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Background & Aims: Homozygous individuals with alpha-1-antitrypsin deficiency (AATD) type PiZ have an increased risk of chronic liver disease and hepatocellular carcinoma (HCC). It is noteworthy that HCCs are composed by hepatocytes without accumulation of AAT, but the reason for this remains unclear. The aim of this study was to determine liver pathology in PiZ mice, focusing the attention on the distribution of AAT globules in normal liver, regenerative foci and neoplastic nodules., Methods: Liver of 79 PiZ mice and 18 wild type (Wt) was histologically analysed for steatosis, clear cell foci, hyperplasia and neoplasia. The expression of human-AAT transgene and murine AAT, in non-neoplastic liver and in hyperplastic/neoplastic nodules was tested by qPCR and qRT-PCR. RT-PCR was used to study expression of hepatic markers: albumin, α-foetoprotein, transthyretin, AAT, glucose-6-phospate, tyrosine aminotransferase., Results: Liver pathology was seen more frequently in PiZ (47/79) than in Wt (5/18) and its development was age related. In older PiZ mice (18-24 m), livers showed malignant tumours (HCC and angiosarcoma) (17/50), hyperplastic nodules (28/50), non-specific changes (33/50), whereas only 9/50 were normal. Both human-AATZ DNA and mRNA showed no differences between tumours/nodules and normal liver, while murine-AAT mRNA was reduced in tumours/nodules., Conclusion: Accumulation of AAT is associated with an increased risk of liver nodules. The presence of globule-devoid hepatocytes and the reduced expression of murine-AAT mRNA in hyperplastic and neoplastic nodules suggest that these hepatic lesions in AATD could originate from proliferating dedifferentiated cells, lacking AAT storage and becoming capable of AFP re-expression., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Bardet-Biedl syndrome (BBS) and Laurence-Moon syndrome (LMS) have a similar phenotype, which includes retinal dystrophy, obesity, and hypogenitalism. They are differentiated by the presence of spasticity and the absence of polydactyly in LMS. The aims of this study were to describe the epidemiology of BBS and LMS, further define the phenotype, and examine genotype-phenotype correlation. The study involved 46 patients (26 males, 20 females) from 26 families, with a median age of 44 years (range 1-68 years). Assessments were performed in 1986, 1993, and 2001 and included neurological assessments, anthropometric measurements, and clinical photographs to assess dysmorphic features. The phenotype was highly variable within and between families. Impaired co-ordination and ataxia occurred in 86% (18/21). Thirty percent (14/46) met criteria for psychiatric illness; other medical problems included cholecystectomy in 37% (17/46) and asthma in 28% (13/46). Dysmorphic features included brachycephaly, large ears, and short, narrow palpebral fissures. There was no apparent correlation of clinical or dysmorphic features with genotype. Two patients were diagnosed clinically as LMS but both had mutations in a BBS gene. The features in this population do not support the notion that BBS and LMS are distinct. The lack of a genotype-phenotype correlation implies that BBS proteins interact and are necessary for the development of many organs., ((c) 2005 Wiley-Liss, Inc.)

A distinctive slowly progressive neurodegenerative disorder, which falls under a new category of neurological diseases, the hereditary spastic ataxias (HSA), is described in three independently ascertained Newfoundland kindreds. HSA is a heterogeneous group of disorders in which pyramidal tract features overlap cerebellar characteristics. The families are assumed to have the same condition as, although apparently unrelated, all originate in a historically isolated cluster of rural communities and link to the same locus at 12p13, SAX1. Clinically the phenotype is very variable but lower limb hypertonicity and hyperreflexia are early and prominent generally preceded by eye movement abnormality, an impaired vertical downward saccade and a typical involuntary head jerk. These are followed by variable levels of ataxia, dysarthria, and dysphagia. Onset occurs in the first two decades and can be detected in most by early adulthood. Significant mobility problems are present by the fourth decade with a broad based ataxic and spastic gait. MRI scans of brain and spinal cord were normal. Neuropathology showed degeneration of corticospinal tracts and posterior columns and midbrain neuronal loss. The phenotype is striking in its diversity among and within families and the variability of expression can be observed within the same sibship. Pedigree analysis shows no evidence of anticipation or any sex differences in severity. The condition is unusually prevalent in the province of Newfoundland, which is characteristic of a founder effect followed by isolation and large family size. Fine mapping efforts have reduced the critical interval of the SAX1 locus to 1.9Mb. Identification of the SAX1 gene will help to clarify the pathogenesis of this type of HSA.