Socioeconomic and modifiable predictors of blood pressure control for hypertension in primary care attenders in the Western Cape, South Africa.

BACKGROUND: Low socioeconomic status is associated with the risk of hypertension. There are few reports of the effect of socioeconomic and potentially modifiable factors on the control of hypertension in South Africa (SA). OBJECTIVES: To investigate associations between patients' socio-economic status and characteristics of primary healthcare facilities, and control and treatment of blood pressure in hypertensive patients. METHODS: We enrolled hypertensive patients attending 38 public sector primary care clinics in the Western Cape, SA, in 2011, and followed them up 14 months later as part of a randomised controlled trial. Blood pressure was measured and prescriptions for antihypertension medications were recorded at baseline and follow-up. Logistic regression models assessed associations between patients' socioeconomic status, characteristics of primary healthcare facilities, and control and treatment of blood pressure. RESULTS: Blood pressure was uncontrolled in 60% (1 917/3 220) of patients at baseline, which was less likely in patients with a higher level of education (p=0.001) and in English compared with Afrikaans respondents (p=0.033). Treatment was intensified in 48% (892/1 872) of patients with uncontrolled blood pressure at baseline, which was more likely in patients with higher blood pressure at baseline (p<0.001), concurrent diabetes (p=0.013), more education (p=0.020), and those who attended clinics offering off-site drug supply (p=0.009), with a doctor every day (p=0.004), or with more nurses (p<0.001). CONCLUSION: Patient and clinic factors influence blood pressure control and treatment in primary care clinics in SA. Potential modifiable factors include ensuring effective communication of health messages, providing convenient access to medications, and addressing staff shortages in primary care clinics.

Developing 3D SEM in a broad biological context.

When electron microscopy (EM) was introduced in the 1930s it gave scientists their first look into the nanoworld of cells. Over the last 80 years EM has vastly increased our understanding of the complex cellular structures that underlie the diverse functions that cells need to maintain life. One drawback that has been difficult to overcome was the inherent lack of volume information, mainly due to the limit on the thickness of sections that could be viewed in a transmission electron microscope (TEM). For many years scientists struggled to achieve three-dimensional (3D) EM using serial section reconstructions, TEM tomography, and scanning EM (SEM) techniques such as freeze-fracture. Although each technique yielded some special information, they required a significant amount of time and specialist expertise to obtain even a very small 3D EM dataset. Almost 20 years ago scientists began to exploit SEMs to image blocks of embedded tissues and perform serial sectioning of these tissues inside the SEM chamber. Using first focused ion beams (FIB) and subsequently robotic ultramicrotomes (serial block-face, SBF-SEM) microscopists were able to collect large volumes of 3D EM information at resolutions that could address many important biological questions, and do so in an efficient manner. We present here some examples of 3D EM taken from the many diverse specimens that have been imaged in our core facility. We propose that the next major step forward will be to efficiently correlate functional information obtained using light microscopy (LM) with 3D EM datasets to more completely investigate the important links between cell structures and their functions.

MIR137 variants identified in psychiatric patients affect synaptogenesis and neuronal transmission gene sets.

Sequence analysis of 13 microRNA (miRNA) genes expressed in the human brain and located in genomic regions associated with schizophrenia and/or bipolar disorder, in a northern Swedish patient/control population, resulted in the discovery of two functional variants in the MIR137 gene. On the basis of their location and the allele frequency differences between patients and controls, we explored the hypothesis that the discovered variants impact the expression of the mature miRNA and consequently influence global mRNA expression affecting normal brain functioning. Using neuronal-like SH-SY5Y cells, we demonstrated significantly reduced mature miR-137 levels in the cells expressing the variant miRNA gene. Subsequent transcriptome analysis showed that the reduction in miR-137 expression led to the deregulation of gene sets involved in synaptogenesis and neuronal transmission, all implicated in psychiatric disorders. Our functional findings add to the growing data, which implicate that miR-137 has an important role in the etiology of psychiatric disorders and emphasizes its involvement in nervous system development and proper synaptic function.

[Animal models of Charcot-Marie-Tooth disease and their relevance for understanding the disease in humans]. / Modèles animaux dans la maladie de Charcot-Marie-Tooth et applications de la compréhension de la maladie chez l'homme.

Charcot-Marie-Tooth neuropathies (CMT) are inherited neuromuscular disorders caused by length-dependent neurodegeneration of peripheral nerves. More than 900 mutations in 60 different genes are responsible for Charcot-Marie-Tooth neuropathy. Despite significant progress in therapeutic strategies, the disease remains incurable. The increasing number of genes linked to the disease, and their considerable clinical and genetic heterogeneity renders the development of these strategies particularly challenging. In this context, cellular and animals models provide powerful tools. Efficient motor and sensory tests have been developed to assess the behavioral phenotype in transgenic animal models (rodents and fly). When these models reproduce a phenotype comparable to CMT, they allow therapeutic approaches and the discovery of modifiers and biomarkers. The majority of these models concern the demyelinating form (type 1) of the disease. The axonal form (type 2) is less common. Both forms can further be divided into multiple subtypes reflecting the heterogeneity of the disease. In this review, we describe the most convincing transgenic rodent and fly models of CMT and how some of them led to clinical trials.

Distal myopathy with upper limb predominance caused by filamin C haploinsufficiency.

OBJECTIVE: In this study, we investigated the detailed clinical findings and underlying genetic defect in 3 presumably related Bulgarian families displaying dominantly transmitted adult onset distal myopathy with upper limb predominance. METHODS: We performed neurologic, electrophysiologic, radiologic, and histopathologic analyses of 13 patients and 13 at-risk but asymptomatic individuals from 3 generations. Genome-wide parametric linkage analysis was followed by bidirectional sequencing of the filamin C (FLNC) gene. We characterized the identified nonsense mutation at cDNA and protein level. RESULTS: Based on clinical findings, no known myopathy subtype was implicated in our distal myopathy patients. Light microscopic analysis of affected muscle tissue showed no specific hallmarks; however, the electron microscopy revealed changes compatible with myofibrillar myopathy. Linkage studies delineated a 9.76 Mb region on chromosome 7q22.1-q35 containing filamin C (FLNC), a gene previously associated with myofibrillar myopathy. Mutation analysis revealed a novel c.5160delC frameshift deletion in all patients of the 3 families. The mutation results in a premature stop codon (p.Phe1720LeufsX63) that triggers nonsense-mediated mRNA decay. FLNC transcript levels were reduced in muscle and lymphoblast cells from affected subjects and partial loss of FLNC in muscle tissue was confirmed by protein analysis. CONCLUSIONS: The FLNC mutation that we identified is distinct in terms of the associated phenotype, muscle morphology, and underlying molecular mechanism, thus extending the currently recognized clinical and genetic spectrum of filaminopathies. We conclude that filamin C is a dosage-sensitive gene and that FLNC haploinsufficiency can cause a specific type of myopathy in humans.

Dominant GDAP1 mutations cause predominantly mild CMT phenotypes.

OBJECTIVE: Ganglioside-induced differentiation associated-protein 1 (GDAP1) mutations are commonly associated with autosomal recessive Charcot-Marie-Tooth (ARCMT) neuropathy; however, in rare instances, they also lead to autosomal dominant Charcot-Marie-Tooth (ADCMT). We aimed to investigate the frequency of disease-causing heterozygous GDAP1 mutations in ADCMT and their associated phenotype. METHODS: We performed mutation analysis in a large cohort of ADCMT patients by means of bidirectional sequencing of coding regions and exon-intron boundaries of GDAP1. Intragenic GDAP1 deletions were excluded using an allele quantification assay. We confirmed the pathogenic character of one sequence variant by in vitro experiments assaying mitochondrial morphology and function. RESULTS: In 8 Charcot-Marie-Tooth disease (CMT) families we identified 4 pathogenic heterozygous GDAP1 mutations, 3 of which are novel. Three of the mutations displayed reduced disease penetrance. Disease onset in the affected individuals was variable, ranging from early childhood to adulthood. Disease progression was slow in most patients and overall severity milder than typically seen in autosomal recessive GDAP1 mutations. Electrophysiologic changes are heterogeneous but compatible with axonal neuropathy in the majority of patients. CONCLUSIONS: With this study, we broaden the phenotypic and genetic spectrum of autosomal dominant GDAP1-associated neuropathies. We show that patients with dominant GDAP1 mutations may display clear axonal CMT, but may also have only minimal clinical and electrophysiologic abnormalities. We demonstrate that cell-based functional assays can be reliably used to test the pathogenicity of unknown variants. We discuss the implications of phenotypic variability and the reduced penetrance of autosomal dominant GDAP1 mutations for CMT diagnostic testing and counseling.

N88S mutation in the BSCL2 gene in a Serbian family with distal hereditary motor neuropathy type V or Silver syndrome.

BACKGROUND: Distal hereditary motor neuropathy type V (dHMN-V) and Silver syndrome are rare phenotypically overlapping diseases which can be caused by mutations in the Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2) gene or Seipin. AIM: To report the first Serbian family with a BSCL2 mutation showing variable expression within the family. PATIENTS AND METHODS: A 55-year-old woman presented with weakness of both hands at the age of 45. At age 47, she noticed distal muscle weakness and atrophy in her legs. Physical examination revealed atrophy and weakness of small hand muscles and mild atrophy and weakness of the lower limbs. There was generalized hyperreflexia with the exception of ankle reflexes which were diminished. Her 25year-old son had only stiffness of both legs at the age of 22. Physical examination revealed only generalized hyporeflexia. The third affected member in this family was her 55year-old cousin who showed a more prominent involvement of leg muscles with mild asymmetrical weakness of hand muscles and no pyramidal tract features. RESULTS: In all three patients sensory nerve conduction velocities (NCV) were normal in all extremities. Compound muscle action potential (CMAP) amplitudes were markedly reduced in all patients. Concentric needle EMG showed evidence of chronic denervation in distal muscles. DNA sequencing of BSCL2 was performed and a heterozygous N88S missense mutation in BSCL2 gene was detected in all three patients. CONCLUSION: This report is further confirmation of phenotypic heterogenity due to the N88S mutation of BSCL2 gene in the same family.

Effect on tuberculosis outcomes of educational outreach to South African clinics during two randomised trials.

SETTING: Public sector primary care clinics in Free State Province, South Africa. OBJECTIVES: To investigate the effects of on-site in-service clinical skills training for nurse practitioners on tuberculosis (TB) treatment outcomes in the same clinics. DESIGN: Analysis of TB programme data from clinics taking part in two consecutive randomised trials of educational outreach aimed at improving respiratory and human immunodeficiency virus/acquired immune-deficiency syndrome care based on the Practical Approach to Lung Health. We compared treatment outcomes between control and intervention clinics among all patients diagnosed with TB during either trial. RESULTS: During the two trials, participating clinics treated 4187 and 2333 TB patients, respectively. Neither intervention was associated with better outcomes overall. However, among retreatment patients, cure or completion rates in intervention clinics were significantly higher during the second trial (OR 1.78, 95%CI 1.13-2.76). Patients in clinics that had received both interventions had higher cure or completion rates (OR 1.99, 95%CI 1.53-2.58) and lower default rates (OR 0.25, 95%CI 0.097-0.63) than patients in clinics that had received neither intervention. CONCLUSION: Although not primarily focused on TB treatment, the interventions appeared to improve successful treatment completion rates among TB retreatment cases. Integrated care programmes support attainment of important TB programme goals.

Further evidence that mutations in FGD4/frabin cause Charcot-Marie-Tooth disease type 4H.

BACKGROUND: Autosomal recessive demyelinating Charcot-Marie-Tooth neuropathy type 4H (CMT4H) manifests early onset, severe functional impairment, deforming scoliosis, and myelin outfoldings in the nerve biopsy. Mutations in the FGD4 gene encoding the Rho-GTPase guanine-nucleotide-exchange-factor frabin were reported in five families. OBJECTIVE: To characterize a novel mutation in FGD4 and describe the related phenotype. METHODS: A 20-year-old woman born of healthy consanguineous parents and affected with early-onset peroneal muscular atrophy underwent standard clinical, electrophysiologic, and pathologic (sural nerve biopsy) investigations. Mutational analysis of FGD4 was performed by direct sequencing of genomic DNA. Transcriptional analysis was done by reverse transcriptase PCR on leukocyte RNA. RESULTS: The proband disclosed a moderately severe, scarcely progressive CMT, markedly slowed nerve conduction velocities, and a demyelinating neuropathy characterized by prominent myelin outfoldings. Mutational analysis disclosed a c.1762-2a>g transition in the splice-acceptor site of intron 14, which was predicted to cause a truncated frabin (p.Tyr587fsX14). CONCLUSIONS: The report confirms genetic heterogeneity of FGD4, demonstrates that CMT4H has variable functional impairment, and suggests that frabin plays a crucial role during myelin formation.

Autosomal dominant congenital spinal muscular atrophy--a possible developmental deficiency of motor neurones?

We describe a kindred with an unusual congenital lower motor neuron disorder with significant but static muscle weakness predominantly affecting the lower limbs. The proband had talipes equinovarus and congenital hip contractures and did not walk until 19 months of age. Lower-extremity predominant, primarily proximal weakness was identified on assessment at three years. Over a 20 year follow-up there has been no clinical progression. The proband has a four-year-old daughter with very similar clinical findings. Electromyography and muscle biopsy suggest reduced numbers of giant normal duration motor units with little evidence of denervation or reinnervation. Dominant congenital spinal muscular atrophy predominantly affecting the lower limbs is rarely described. It is possible that the disorder is due to a congenital deficiency of motor neurons.

Two novel mutations in the GDAP1 and PRX genes in early onset Charcot-Marie-Tooth syndrome.

Autosomal recessive Charcot-Marie-Tooth syndrome (AR-CMT) is often characterised by an infantile disease onset and a severe phenotype. Mutations in the ganglioside-induced differentiation-associated protein 1 (GDAP1) gene are thought to be a common cause of AR-CMT. Mutations in the periaxin (PRX) gene are rare. They are associated with severe demyelination of the peripheral nerves and sometimes lead to prominent sensory disturbances. To evaluate the frequency of GDAP1 and PRX mutations in early onset CMT, we examined seven AR-CMT families and 12 sporadic CMT patients, all presenting with progressive distal muscle weakness and wasting. In one family also prominent sensory abnormalities and sensory ataxia were apparent from early childhood. In three families we detected four GDAP1 mutations (L58LfsX4, R191X, L239F and P153L), one of which is novel and is predicted to cause a loss of protein function. In one additional family with prominent sensory abnormalities a novel homozygous PRX mutation was found (A700PfsX17). No mutations were identified in 12 sporadic cases. This study suggests that mutations in the GDAP1 gene are a common cause of early-onset AR-CMT. In patients with early-onset demyelinating AR-CMT and severe sensory loss PRX is one of the genes to be tested.

Charcot-Marie-Tooth disease: a clinico-genetic confrontation.

Charcot-Marie-Tooth disease (CMT) is the most common neuromuscular disorder. It represents a group of clinically and genetically heterogeneous inherited neuropathies. Here, we review the results of molecular genetic investigations and the clinical and neurophysiological features of the different CMT subtypes. The products of genes associated with CMT phenotypes are important for the neuronal structure maintenance, axonal transport, nerve signal transduction and functions related to the cellular integrity. Identifying the molecular basis of CMT and studying the relevant genes and their functions is important to understand the pathophysiological mechanisms of these neurodegenerative disorders, and the processes involved in the normal development and function of the peripheral nervous system. The results of molecular genetic investigations have impact on the appropriate diagnosis, genetic counselling and possible new therapeutic options for CMT patients.

Phenotype of Charcot-Marie-Tooth disease Type 2.

OBJECTIVE: To investigate the clinical and electrophysiologic phenotype of Charcot-Marie-Tooth disease (CMT) Type 2 in a large number of affected families. METHODS: We excluded CMT Type 1, hereditary neuropathy with liability to pressure palsies, and CMT due to Cx32 gene mutations by DNA analysis. We performed genetic analysis of the presently known CMT Type 2 genes. RESULTS: Sixty-one persons from 18 families were affected. Ninety percent of patients were able to walk with or without the help of aids. Proximal leg muscle weakness was present in 13%. Asymmetrical features were present in 15%. Normal or brisk knee reflexes were present in 36%. Extensor plantar responses without associated spasticity occurred in 10 patients from eight families. Only three causative mutations were identified in the MFN2, BSCL2, and RAB7 genes. No mutations were found in the NEFL, HSPB1, HSPB8, GARS, DNM2, and GDAP1 genes. CONCLUSIONS: At group level, the clinical phenotype of Charcot-Marie-Tooth disease (CMT) Type 2 is uniform, with symmetric, distal weakness, atrophy and sensory disturbances, more pronounced in the legs than in the arms, notwithstanding the genetic heterogeneity. Brisk reflexes, extensor plantar responses, and asymmetrical muscle involvement can be considered part of the CMT Type 2 phenotype. The causative gene mutation was found in only 17% of the families we studied.

Spastin gene mutations in Bulgarian patients with hereditary spastic paraplegia.

Hereditary spastic paraplegia (HSP) is an extremely heterogeneous group of neurodegenerative disorders affecting the longest axons in the central nervous system. The most common genetic form accounting for about 40% of the autosomal-dominant HSP (ADHSP) cases is spastin gene, SPG4. We performed mutation screening of the spastin gene on 36 unrelated HSP patients from three different ethnic groups (Bulgarian, Turks and Gypsies) and found four new mutations and one already reported. The phenotype-genotype correlations in Bulgarian SPG4 patients showed a great difference in the age at disease onset between patients with missense mutations and those harboring deletions and splice-site mutations. Our study is the first to present corroborative clinical data in favor of the general hypothesis that the clinical course of the disease is related to the type of the spastin mutation. The clinical and genealogical findings in Bulgarian SPG4 patients suggest that a positive family history for inheritance as an autosomal-dominant trait is a strong indication for spastin mutation screening.

Novel mutations in the HSN2 gene causing hereditary sensory and autonomic neuropathy type II.

Hereditary sensory and autonomic neuropathy type II (HSAN-II) is caused by recessive mutations in the HSN2 gene assigned to chromosome 12p13.33. The authors report three unrelated HSAN-II families with homozygous or compound heterozygous mutations resulting in the truncation of the HSN2 protein. Genotype-phenotype correlations indicated that HSN2 mutations are associated with an early childhood onset of a predominantly sensory neuropathy, complicated by acromutilations in both upper and lower limbs.

Autosomal dominant striatal degeneration (ADSD): clinical description and mapping to 5q13-5q14.

OBJECTIVE: To describe the clinical and neuroradiologic features and chromosomal mapping of a novel autosomal dominant disease affecting the basal ganglia. METHODS: The authors characterized a large family with autosomal dominant basal ganglia disease (ADSD) clinically and by MRI, MR spectroscopy (MRS), and SPECT. The authors performed a whole genome genetic linkage scan to map the underlying genetic defect. RESULTS: The main clinical features of the disease are dysarthria and gait disturbance without any apparent reduction in life expectancy. MRI demonstrated a distinctive lesion pattern restricted mainly to the putamen and caudate nucleus. Genetic linkage analysis localized the causative genetic defect to a 3.25 megabase candidate region on chromosome 5q13.3-q14.1. CONCLUSIONS: ADSD is an autosomal dominant basal ganglia disease mapping to chromosome 5q13.3-q14.1.

Absence of KIF1B mutation in a large Turkish CMT2A family suggests involvement of a second gene.

BACKGROUND: Charcot-Marie-Tooth disease type 2A (CMT2A) was assigned to a 19.3-cM region on chromosome 1p35-36. A missense mutation in the kinesin family member 1B gene (KIF1B) was reported in a single CMT2A family. OBJECTIVE: To report the clinical and genetic data of a Turkish family with CMT2A. METHODS: Linkage to CMT2 loci was investigated in the family. Haplotype analysis of the CMT2A region was completed using additional single-nucleotide polymorphism and short tandem repeat markers. The KIF1B gene was sequenced on genomic DNA and cDNA in two patients. RESULTS: A recombination event narrowed the CMT2A locus to a 9.3-cM region flanked by D1S160 and D1S434. No mutation in KIF1B was found. CONCLUSION: The exclusion of KIF1B gene mutations in this family suggests the involvement of another CMT2A gene in the linked region.

SPTLC1 mutation in twin sisters with hereditary sensory neuropathy type I.

Hereditary sensory neuropathy type I (HSN I) is an autosomal dominant ulceromutilating disorder of the peripheral nervous system characterized by progressive sensory loss. HSN I locus maps to chromosome 9q22.1-22.3 and is caused by mutations in the gene coding for serine palmitoyltransferase long-chain base subunit 1 (SPTLC1). A novel missense mutation in exon 13 of the SPTLC1 gene (c.1160G-->C; p.G387A) in twin sisters with a severe HSN I phenotype is reported.

Charcot-Marie-Tooth disease with giant axons: a clinicopathological and genetic entity.

The authors report an Italian family with autosomal-dominant Charcot-Marie-Tooth disease (CMT) in which there were giant axons in the sural nerve biopsy. Linkage to the known CMT2 loci (CMT2A, CMT2B, CMT2D, CMT2F) and mutations in the known CMT2 genes (Cx32, MPZ, NEFL), GAN, NEFM, and CMT1A duplication/HNPP deletion were excluded. This family with CMT and giant axons has a pathologic and genetic entity distinct from classic CMT.