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Neuronal ceroid lipofuscinoses (NCLs) are autosomal recessive neurodegenerative disorders typically characterized by the accumulation of autofluorescent material in tissues. On the basis of clinical features, age at onset, and molecular genetic defects, it is possible to distinguish at least nine forms. The CLN8 form was first described in Finland, where all the patients are homozygous for a p.Arg24Gly mutation in CLN8. More recently, it has been found that a subset of a Turkish variant of late infantile NCL (v-LINCL) is also associated with CLN8 mutations. To identify the molecular defect in Italian patients with v-LINCL, the CLN8 gene was directly sequenced in 10 patients. Controls were screened by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Five fluorescent-labeled microsatellite markers covering 1 cM around the gene were used for haplotype analysis. In three Italian v-LINCL patients, identified in a small area in southern Italy, we detected four new mutations in CLN8: c.66delG (p.Gly22fs), c.88G>C (p.Ala30Pro), c.473A>G (p.Tyr158Cys), and c.581A>G (p.Gln194Arg). The single-base deletion was found in two unrelated patients. The novel missense mutations were not identified in ethnically matched control chromosomes. Our findings expand the number of CLN8 variants and corroborate the notion that CLN8 patients are not confined to the Finnish population.

Purpose Neural tube defects (NTDs) occur in 1:1000 births. The etiology is complex, with the influence of environmental and genetic factors. Environmental factors, such as folate deficiency, diabetes, or hypoxia strongly contribute to the occurrence of NTD. Also, there is a strong genetic contribution to NTD, as highlighted by the number of genes so far identified in several different developmental pathways usually altered in NTD. Each gene identified so far accounts for a small percentage of all NTD cases, indicating a very high heterogeneity. Methods Exome sequencing was performed in seven sporadic patients with severe mielomeningocele. Novel coding variants shared by two or more patients were selected for further analysis. Results We identified in two unrelated patients two different variants in TNIP1 , a gene not previously involved in NTD whose main role is downregulation of the NF-kB pathway. One variant, c.1089T>G ( p.Phe363Leu ), is de novo, whereas the c.1781C>T ( p.Pro594Leu ) is absent in the mother, but could not be tested in the father, as he was unavailable. The latter variant is a very rare variant in the ExAC database. Conclusions These findings suggest that TNIP1 is a new potential predisposing gene to spina bifida (SB) and its pathway needs to be investigated in human NTD in order to confirm its role and to plan appropriate counseling to families.

We report the molecular findings in 14 patients (12 families) with X‐linked adrenoleukodystrophy (X‐ALD, MIM# 300100), a well‐defined peroxisomal disorder attributed to mutations in the ABCD1 gene on chromosome Xq28. With the aims of determining the spectrum of mutations and developing an efficient molecular genetic test for analysis of at‐risk women whose carrier status is unknown, and to offer molecular confirmation of their status to obligate heterozygotes, regardless of their clinical status, we carried out molecular screening by setting up a denaturing high‐performance liquid chromatography (DHPLC)‐based protocol. We identified eleven hemizygous base changes in ABCD1, including seven new mutations (c.145underscore;146ins4, c.264C>G, c.919C>T, c.994C>T, c.1027G>A, c.1508T>C, and c.1540A>C, resulting in the p.Pro193fs, p.Cys88Trp, p.Gln307X, p.Gln332X, p.Gly343Ser, p.Leu503Pro, and p.Ser514Arg changes, respectively). Adding new variants to the repertoire of ABCD1 mutations in X‐ALD, our data provide an efficient, cost‐effective, and reliable DHPLC detection protocol for mutation screening of X‐ALD families. © 2005 Wiley‐Liss, Inc.

The neuronal ceroid lipofuscinoses (NCL) are the most common group of progressive neurodegenerative diseases of childhood. The overall clinical features are highly similar regardless of the age at disease manifestation, the extent and shape of abnormally stored cytosomes and the severity of clinical course, and are generally characterized by failure and regression of psychomotor development, impaired vision, seizures and fatal outcome. The expanding array of genetic etiologies and disease-associated mutations in NCL provide the basis for the heterogeneity of these clinical conditions and are the focus of this review. Less understood are the pathogenic mechanisms, but common themes and molecular pathways are now emerging and new players are expected to come into the scene of NCL.