Diagnostic laboratory testing for Charcot Marie Tooth disease (CMT): the spectrum of gene defects in Norwegian patients with CMT and its implications for future genetic test strategies.

This article is part of Rune Østern's doctoral thesis which is available in Munin at http://hdl.handle.net/10037/6965The importance of diagnosing and treating co-occurring psychiatric disorders among substance abusers in treatment has received much attention. The aim of this study was to investigate to which extent co-occurring psychiatric disorders are diagnosed in a clinical population of substance abusers, and which factors (including the use of MINI-Plus) that influence the diagnosing of co-occurring psychiatric disorders. Patients (N = 275) who received inpatient substance use treatment in five different units in Northern Norway participated in the study. The patients’ clinicians gave information on diagnoses given during the stay in the units, and whether a systematic diagnostic tool was used for the diagnosing (MINI-Plus). Predictors of independent co-occurring psychiatric disorders were examined utilizing hierarchical regression analysis. One third of the patients were given an independent psychiatric diagnosis. Less than half of the patients were assessed using a diagnostic tool. The main predictor of diagnosing of independent psychiatric disorders was the use of the diagnostic tool MINI-Plus. Younger patients and patients that used less alcohol, were given independent psychiatric diagnoses more frequently. The number of co-occurring independent psychiatric diagnoses was lower compared to other studies using standardized diagnostic tools. The low number of patients assessed by such a tool, and the strong relationship between the use of such a tool and the diagnosing of co-occurring psychiatric disorders, suggest that the implementation of standardized diagnostic tools should be addressed in the units. Generally, patients suffering from substance use disorders should be systematically screened for other psychiatric disorders, in order to improve their treatment and health

Börjeson–Forssman–Lehmann syndrome: Delineating the clinical and allelic spectrum in 14 new families

Börjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked intellectual disability syndrome caused by variants in the PHF6 gene. We ascertained 19 individuals from 15 families with likely pathogenic or pathogenic PHF6 variants (11 males and 8 females). One family had previously been reported. Six variants were novel. We analysed the clinical and genetic findings in our series and compared them with reported BFLS patients. Affected males had classic features of BFLS including intellectual disability, distinctive facies, large ears, gynaecomastia, hypogonadism and truncal obesity. Carrier female relatives of affected males were unaffected or had only mild symptoms. The phenotype of affected females with de novo variants overlapped with the males but included linear skin hyperpigmentation and a higher frequency of dental, retinal and cortical brain anomalies. Complications observed in our series included keloid scarring, digital fibromas, absent vaginal orifice, neuropathy, umbilical hernias, and talipes. Our analysis highlighted sex-specific differences in PHF6 variant types and locations. Affected males often have missense variants or small in-frame deletions while affected females tend to have truncating variants or large deletions/duplications. Missense variants were found in a minority of affected females and clustered in the highly constrained PHD2 domain of PHF6. We propose recommendations for the evaluation and management of BFLS patients. These results further delineate and extend the genetic and phenotypic spectrum of BFLS

Charcot-Marie-Tooth disease (CMT): statistical analysis and revision of molecular genetic diagnostics in a patient population and identification of the disease locus in a large Norwegian family with CMT.

CMT is a common inherited disease of the peripheral nerves that may be caused by mutations in multiple genes, most are rare. Our aim was to describe the spectrum of mutations and genes in Norwegian CMT patients, identify factors associated with diagnostic findings, revise the testprotocol, and evaluate the assessments of genetic variants of uncertain clinical significance. Furthermore, we searched to identify the disease associated gene in a large family with a CMT2-like-disorder. We evaluated the data given in laboratory request forms accompanying 559 samples sent for CMT testing during a seven year period. Diagnostic testing was in compliance with recommended algorithms. In paper I we suggest a simplified algorithm intended for diagnostic CMT testing in referral laboratories. Segregation analysis of twenty-two relatives (9 affected) from eight families led to the reclassification of four sequence variants of uncertain clinical significance (paper II). The results of paper II demonstrate the importance of precise clinical data, particularly when investigating variants of uncertain clinical significance. In paper III we performed whole genome linkage analysis, haplotype analysis, SOD1 sequencing and clinical and neurophysiological investigations in a large kindred with a CMT2-like-disorder. The mutation c.140A>G, p.His47Arg in SOD1 segregated with the disease. The results of paper III illustrate the complex genetic etiology of lower motor neuron disease, and identify a common cause of CMT2-like disease in Norway

Segregation analysis in families with Charcot-Marie-Tooth disease allows reclassification of putative disease causing mutations

BACKGROUND: The identification of disease causing, or putative disease causing, mutations in index patients with Charcot-Marie-Tooth disease (CMT) allows for genetic testing of family members. Relevant variants identified in index patients are of either definite, likely or uncertain pathogenicity. The main objective of this study was to make an evaluation of the family investigations performed as part of the assessment of genetic variants of unknown clinical significance (VUS). METHODS: Between 2004 and 2010 molecular genetic family investigations were requested for 87 family members from 41 families harbouring PMP22dup or genetic variants in GJB1, MPZ, MFN2 and NEFL. Relatives were tested for the family mutation and data from the requisitions were evaluated by means of statistical tools. RESULTS: The results within each indication category are presented and discussed in detail. Twenty-two relatives (9 affected) from eight families were included in the segregation analyses, which invoked reclassification of three MFN2 mutations, two of which were de novo substitutions (c.2146_2148dup, c.692C > T). One MFN2 substitution was downgraded due to non-segregation (c.1709 A > G), and a MPZ substitution (c.103 G > A) upgraded due to segregation with the phenotype in the family. CONCLUSIONS: The results allow for the evaluation of the patient phenotypes ascertained in families, as opposed to the phenotypic descriptions of index patients. They indicate that de novo MFN2 mutations are regularly found in patients with a classical CMT2 phenotype. They also demonstrate the importance of a precise clinical and neurophysiologic diagnosis of affected family members. This particularly applies for the examination of variants of uncertain clinical significance. Finally, the fact that 14,6% of affected relatives tested for (probable or certain) pathogenic mutations were mutation negative, demonstrates that clinical evaluation alone is not always sufficient in order to determine their diagnosis. We believe that the results will aid in the estimation and planning of resources required for the various aspects of family evaluations in CMT

Mutations in RPSA and NKX2-3 link development of the spleen and intestinal vasculature

Idiopathic intestinal varicosis is a developmental disorder defined by dilated and convoluted submucosal veins in the colon or small bowel. A limited number of families with idiopathic intestinal varices has been reported, but the genetic cause has not yet been identified. We performed whole exome and targeted Sanger sequencing of candidate genes in five intestinal varicosis families. In four families mutations in the RPSA gene were found, a gene previously linked to congenital asplenia. Individuals in these pedigrees had intestinal varicose veins and angiodysplasias, often in combination with asplenia. In a further four generation pedigree that only showed intestinal varicosities, the RPSA gene was normal. Instead, a nonsense mutation in the homeobox gene NKX2-3 was detected which co-segregated with the disease in this large family with a LOD score of 3.3. NKX2-3 is a component of a molecular pathway underlying spleen and gut vasculature development in mice. Our results provide a molecular basis for familial idiopathic intestinal varices. We provide evidence for a relationship between the molecular pathways underlying the development of the spleen and intestinal mucosal vasculature that is conserved between humans and mice. We propose that clinical management of intestinal varices, should include assessment of a functional spleen. This article is protected by copyright. All rights reserved.</p

Mutations in ACTL6B Cause Neurodevelopmental Deficits and Epilepsy and Lead to Loss of Dendrites in Human Neurons

We identified individuals with variations in ACTL6B, a component of the chromatin remodeling machinery including the BAF complex. Ten individuals harbored bi-allelic mutations and presented with global developmental delay, epileptic encephalopathy, and spasticity, and ten individuals with de novo heterozygous mutations displayed intellectual disability, ambulation deficits, severe language impairment, hypotonia, Rett-like stereotypies, and minor facial dysmorphisms (wide mouth, diastema, bulbous nose). Nine of these ten unrelated individuals had the identical de novo c.1027G>A (p.Gly343Arg) mutation. Human-derived neurons were generated that recaptured ACTL6B expression patterns in development from progenitor cell to post-mitotic neuron, validating the use of this model. Engineered knock-out of ACTL6B in wild-type human neurons resulted in profound deficits in dendrite development, a result recapitulated in two individuals with different bi-allelic mutations, and reversed on clonal genetic repair or exogenous expression of ACTL6B. Whole-transcriptome analyses and whole-genomic profiling of the BAF complex in wild-type and bi-allelic mutant ACTL6B neural progenitor cells and neurons revealed increased genomic binding of the BAF complex in ACTL6B mutants, with corresponding transcriptional changes in several genes including TPPP and FSCN1, suggesting that altered regulation of some cytoskeletal genes contribute to altered dendrite development. Assessment of bi-alleic and heterozygous ACTL6B mutations on an ACTL6B knock-out human background demonstrated that bi-allelic mutations mimic engineered deletion deficits while heterozygous mutations do not, suggesting that the former are loss of function and the latter are gain of function. These results reveal a role for ACTL6B in neurodevelopment and implicate another component of chromatin remodeling machinery in brain disease

Clinical and genetic characteristics of late-onset Huntington's disease

Background: The frequency of late-onset Huntington's disease (&gt;59 years) is assumed to be low and the clinical course milder. However, previous literature on late-onset disease is scarce and inconclusive. Objective: Our aim is to study clinical characteristics of late-onset compared to common-onset HD patients in a large cohort of HD patients from the Registry database. Methods: Participants with late- and common-onset (30–50 years)were compared for first clinical symptoms, disease progression, CAG repeat size and family history. Participants with a missing CAG repeat size, a repeat size of ≤35 or a UHDRS motor score of ≤5 were excluded. Results: Of 6007 eligible participants, 687 had late-onset (11.4%) and 3216 (53.5%) common-onset HD. Late-onset (n = 577) had significantly more gait and balance problems as first symptom compared to common-onset (n = 2408) (P &lt;.001). Overall motor and cognitive performance (P &lt;.001) were worse, however only disease motor progression was slower (coefficient, −0.58; SE 0.16; P &lt;.001) compared to the common-onset group. Repeat size was significantly lower in the late-onset (n = 40.8; SD 1.6) compared to common-onset (n = 44.4; SD 2.8) (P &lt;.001). Fewer late-onset patients (n = 451) had a positive family history compared to common-onset (n = 2940) (P &lt;.001). Conclusions: Late-onset patients present more frequently with gait and balance problems as first symptom, and disease progression is not milder compared to common-onset HD patients apart from motor progression. The family history is likely to be negative, which might make diagnosing HD more difficult in this population. However, the balance and gait problems might be helpful in diagnosing HD in elderly patients