Horizontal gaze palsy with progressive scoliosis can result from compound heterozygous mutations in ROBO3

Background

Horizontal gaze palsy with progressive scoliosis (HGPPS) is an autosomal recessive disorder characterised by congenital absence of horizontal gaze, progressive scoliosis, and failure of the corticospinal and somatosensory axon tracts to decussate in the medulla. We previously reported that HGPPS patients from consanguineous pedigrees harbour homozygous mutations in the axon guidance molecule ROBO3.

Methods

We now report two sporadic HGPPS children of non‐consanguineous parents who harbour compound heterozygous mutations in ROBO3. The mother of one of the children also had scoliosis DNA was extracted from a blood sample from each participant using a standard protocol, and the coding exons of ROBO3 were amplified and sequenced as previously described.

Results

Each patient harboured two unique heterozygous mutations in ROBO3, having inherited one mutation from each parent.

Conclusions

HGPPS can result from compound heterozygous mutations. More comprehensive examinations of parents and siblings of HGPPS patients are required to determine if the incidence of scoliosis in individuals harbouring heterozygous ROBO3 mutations is greater than in the general population.     

Mutation screening in Borjeson-Forssman-Lehmann syndrome: identification of a novel de novo PHF6 mutation in a female patient

Background

Börjeson‐Forssman‐Lehmann syndrome (BFLS; MIM 301900) is an infrequently described X linked disorder caused by mutations in PHF6, a novel zinc finger gene of unknown function.

Objective

To present the results of mutation screening in individuals referred for PHF6 testing and discuss the value of prior X‐inactivation testing in the mothers of these individuals.

Results

25 unrelated individuals were screened (24 male, one female). Five PHF6 mutations were detected, two of which (c.940A→G and c.27_28insA) were novel. One of these new mutations, c.27_28insA, was identified in a female BFLS patient. This was shown to be a de novo mutation arising on the paternal chromosome. This is the first report of a clinically diagnosed BFLS female with a confirmed PHF6 mutation. In addition, the X‐inactivation status of the mothers of 19 males with suggested clinical diagnosis of BFLS was determined. Skewed (⩾70%) X‐inactivation was present in five mothers, three of whom had sons in whom a PHF6 mutation was detected. The mutation positive female also showed skewing.

Conclusions

The results indicate that the success of PHF6 screening in males suspected of having BFLS is markedly increased if there is a positive family history and/or skewed X‐inactivation is found in the mother.     

Assessment of psychological barriers to cervical cancer screening among women in Kumasi,Ghana using a mixed methods approach

Background

Cervical cancer is the leading cause of cancer death among women in Ghana, West Africa. The cervical cancer mortality rate in Ghana is more than three times the global cervical cancer mortality rate. Pap tests and visual inspection with acetic acid wash are widely available throughout Ghana, yet less that 3% of Ghanaian women get a cervical cancer screening at regular intervals.

Objective

This exploratory study was to identify psychological barriers to cervical cancer screening among Ghanaian women with and without cancer using a mixed methods approach.

Methods

Semi-structured interviews were conducted with 49 Ghanaian women with cancer and 171 Ghanaian women who did not have cancer.

Results

The results of the quantitative analysis indicated that cancer patients where not more likely to have greater knowledge of cancer signs and symptoms than women without cancer. Analysis of the qualitative data revealed several psychological barriers to cervical cancer screening including, common myths about cervical cancer, misconceptions about cervical cancer screening, the lack of spousal support for screening, cultural taboos regarding the gender of healthcare providers, and the stigmatization of women with cervical cancer.

Conclusion

The results of this study can be used to inform the development of culturally relevant cervical cancer education interventions aimed at addressing the psychological barriers to cervical cancer screening perceived by Ghanaian women.     

Is the E133K allele of VG5Q associated with Klippel‐Trenaunay and other overgrowth syndromes?

Background

It has been reported that the activating mutation, E133K, in the angiogenic factor VG5Q (formally named AGGF1) causes Klippel‐Trenaunay Syndrome (KTS), a rare vascular disease associated with asymmetric overgrowth. This proposal followed from the observation that five out of 130 KTS patients were constitutionally heterozygous for VG5Q, E133K.

Objective

To explore the possibility that VG5Q, and specifically E133K, is implicated in other mosaic overgrowth syndromes.

Results

24 patients were analysed for this sequence change.One patient was constitutionally heterozygous for E133K. Analysis of both parents revealed that the patient''s mother, who was healthy, also carried E133K. An analysis of 275 healthy controls showed that 3.3% (9/275) of the population were carriers of E133K.

Conclusions

The findings bring into question the assertion that VG5Q, E133K is a mutation and that it causes KTS.     

Measurement of the clinical utility of a combined mutation detection protocol in carriers of Duchenne and Becker muscular dystrophy

Background

Recent methodological advances have improved the detection rate for dystrophin mutations, but there are no published studies that have measured the clinical utility of these protocols for carrier detection compared with conventional carrier testing protocols that use pedigree, serum creatine kinase levels and linkage analysis.

Methods and subjects

The clinical utility of a combined mutation detection protocol was measured. It involved quantitative PCR procedures followed by DNA sequence analysis for the identification of dystrophin mutation carriers in 2101 women at risk of being carriers from 348 mutation‐known Duchenne or Becker muscular dystrophy pedigrees.

Results

The combined mutation detection protocol identified a mutation in 96% and 82% of index cases of Duchenne muscular dystrophy and Becker muscular dystrophy, respectively. An additional 692 (33%) potential carriers were correctly classified by the combined mutation detection protocol compared with pedigree, serum creatine kinase levels and linkage analysis. Significantly lower mutation carrier rates were identified in the mothers of isolated cases with deletion mutations than predicted from theoretical considerations, but these findings were not confirmed for duplication and DNA sequence mutations.

Conclusions

There are significant clinical benefits to be gained from a combined mutation detection protocol for carrier detection. It is recommended that mutation‐specific carrier frequencies for the different classes of dystrophin mutations should be taken into account in genetic counselling practice.Duchenne and Becker muscular dystrophies (D/BMD) are allelic disorders of skeletal muscle in which the major clinical feature is progressive muscle weakness (Online Mendelian Inheritance in Man (OMIM) 310200 & 300376).¹ The clinical diagnosis of D/BMD can be confirmed either by the identification of a mutation in the dystrophin gene or by histological analysis of a patient''s affected muscle tissue; however, DNA testing has been found to be more acceptable than muscle biopsy owing to its less invasive nature, minimal side effects and reduced costs. The potential benefits of identifying a dystrophin mutation in a male with symptoms include the confirmation of the clinical diagnosis as the basis for management, the ability to determine the carrier status of female relatives and possibly as a future precondition for therapy.The standard molecular genetic protocol for the diagnosis of D/BMD is multiplex PCR of a subset of dystrophin exons.^2,3 This technique is able to detect ∼95% of deletion mutations, but is unable to detect exon duplications and DNA sequence mutations in males with symptoms. Carrier testing in diagnostic laboratories has been principally based on linkage studies, initially using restriction fragment length polymorphisms detected by Southern blot analysis,⁴ and subsequently by PCR amplification of short tandem repeat (STR) loci.⁵ Linkage studies can be used to identify deletion mutation carriers on the basis of the presence of an informative STR locus within the deletion interval, and the demonstration of either heterozygosity or apparent non‐Mendelian inheritance, but are unable to determine maternal carrier status for duplication or DNA sequence mutations.⁶ As linkage results are frequently compromised by the unavailability of DNA samples, the distribution and informativeness of STRs, and the possibility of gonadal mosaicism, adjunct techniques such as fluorescence in situ hybridisation and pulsed field gel electrophoresis have been used by reference laboratories to resolve such cases.⁷The recent introduction of quantitative PCR‐based techniques, such as multiplex ligation‐dependent probe amplification (MLPA), have significantly improved mutation detection for exon deletions and duplications in males with symptoms and carrier females.^8,9 Similarly, point mutation detection has been improved by the availability of techniques such as detection of virtually all mutations, denaturing gradient gel electrophoresis, denaturing high‐performance liquid chromatography and protein truncation test, but the falling costs of DNA sequencing and the availability of semi‐automated DNA analysis software have made direct DNA sequence analysis of the dystrophin gene feasible.¹⁰ Mutation detection protocols based on the sequential analysis of samples by MLPA and DNA sequence analysis therefore have the potential for high mutation detection sensitivities. While there are several published studies that address issues of analytical and clinical validity of either MLPA or DNA sequence analysis for dystrophin mutation detection, studies that have measured the clinical utility of combined MLPA and DNA sequence analysis compared to that of conventional protocols for carrier detection available to non‐reference laboratories are lacking.     

Molecular analysis of exons 8, 9 and 10 of the fibroblast growth factor receptor 2 (FGFR2) gene in two families with index cases of Apert Syndrome

Introduction:

Apert syndrome (AS) is a craniosynostosis condition caused by mutations in the Fibroblast Growth Factor Receptor 2 (FGFR2) gene. Clinical features include cutaneous and osseous symmetric syndactily in hands and feet, with variable presentations in bones, brain, skin and other internal organs.

Methods:

Members of two families with an index case of Apert Syndrome were assessed to describe relevant clinical features and molecular analysis (sequencing and amplification) of exons 8, 9 and 10 of FGFR2 gen.

Results:

Family 1 consists of the mother, the index case and half -brother who has a cleft lip and palate. In this family we found a single FGFR2 mutation, S252W, in the sequence of exon 8. Although mutations were not found in the study of the patient affected with cleft lip and palate, it is known that these diseases share signaling pathways, allowing suspected alterations in shared genes. In the patient of family 2, we found a sequence variant T78.501A located near the splicing site, which could interfere in this process, and consequently with the protein function.     

Analysis of the LRRK2 p.G2019S mutation in Colombian Parkinson's Disease Patients

Introduction:

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2 or Dardarin) are considered to be a common cause of autosomal dominant and sporadic Parkinson´s disease, but the prevalence of these mutations varies among populations.

Objective:

to analyzed the frequency of the LRRK2 p.G2019S mutation (c.6055 G>A transition) in a sample of Colombian patients.

Methods:

In the present study we have analyzed the frequency of the LRRK2 p.G2019S mutation in 154 patients with familial or sporadic Parkinson Disease, including early and late onset patients, and 162 normal controls.

Results:

Our results show occurrence of this mutation in two cases (2/154, 1.3%) with classical Parkinson´s signs, and one completely asymptomatic control (1/162, 0.6%).

Conclusion:

The p.G2019S mutation is not an important causal factor of Parkinson Disease in Colombia having similar frequencies to those reported in other Latin American populations.     

Insomnia Did Not Predict Incident Hypertension in Older Adults in the Cardiovascular Health Study

Study Objective:

We hypothesized that the sleep complaints of insomnia predict incident hypertension, particularly in African Americans. The purpose of this study was to analyze insomnia complaints as predictors of incident hypertension in the Cardiovascular Health Study (CHS), stratifying by gender and allowing for race and sleep variable interaction.

Design:

This is a prospective cohort study over a 6-year period of follow-up.

Setting:

This is a community-based study of participants in Forsyth County, North Carolina; Pittsburgh, Pennsylvania; Sacramento County, California; and Washington County, Maryland.

Participants:

The study analyzed data from 1419 older individuals (baseline mean age 73.4 ± 4.4 years) from the Cardiovascular Health Study who were not hypertensive at baseline.

Interventions:

none

Measurements:

We constructed relative risks of incident hypertension over a 6-year period for insomnia complaints singly and in combination.

Results:

Difficulty falling asleep, singly or in combination with other sleep complaints, predicted a statistically significant reduction of risk for incident hypertension for non-African American men in 6 years of follow-up. Insomnia complaints did not predict incident hypertension in 6 years of follow-up in women or in African Americans, although there may not have been enough power to show a significant association for African Americans.

Conclusions:

Insomnia did not predict hypertension in this older cohort which was free of hypertension at baseline. Difficulty falling asleep was associated with reduced risk of hypertension in non-African American men.

Citation:

Phillips B; Bůžková P; Enright P. Insomnia did not predict incident hypertension in older adults in the cardiovascular health study. SLEEP 2009;32(1):65-72.     

Spastin mutations are frequent in sporadic spastic paraparesis and their spectrum is different from that observed in familial cases

Background

SPG4 encodes spastin, a member of the AAA protein family, and is the major gene responsible for autosomal dominant spastic paraplegia. It accounts for 10–40% of families with pure (or eventually complicated) hereditary spastic paraparesis (HSP).

Objective

To assess the frequency of SPG4 mutation in patients with spastic paraplegia but without family histories.

Methods

146 mostly European probands with progressive spastic paraplegia were studied (103 with pure spastic paraplegia and 43 with additional features). Major neurological causes of paraplegia were excluded. None had a family history of paraplegia. DNA was screened by DHPLC for mutations in the 17 coding exons of the SPG4 gene. Sequence variants were characterised by direct sequencing. A panel of 600 control chromosomes was used to rule out polymorphisms.

Results

The overall rate of mutations was 12%; 19 different mutations were identified in 18 patients, 13 of which were novel. In one family, where both parents were examined and found to be normal, the mutation was transmitted by the asymptomatic mother, indicating reduced penetrance. The parents of other patients were not available for analysis but were reported to be normal. There was no evidence for de novo mutations. The mutations found in these apparently isolated patients were mostly of the missense type and tended to be associated with a less severe phenotype than previously described in patients with inherited mutations.

Conclusions

: The unexpected presence of SPG4 gene mutations in patients with sporadic spastic paraplegia suggests that gene testing should be done in individuals with pure or complicated spastic paraplegia without family histories.     

Novel nonsense mutation of BRCA2 gene in a Moroccan man with familial breast cancer

Background

Breast cancer is the most common cancer in women worldwide. About 5 to 10% of cases are due to an inherited predisposition in two major genes, BRCA1 and BRCA2, transmitted as an autosomal dominant form. Male breast cancer is rare and is mainly due to BRCA2 than BRCA1 germline mutations.

Objective

Molecular study of BRCA2 gene in man with familial breast cancer.

Methods

PCR and direct sequencing of BRCA2 gene.

Results

Identification of novel heterozygous germline mutation c.6428C>A ; p.Ser2143Stop of BRCA2 gene.     

Late recurrence of sigmoid carcinoma mimicking primary vulvar cancer: case report and review of the literature

Objective

To demonstrate a unique case report about late and isolated vulvar metastasis of sigmoid adeno-carcinoma with review of the literature.

Material-method

57 year old postmenopausal patient with prior sigmoid colon cancer history was admitted with isolated vulvar mass. Immunohistochemistry (IHC) and KRAS gen mutation analysis following surgery were performed to discriminate the metastasis from a vulvar primary malignancy. Further imaging techniques were also performed to exclude additional tumours.

Results

Immunohistochemistry (IHC) and KRAS gene mutation analysis revealed isolated metastasis of the colonic adeno-carcinoma in the vulva.

Conclusion

Isolated and late occurring vulvar metastasis of colonic origin is very unusual. Careful evaluation and IHC is useful for such cases.     

AHI1 mutations cause both retinal dystrophy and renal cystic disease in Joubert syndrome

Background

Joubert syndrome (JS) is an autosomal recessive disorder characterised by hypotonia, ataxia, mental retardation, altered respiratory pattern, abnormal eye movements, and a brain malformation known as the molar tooth sign (MTS) on cranial MRI. Four genetic loci have been mapped, with two genes identified (AHI1 and NPHP1).

Methods

We screened a cohort of 117 JS subjects for AHI1 mutations by a combination of haplotype analysis and sequencing of the gene, and for the homozygous NPHP1 deletion by sequencing and marker analysis.

Results

We identified a total of 15 novel AHI1 mutations in 13 families, including nonsense, missense, splice site, and insertion mutations, with some clustering in the WD40 domains. Eight families were consanguineous, but no single founder mutation was apparent. In addition to the MTS, retinal dystrophy was present in 11 of 12 informative families; however, no subjects exhibited variable features of JS such as polydactyly, encephalocele, colobomas, or liver fibrosis. In contrast to previous reports, we identified two families with affected siblings who developed renal disease consistent with nephronophthisis (NPH) in their 20s. In addition, two individuals with classic NPH were found to have homozygous NPHP1 deletions.

Conclusions

Overall, 11% of subjects had AHI1 mutations, while ∼2% had the NPHP1 deletion, representing a total of less than 15% in a large JS cohort. Some preliminary genotype‐phenotype correlations are possible, notably the association of renal impairment, specifically NPH, in those with NPHP1 deletions. Subjects with AHI1 mutations may be at risk of developing both retinal dystrophy and progressive kidney disease.     

A common nonsense mutation in EphB2 is associated with prostate cancer risk in African American men with a positive family history

Background

The EphB2 gene was recently implicated as a prostate cancer (PC) tumour suppressor gene, with somatic inactivating mutations occurring in ∼10% of sporadic tumours. We evaluated the contribution of EphB2 to inherited PC susceptibility in African Americans (AA) by screening the gene for germline polymorphisms.

Methods

Direct sequencing of the coding region of EphB2 was performed on 72 probands from the African American Hereditary Prostate Cancer Study (AAHPC). A case‐control association analysis was then carried out using the AAHPC probands and an additional 183 cases of sporadic PC compared with 329 healthy AA male controls. In addition, we performed an ancestry adjusted association study where we adjusted for individual ancestry among all subjects, in order to rule out a spurious association due to population stratification.

Results

Ten coding sequence variants were identified, including the K1019X (3055A→T) nonsense mutation which was present in 15.3% of the AAHPC probands but only 1.7% of 231 European American (EA) control samples. We observed that the 3055A→T mutation significantly increased risk for prostate cancer over twofold (Fisher''s two sided test, p = 0.003). The T allele was significantly more common among AAHPC probands (15.3%) than among healthy AA male controls (5.2%) (odds ratio 3.31; 95% confidence interval 1.5 to 7.4; p = 0.008). The ancestry adjusted analyses confirmed the association.

Conclusions

Our data show that the K1019X mutation in the EphB2 gene differs in frequency between AA and EA, is associated with increased risk for PC in AA men with a positive family history, and may be an important genetic risk factor for prostate cancer in AA.     

Therapeutic Potential of Proteasome Inhibition in Duchenne and Becker Muscular Dystrophies

Duchenne muscular dystrophy (DMD) and its milder allelic variant, Becker muscular dystrophy (BMD), result from mutations of the dystrophin gene and lead to progressive muscle deterioration. Enhanced activation of proteasomal degradation underlies critical steps in the pathogenesis of the DMD/BMD dystrophic process. Previously, we demonstrated that treatment with the proteasome inhibitor MG-132 rescues the cell membrane localization of dystrophin and the dystrophin glycoprotein complex in mdx mice, a natural genetic mouse model of DMD. The current work aims to thoroughly define the therapeutic potential in dystrophinopathies of Velcade, a drug that selectively blocks the ubiquitin-proteasome pathway. Velcade is particularly intriguing since it has been approved for the treatment of multiple myeloma. Therefore, its side effects in humans have been explored. Velcade effects were analyzed through two independent methodological approaches. First, we administered the drug systemically in mdx mice over a 2-week period. In this system, Velcade restores the membrane expression of dystrophin and dystrophin glycoprotein complex members and improves the dystrophic phenotype. In a second approach, we treated with the compound explants from muscle biopsies of DMD or BMD patients. We show that the inhibition of the proteasome pathway up-regulates dystrophin, α-sarcoglycan, and β-dystroglycan protein levels in explants from BMD patients, whereas it increases the proteins of the dystrophin glycoprotein complex in DMD cases.Duchenne muscular dystrophy (DMD) is an incurable inherited disease, characterized by progressive muscle degeneration and weakness. The pathology results from the mutation of the DMD gene, which leads to deficiency of dystrophin, a 427-kDa protein found throughout the cytoplasmic face of the plasma membrane in both skeletal and cardiac muscle. Becker muscular dystrophy (BMD), a much milder allelic form of the disease, is caused by a reduction in the amount, or an alteration in the size, of dystrophin protein. In muscle cells, dystrophin binds through its amino-terminus to cytoskeletal F-actin and through the carboxyl-terminus to β-dystroglycan, a transmembrane component of a multimolecular complex [the dystrophin-glycoprotein complex (DGC)], which includes α, β, γ, δ-sarcoglycan, α, β-dystroglycan, the syntrophins, and dystrobrevin. In the DGC, dystroglycan appears to play a critical role, since it connects dystrophin with the DGC and it also binds laminin in the extracellular space, thus creating a mechanical linkage between cytoskeleton and extracellular matrix.¹Dystrophin deficiency is associated with a severe decrease or absence in the expression and membrane localization of the members of the DGC.² It is feasible that dystrophin primary genetic loss leads to plasma membrane instability, thus causing a disarray of the multimeric complex and addressing its components to intracellular proteolysis. Indeed, different reports indicated that activation of protein degradation through the ubiquitin-proteasome system occurs in the pathogenesis of the DMD/BMD degenerative process.³Consistently, our initial studies showed that local and systemic treatment with the proteasome inhibitor MG-132 rescues the expression of the DGC in mdx mice, a natural genetic mouse model of DMD.⁴ The effects of MG-132 were confirmed in freshly isolated skeletal muscle biopsies from patients affected by DMD or BMD, thus suggesting a possible therapeutic implication for these agents.⁵In the present study we investigated the effects of the drug Velcade (bortezomib, PS-341), a proteasome inhibitor that belongs to the class of peptide boronates. Velcade is particularly appealing to us for different reasons.First, while MG-132 exerts an inhibitory action on both the proteasome and the calpain system, Velcade displays a selective and high affinity to the proteasome. Therefore, this drug is an optimal probe to test the therapeutic potential of the inhibition of the proteasome pathway in muscular dystrophies. Secondarily, Velcade has been already approved by the Food and Drug Administration and the European Medicines Agency for the treatment of multiple myeloma. Thus, its side effects have been already explored and managed.^6,7 Finally, Velcade is able to reduce the activity of nuclear factor-kappa B (NF-κB).⁸ Because NF-κB pathway has been shown to be involved in inflammation responses in myopathies and DMD, Velcade effects on this signaling molecule may have important clinical implications.⁹Our previous results had indicated that Velcade, once injected locally into the gastrocnemius muscles of mdx mice, could up-regulate the expression and membrane localization of dystrophin and members of the DGC.¹⁰ However, the long-term actions of this proteasome inhibitor and its possible side effects in dystrophic animals are not known yet. To thoroughly evaluate Velcade’s therapeutic potential in dystrophinopathies, we adopted an integrated approach. First, we analyzed its efficacy using a systemic treatment and assessed the rescue of the dystrophic phenotype of mdx mice.The mdx mouse model is characterized by a primary genetic defect of dystrophin due to a missense mutation in exon 23, which leads to a premature stop codon. Skeletal muscle tissue from mdx mutants is histologically normal early in postnatal development, but starting around 3 to 4 weeks of age, muscle necrosis develops, with some visible muscle weakness. Although skeletal limb muscles are characterized by a persistent and progressive degeneration and necrosis, at approximately 6 to 8 weeks of age, the muscle damage appears to plateau and it is possible to observe the beginning of a regenerative response activated by satellite cells, which continues until 12 weeks of age.¹¹Concurrently, we investigated the effects of the drug in human muscle explants of fresh biopsies from patients with DMD and BMD.     

Penetrance of adrenocortical tumours associated with the germline TP53 R337H mutation

Background

An inherited germline P53 mutation has been identified in cases of childhood adrenocortical carcinoma (ACT), a neoplasm with a high incidence in southern Brazil. The penetrance of ACT in carriers of the point mutation, which encodes an arginine‐to‐histidine substitution at codon 337 of TP53 (R337H), has not been determined.

Objective

To investigate the penetrance of childhood ACT in carriers of the R337H TP53 mutation.

Methods

The family histories of 30 kindreds of 41 southern Brazilian children with ACT were obtained. A PCR based assay was used to detect this P53 mutation in a large number of relatives of children with ACT. In all, 927 individuals were tested for the mutation, 232 from the non‐carrier and 695 (including the 40 probands) from the carrier parental lines.

Results

40 children with ACT carried the TP53 R337H mutation; the remaining child with ACT was not tested. There was no evidence of Li‐Fraumeni syndrome in any of the kindreds; however, seven met the criteria for Li‐Fraumeni‐like syndrome. The carrier parental line was identified in each kindred. Of the 695 individuals tested in the carrier parental line, 240 (34.5%) were positive for the mutation, while none of the 232 individuals in the other parental line carried the mutation. The penetrance of ACT was 9.9% (95% confidence interval, 8.7% to 11.1%).

Conclusions

The TP53 R337H mutation dramatically increases predisposition to childhood ACT but not to other cancers, and explains the increased frequency of ACT observed in this geographic region.     

Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly

Background

Porencephaly (cystic cavities of the brain) is caused by perinatal vascular accidents from various causes. Several familial cases have been described and autosomal dominant inheritance linked to chromosome 13q has been suggested. COL4A1 is an essential component in basal membrane stability. Mouse mutants bearing an in‐frame deletion of exon 40 of Col4a1 either die from haemorrhage in the perinatal period or have porencephaly in survivors. A report of inherited mutations in COL4A1 in two families has shown that familial porencephaly may have the same cause in humans.

Objective

To describe three novel COL4A1 mutations.

Results

The three mutations occurred in three unrelated Dutch families. There were two missense mutations of glycine residues predicted to result in abnormal collagen IV assembly, and one mutation predicted to abolish the traditional COL4A1 start codon. The last mutation was also present in an asymptomatic obligate carrier with white matter abnormalities on brain magnetic resonance imaging.

Conclusions

This observation confirms COL4A1 as a major locus for genetic predisposition to perinatal cerebral haemorrhage and porencephaly and suggests variable expression of COL4A1 mutations.     

Unilateral Hypoglossal Nerve Injury in a Collegiate Wrestler: A Case Report

Objective:

To introduce the case of a collegiate wrestler who suffered a traumatic unilateral hypoglossal nerve injury. This case presents the opportunity to discuss the diagnosis and treatment of a 20-year-old man with an injury to his right hypoglossal nerve.

Background:

Injuries to the hypoglossal nerve (cranial nerve XII) are rare. Most reported cases are the result of malignancy, with traumatic causes less common. In this case, a collegiate wrestler struck his head on the wrestling mat during practice. No loss of consciousness occurred. The wrestler initially demonstrated signs and symptoms of a mild concussion, with dizziness and a headache. These concussion symptoms cleared quickly, but the athlete complained of difficulty swallowing (dysphagia) and demonstrated slurred speech (dysarthria). Also, his tongue deviated toward the right. No other neurologic deficits were observed.

Differential Diagnosis:

Occipital-cervical junction fracture, syringomyelia, malignancy, iatrogenic causes, cranial nerve injury.

Treatment:

After initial injury recognition, the athletic trainer placed the patient in a cervical collar and transported him to the emergency department. The patient received prednisone, and the emergency medicine physician ordered cervical spine plain radiographs, brain computed tomography, and brain and internal auditory canal magnetic resonance imaging. The physician consulted a neurologist, who managed the patient conservatively, with rest and no contact activity. The neurologist allowed the patient to participate in wrestling 7 months after injury.

Uniqueness:

To our knowledge, no other reports of unilateral hypoglossal nerve injury from relatively low-energy trauma (including athletics) exist.

Conclusions:

Hypoglossal nerve injury should be considered in individuals with head injury who experience dysphagia and dysarthria. Athletes with head injuries require cranial nerve assessments.