequence of the repeat region. As an A (adenine) insertion in 5' upstream of (GAAA)(n) repeat unit was type C, this type was differentiated from type A.

Sequence analysis of two de novo mutation alleles at the DXS10011 locus.

We have detected two unusual alleles at the DXS10011 locus in two paternity trio cases. In one case, one allele of the daughter was found not to have been derived from the mother but the other allele was shared with the father. In the other case, the mother and the son shared no bands. Paternity in both cases was established using conventional polymorphic markers in addition to DNA markers (probabilities: >0.999999). Sequencing showed that the two de novo alleles of the children acquired a single unit (GAAA).

A fatal case of amniotic fluid embolism with elevation of serum mast cell tryptase.

A case of a 40-year-old female who died of amniotic fluid embolism is presented. This case showed typical histological findings of this syndrome. Postmortem serum of this case showed an elevated tryptase level (67.2ng/ml, normal levels <10ng/ml). Tryptase is a neutral protease of mast cells, and an important indicator of mast cell activation and degranulation. Thus, mast cell activation, a central feature of anaphylaxis, may have been involved in the pathogenetic mechanism of this case.