Asymptomatic Sisters Research Articles

Mitochondrial myopathy with dystrophic features due to a novel mutation in the MTTM gene

A 61-year-old woman with a 5-year history of progressive muscle weakness and atrophy had a muscle biopsy characterized by a combination of dystrophic features (necrotic fibers and endomysial fibrosis) and mitochondrial alterations [ragged-red, cytochrome c oxidase (COX)-negative fibers]. Sequencing of the whole mtDNA, assessment of the mutation load in muscle and accessible nonmuscle tissues, and single fiber polymerase chain reaction. Muscle mitochondrial DNA (mtDNA) sequencing revealed a novel heteroplasmic mutation (m.4403G>A) in the gene (MTTM) that encodes tRNA(Met). The mutation was not present in accessible nonmuscle tissues from the patient or 2 asymptomatic sisters. The clinical features and muscle morphology in this patient are very similar to those described in a previous patient with a different mutation, also in MTTM, which suggests that mutations in this gene confer a distinctive "dystrophic" quality. This may be a diagnostic clue in patients with isolated mitochondrial myopathy.

Identification of a novel Wilson disease gene mutation frequent in Upper Austria: a genetic and clinical study

Wilson disease (WD), a disorder of copper metabolism is caused by mutations in the ATP7B gene, a copper transporting ATPase. In the present study we describe a novel mutation in exon 9 of the ATP7B gene. The ATP7B gene was analyzed for mutations by denaturing HPLC and direct sequencing. DNA from 100 healthy blood donors from the same geographic area was examined as control. Sixteen (7.4%) out of the 216 patients diagnosed with WD in Austria carried the newly identified R816S(c.2448G>T) point mutation in exon 9 (4 male, age: 19 (6-30) years, median (range)). One patient was homozygous for R816S(c.2448G>T). Thirteen patients were compound heterozygotes (p.H1069Q(c.3207C>A)/R816S(c.2448G>T) (N=6), P539L/R816S(c.2448G>T) (N=3), each one G710S/R816S(c.2448G>T), P767P(2299insC)/R816S(c.2448G>T), W779G/R816S(c.2448G>T), T1220M/R816S(c.2448G>T)). In two patients no second mutation was identified. Interestingly, all but three of the patients originated within a distinct geographical area in Austria. Eleven patients presented with hepatic disease, 3 patients with neurological disease and 2 were asymptomatic sisters of an index case. A liver biopsy was available in 14 patients. Three patients showed advanced liver disease with liver transplantation for acute hepatic failure in two. The remaining patients had only mild histological changes, most commonly steatosis. Chronic hepatitis was described in five patients. Kayser-Fleischer ring was present in five patients. None of the 100 healthy controls carried the mutation. We describe a novel mutation in the ATP7B gene, occurring in patients originated from a distinct geographical area in Austria associated with a variable course of the disease.

A novel SDHD mutation associated with neck paraganglioma

The aim of this study was to describe a previously unreported mutation in the SDHD gene, which has been linked to familial paraganglioma. Clinical data were collected from all members of the family, which had four siblings affected with paraganglioma. For the index patient, genomic DNA extraction from whole blood was performed using the High Pure PCR Template Preparation kit. The nucleotide sequence in the index patient revealed a deletion in the SDHD gene, c.165_169+14del. The loss of nucleotides in the DNA led to production of an anomalous protein. RNA analysis showed the absence of exon 2 in the sequence that corresponded to the mRNA from the index case. Genetic testing of this deletion was extended to the symptomatic and asymptomatic brothers and sisters of the index patient and other family members at risk. The deletion was detected in both symptomatic brothers, in accordance with their phenotype, but not in the asymptomatic sister. In the other asymptomatic brother (II.7) the deletion was detected and magnetic resonance angiography revealed the vascular characteristics of two tumors in both carotid bifurcations. Thus, we report a novel punctual mutation in the SDHD gene, which is related to familial paraganglioma: the deletion was c.165_169 + 14del.

Digenic Inheritance of Hepatocyte Nuclear Factor-1α and -1β With Maturity-Onset Diabetes of the Young, Polycystic Thyroid, and Urogenital Malformations

Heterozygous mutations of the POU A/homeodomain transcription factors hepatocyte nuclear factor (HNF)-1α and -1β cause maturity-onset diabetes of the young (MODY) in humans (1). HNF-1α and -1β act in a complex network of transcription factors regulating tissue-specific gene expression in the pancreas and other epithelial organs. Patients with mutations of HNF-1β (MODY5) are characterized by urogenital malformations, while extrapancreatic manifestations in patients with diabetes and HNF-1α mutations (MODY3) are not well known (2). After an occasional blood glucose reading of 13.4 mmo/l, the diagnosis of diabetes was established in a 13-year-old girl. She was asymptomatic except for mild chronic lower abdominal discomfort. Her fasting glucose was 9.3 mmol/l, A1C was 8.5% (normal 4.2–6.1), and urine ketones were negative. After brief insulin treatment, she received 0.5 mg/day glimepiride, with a current A1C of 5.6%. Her father (Fig. 1), diagnosed with diabetes at the age of 27 years, has received insulin since the age of 38 years. The paternal grandmother had diabetes treated with glibenclamide until she died 20 years ago, aged 62 years. Two asymptomatic sisters of the index patient were diagnosed with diabetes at the age of 14 years and 19 years. Their fasting serum glucose was 7.3 and 6.8 mmol/l, respectively, and A1C was 6.0 and 6.1%. Two hours after a 75-g oral glucose challenge, their glucose levels were 10.1 and 13.1 mmol/l, respectively. …

Ultrasonographic screening of the abdominal aorta among siblings of patients with abdominal aortic aneurysms.

To evaluate the prevalence of abdominal aortic dilatations among asymptomatic brothers and sisters of patients with abdominal aortic aneurysms (AAAs), an ultrasonographic screening study was performed. One hundred and two siblings of patients operated on for AAAs at two Swedish hospitals were invited to attend, and 87 of them (35 men and 52 women) from 32 different families, accepted the invitation. Their median age was 63 years (range 39-82 years). Aortic dilatation was diagnosed in ten of the brothers (29 per cent) and three of the sisters (6 per cent). In ten cases (eight men and two women) there was a localized dilatation caudal to the coeliac axis, and in three a general dilatation of the abdominal aorta with the diameter at the coeliac axis greater than 29 mm. None of the aortic dilatations had been known before this study was performed. The conclusion is that the prevalence of asymptomatic aortic dilatations among brothers of patients with AAAs seems to be high and that this group should be selected for further screening studies.

Isolated elevated sweat chloride concentrations in the presence of the rare mutation S1455X: An extremely mild form of CFTR dysfunction

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) have been shown to cause typical cystic fibrosis (CF) and several milder phenotypes. We report on two asymptomatic sisters who had isolated increased sweat chloride concentrations, and in whom systematic scanning of the whole coding region of the CFTR gene revealed the F508del/S1455X genotype.

Familial bidirectional ventricular tachycardia

The occurrence of incessant ventricular arrhythmia with bouts of polymorphous and bidirectional ventricular tachycardia is described in two totally asymptomatic sisters, with structurally normal hearts and no QT prolongation. Familial survey revealed the occurrence of increased ventricular ectopic activity in the father, brother and another sister.