Valentina Dessì

Bannayan-Riley-Ruvalcaba syndrome with reactive nodular lymphoid hyperplasia and autism and a PTEN mutation.

Loredana Boccone,* Valentina Dessı̀, Antonietta Zappu, Silvia Piga, Maria Bonaria Piludu, Marco Rais, Carlo Massidda, Stefano De Virgiliis, Antonio Cao, and Georgios Loudianos Ospedale Regionale Microcitemie, Cagliari, Italy Dipartimento di Scienze Biomediche e Biotecnologie, USC, Italy Istituto di Neurogenetica e Neurofarmacologia, CNR-Cagliari, Italy U.O. Anatomia Patologica, Ospedale Businco, Cagliari, Italy Chirurgia Oncologica, Ospedale Businco, Cagliari, Italy

Allan–Herndon–Dudley syndrome (AHDS) caused by a novel SLC16A2 gene mutation showing severe neurologic features and unexpectedly low TRH-stimulated serum TSH

Thyroid hormones are known to be essential for growth, development and metabolism. Recently mutations in the SLC16A2 gene coding for the monocarboxylate thyroid hormone transporter 8, MCT8, have been associated with Allan-Herndon-Dudley syndrome (AHDS), an X-linked condition characterized by severe mental retardation, dysarthria, athetoid movements, muscle hypoplasia and spastic paraplegia. Here we describe in detail the clinical and biochemical features in a boy affected by AHDS with severe neurological abnormalities and a novel de novo SLC16A2 gene insertion, 1343-1344insGCCC, resulting in a truncated protein lacking the last four transmembrane domains (TMDs) as well as the carboxyl cytoplasmic end. He presents mental retardation, axial hypotonia, hypertonia of arms and legs, paroxysmal dyskinesias, seizures. The endocrine phenotype showed low serum total and free thyroxine (T4), very elevated total and free triiodothyronine (T3) and normal thyrotropin (TSH) with blunted response to thyrotropin-releasing hormone (TRH). The latter finding was unexpected and suggested that the lack of functional MCT8 was counterbalanced at the thyrotrope cell level by high serum T3 concentration and/or by increased intrapituitary type 2 deiodinase (D2) activity. Our case constitutes a relevant contribution to better characterize this disorder and to elucidate the functional consequences of SLC16A2 gene mutations.

Allan–Herndon–Dudley syndrome (AHDS) in two consecutive generations caused by a missense MCT8 gene mutation. Phenotypic variability with the presence of normal serum T3 levels

Allan-Herndon-Dudley syndrome (AHDS), an X linked condition, is characterized by severe intellectual disability, dysarthria, athetoid movements, muscle hypoplasia and spastic paraplegia in combination with altered TH levels, in particular, high serum T3 levels. Mutations in the MCT8 gene coding for the monocarboxylate thyroid hormone transporter 8 have been associated with AHDS. Here we describe a family with the presence of a MCT8 gene mutation, p.A224T, in three consecutive generations. In two generations its presence was detected in the hemizygous state in two males with neurological abnormalities including mental retardation, axial hypotonia, hypertonia of arms and legs and athetoid movements. One of them presented normal thyroid hormone levels. Mutation was also detected, although in the heterozygous state, in three females showing thyroid hormone levels in the normal range. Our results show the difficulty of distinguishing AHDS from patients with X-linked intellectual disability solely on the basis of clinical features and biochemical tests, and we advise screening for MCT8 mutations in either young or older patients with severe intellectual disability, axial hypotonia/dystonia, poor head control, spastic paraplegia, and athetoid movements even when they have normal thyroid hormone profiles.

Mutation analysis of the ATP7B gene in a new group of Wilson's disease patients: Contribution to diagnosis.

Wilsons disease (WD), an autosomal recessive disorder of copper transport with a broad range of genotypic and phenotypic characteristics, results from mutations in the ATP7B gene. Herein we report the results of mutation analysis of the ATP7B gene in a group of 118 Wilson disease families (236 chromosomes) prevalently of Italian origin. Using DNA sequencing we identified 83 disease-causing mutations. Eleven were novel, while twenty one already described mutations were identified in new populations in this study. In particular, mutation analysis of 13 families of Romanian origin showed a high prevalence of the p.H1069Q mutation (50%). Detection of new mutations in the ATP7B gene in new populations increases our capability of molecular analysis that is essential for early diagnosis and treatment of WD.

RNA analysis of consensus sequence splicing mutations: implications for the diagnosis of Wilson disease.

Wilson disease (WD) is an autosomal recessive disorder caused by a defective function of the copper-transporting ATP7B protein. This results in progressive copper overload and consequent liver, brain, and kidney damage. Approximately 300 WD-causing mutations have been described to date. Missense mutations are largely prevalent, while splice-site mutations are rarer. Of these, only a minority are detected in splicing consensus sequences. Further, few splicing mutations have been studied at the RNA level. In this study we report the RNA molecular characterization of three consensus splice-site mutations identified by DNA analysis in WD patients. One of them, c.51 + 4 A --> T, resides in the consensus sequence of the donor splice site of intron 1; the second, c. 2121 + 3 A --> G, occurred in position + 3 of intron 7; and the c.2447 + 5 G --> A is localized in the consensus sequence of the donor splice site of intron 9. Analysis revealed predominantly abnormal splicing in the samples carrying mutations compared to the normal controls. These results strongly suggest that consensus sequence splice-site mutations result in disease by interfering with the production of the normal WD protein. Our data contribute to understanding the mutational spectrum that affect splicing and improve our capability in WD diagnosis.

Bannayan-Riley-Ruvalcaba syndrome with posterior subcapsular congenital cataract and a consensus sequence splicing PTEN mutation.

This study, combined with the previously reported c.634+1G >T mutation [Agrawal et al., 2005] reveal that exon 6 skipping of PTEN gene produces two different phenotypes of CS and BRRS associated with posterior subcapsular congenital cataract. These data suggest the contribution of other factors that could act downstream of the mutations determining phenotypic variability [Weng et al., 2001]. In conclusion, this study expands our knowledge on the phenotypic variability of BRRS syndrome and suggests a new mechanism for posterior subcapsular congenital cataract due to altered function of the PTEN protein. Further investigations involving a larger number of patients will be required to confirm these data.

Acute Liver Failure Because of Wilson Disease With Overlapping Autoimmune Hepatitis Features: The Coexistence of Two Diseases?

WCC, 10/L 6.2 8.5 4.5–13 Hb, g/dL 9.1 7.1 12–15.2 Hct, % 25 20.1 36–47 Reticulocyte, % 6.58 — 0.5–1.5 Haptoglobin, mg/dL <5.83 — 0–200 PLT, 10/L 73 38 150–450 TB, mg/dL 10.7 16.10 0.2–1.1 CB, mg/dL 4.4 7.6 0.1–0.3 A failure and death (1). Wilson disease (WD), an autosomal recessive disease of copper transport, is owing to mutation in ATP7B (2). Establishing the diagnosis of WD in the setting of ALF is critical because it allows treatment for prompt removal of serum copper and stabilization of the patient to facilitate lifesaving orthotopic liver transplantation (OLT). Autoimmune hepatitis (AIH) is a progressive inflammatory liver disorder characterized serologically by high levels of transaminases and immunoglobulin G, and presence of autoantibodies, and histologically by interface hepatitis in the absence of known etiology (3). Unlike patients with ALF owing to WD, patients presenting with ALF owing to AIH may respond better to medical treatment with immunosuppressive agents, therefore circumventing the need for liver transplantation. Herein we report a case of ALF caused by WD showing strong autoimmune features.