Background and objectives: Hepatocyte nuclear factor 1␤ (HNF1␤) is a transcription factor that is critical for the development of kidney and pancreas. In humans, mutations in HNF1B lead to congenital anomalies of the kidney and urinary tract, pancreas atrophy, and maturity-onset diabetes of the young type 5 and genital malformations.Design, setting, participants, & measurements: We report HNF1B screening in a cohort of 377 unrelated cases with various kidney phenotypes (hyperechogenic kidneys with size not more than ؉3 SD, multicystic kidney disease, renal agenesis, renal hypoplasia, cystic dysplasia, or hyperuricemic tubulointerstitial nephropathy not associated with UMOD mutation).Results: We found a heterozygous mutation in 75 (19.9%) index cases, consisting of a deletion of the whole gene in 42, deletion of one exon in one, and small mutations in 32. Eighteen mutations were novel. De novo mutations accounted for 66% of deletions and 40% of small mutations. In patients who carried HNF1B mutation and for whom we were able to study prenatal ultrasonography (56 probands), isolated hyperechogenic kidneys with normal or slightly enhanced size were the more frequent (34 of 56) phenotype before birth. Various other prenatal renal phenotypes were associated with HNF1B mutations, at a lesser frequency. Diabetes developed in four probands. Hyperuricemia and hypomagnesemia, although not systematically investigated, were frequently associated.Conclusions: This large series showed that the severity of the renal disease associated with HNF1B mutations was extremely variable (from prenatal renal failure to normal renal function in adulthood) and was not correlated with the genotype.

Spinocerebellar ataxia 2 (SCA2) is caused by the expansion of an unstable CAG repeat encoding a polyglutamine tract. One hundred and eighty four index patients with autosomal dominant cerebellar ataxia type I were screened for this mutation. We found expansion in 109 patients from 30 families of different geographical origins (15%) and in two isolated cases with no known family histories (2%). The SCA2 chromosomes contained from 34 to 57 repeats and consisted of a pure stretch of CAG, whereas all tested normal chromosomes (14-31 repeats), except one with 14 repeats, were interrupted by 1-3 repeats of CAA. As in other diseases caused by unstable mutations, a strong negative correlation was observed between the age at onset and the size of the CAG repeat (r = -0.81). The frequency of several clinical signs such as myoclonus, dystonia and myokymia increased with the number of CAG repeats whereas the frequency of others was related to disease duration. The CAG repeat was highly unstable during transmission with variations ranging from -8 to +12, and a mean increase of +2.2, but there was no significant difference according to the parental sex. This instability was confirmed by the high degree of gonadal mosaicism observed in sperm DNA of one patient.

BackgroundThis study describes the natural history of Barth syndrome (BTHS).MethodsThe medical records of all patients with BTHS living in France were identified in multiple sources and reviewed.ResultsWe identified 16 BTHS pedigrees that included 22 patients. TAZ mutations were observed in 15 pedigrees. The estimated incidence of BTHS was 1.5 cases per million births (95%CI: 0.2–2.3). The median age at presentation was 3.1 weeks (range, 0–1.4 years), and the median age at last follow-up was 4.75 years (range, 3–15 years). Eleven patients died at a median age of 5.1 months; 9 deaths were related to cardiomyopathy and 2 to sepsis. The 5-year survival rate was 51%, and no deaths were observed in patients ≥3 years. Fourteen patients presented with cardiomyopathy, and cardiomyopathy was documented in 20 during follow-up. Left ventricular systolic function was very poor during the first year of life and tended to normalize over time. Nineteen patients had neutropenia. Metabolic investigations revealed inconstant moderate 3-methylglutaconic aciduria and plasma arginine levels that were reduced or in the low-normal range. Survival correlated with two prognostic factors: severe neutropenia at diagnosis (<0.5 × 109/L) and birth year. Specifically, the survival rate was 70% for patients born after 2000 and 20% for those born before 2000.ConclusionsThis survey found that BTHS outcome was affected by cardiac events and by a risk of infection that was related to neutropenia. Modern management of heart failure and prevention of infection in infancy may improve the survival of patients with BTHS without the need for heart transplantation.