3-Methylglutaconic aciduria type III in a non-Iraqi-Jewish kindred: clinical and molecular findings

Type III 3-methylglutaconic aciduria (MGA) (MIM 258501) consists of early bilateral optic atrophy, later development of spasticity, extrapyramidal dysfunction and occasionally cognitive deficits, and urinary excretion of 3-methylglutaconic acid and 3-methylglutaric acid. The presence of the disorder in an Iraqi-Jewish genetic isolate led to mapping of the OPA3 gene to chromosome 19q13.2-q13.3, followed by isolation of the gene itself. OPA3 consists of two exons and codes for a peptide of 179 amino acids. Iraqi-Jewish patients with type III MGA are homozygous for a splice site founder mutation in OPA3 (IVS1-1G>C) which abolishes mRNA expression in fibroblasts. Here we report a novel mutation in OPA3 (320-337del) in a Kurdish-Turkish patient with optic atrophy and 3-methylglutaconic and 3-methylglutaric aciduria, previously carrying the diagnosis of type IV MGA. We conclude that type III MGA occurs in patients of non-Iraqi-Jewish ancestry, and should be considered in patients with type IV MGA that have optic atrophy and ataxia.     

Oligodontia, short stature and small head circumference with normal intelligence

Complete absence of third molars and mandibular permanent second molars is reported in a 19-year-old female, with occipito-frontal head circumference and height at the 3rd centile. The patient's intelligence, appearance and physical examination were normal. Direct count of the patient's sweat pores in different areas of the palms and digits was normal. Microcephaly, short stature and normal intelligence have been reported in two families as a distinct autosomal dominant syndrome. To the best of our knowledge, oligodontia, in addition to these findings, has not been previously reported.     

Primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a chronic, progressive cholestatic liver disease, which is invariably fatal. Circumstantial and indirect evidence suggests that autoimmune mechanisms have a role in the pathogenesis of PBC. Antimitochondrial antibodies (AMA) are highly sensitive and specific markers that can predict the development of the disease in a healthy individual. Long-term administration of ursodeoxycholic acid (UDCA), a naturally occurring bile acid, safely slows the progression of PBC, delays the need for liver transplantation, and postpones death. An effort should be made to identify the patients with PBC in the asymptomatic stage by the presence of AMA and to conduct a clinical trial in order to assess the benefit of long-term administration of UDCA on the prevention of the overt disease in these individuals.     

A founder truncating variant in GDF1 causes autosomal‐recessive right isomerism and associated congenital heart defects in multiplex Arab kindreds

The genetic basis of congenital heart malformations associated with disruption of left–right (L–R) asymmetry is broad and heterogenous, with variants in over 25 genes implicated thus far. Of these, deleterious variants in the Growth/Differentiation Factor 1 (GDF1) gene have been shown to cause heterotaxy with varied complex heart malformations of left–right patterning, in 23 individuals reported to date, either in monoallelic or biallelic state. We report three unrelated individuals exhibiting right isomerism with congenital heart defects, each originating from a consanguineous kindred of Arab‐Muslim descent. Using whole exome sequencing, a shared novel homozygous truncating c.608G > A (p.W203*) variant in the GDF1 gene was revealed as the molecular basis of their disease. Subsequently, targeted sequencing of this variant showed full segregation with the disease in these families, with a total of over 15 reportedly affected individuals, enabling genetic counseling, prenatal diagnosis, and planning of future pregnancies. Our findings further confirm the association of biallelic GDF1 variants, heterotaxy and congenital heart defects of left–right patterning, and expand the previously described phenotypic spectrum and mutational profile. Moreover, we suggest targeted screening for the p.W203* variant in relevant clinical circumstances.     

Intracranial recurrence of carcinoma after complete surgical resection of stage I, II, and III non-small-cell lung cancer

We retrospectively analyzed the risk of intracranial recurrence of cancer in 1532 patients who were surgically treated between 1977 and 1986 for Stage I, II, or III non-small-cell lung cancer, after rigorous surgical and pathological staging. This analysis was undertaken as a background for a possible randomized clinical trial of prophylactic cranial irradiation in such patients. One hundred four patients (6.8 percent) had documented first recurrences involving the brain, including 98 patients (6.4 percent) in whom the brain was the sole site of first recurrence. Sixty patients (3.9 percent) had only intracranial involvement at the time of death. Prognostic variables that had a significant effect on the time to recurrence in the brain were histologic features of the carcinoma (patients with nonsquamous-cell cancers were more at risk than those with squamous-cell cancer), the T1N1/T2N0 and T2N1 staging subsets (T1, tumor less than or equal to 3 cm in diameter; T2, tumor greater than 3 cm; N0, no regional lymph-node metastasis; N1, ipsilateral hilar-lymph-node metastasis), and initial weight loss of more than 10 percent. We conclude that prophylactic cranial irradiation would at best benefit only a very small subset of these patients. We believe, therefore, that neither prophylactic cranial irradiation nor a randomized trial is indicated in patients with non-small-cell lung cancer who have undergone complete resection.     

Weight change adjusted equations for assessing resting metabolic rate in overweight and obese adults

BackgroundAlthough over one hundred equations have been developed to predict the energy expenditure of individuals, none are sensitive to weight change in assessment of resting metabolic rate (RMR) before and after weight loss.ObjectiveTo formulate adjusted equations for overweight and obese individuals and to compare their accuracy with existing prediction RMR equations before and after weight loss.Subjects/materialsThis is historical prospective study. Participants included 39 overweight and obese men and women before and after losing 10–20% from baseline weight on a diet and physical activity regimen for at least three months. Pre and post weight loss measured RMR results were compared to estimated RMR using several existing prediction equations: Harris and Benedict, Ravussin and Bogardus, and Mifflin et al. To improve the accuracy of these prediction equations, we suggest new equations adjusted for weight loss, based on measured RMR and evaluated their accuracy.ResultsPre and post weight loss data indicated: significant fat reduction in both genders; reduction in free-fat mass only in men, and a significant decrease in measured RMR only in women. Our suggested equations were the most accurate and closest to measured RMR in both genders, in comparison to the Harris and Benedict, Ravussin and Bogardus, and Mifflin et al equation results. Estimated RMR using the latter equations was significantly lower than measured RMR in both genders at pre and post weight loss (P < 0.01).ConclusionsThis study highlights the need for adjusting RMR equations before and after weight loss in overweight and obese individuals. Further research is needed to validate our suggested equations.     

Triple approach for diagnosis and grading of meningiomas: Histology,morphometry of Ki-67/feulgen stainings,and cytogenetics

Summary With regard to meningioma grading and the recently introduced atypical meningioma, we evaluated 160 cases retrospectively by conventional histology and image analysis. For that, the cell nuclei were stained with a Ki-67 (MIB1)/Feulgen-method on paraffin sections, thus enabling the assessment of both the Ki-67 proliferation index and nuclear morphometric features, such as tumour cell arrangement, nuclear pleomorphism, and cellularity.It could be demonstrated that the Ki-67 proliferation index is the most important criterion for distinguishing anaplastic meningiomas (WHO grade III) (mean Ki-67 index: 11%) from those of common type (WHO grade I) (mean Ki-67 index: 0.7%). The parameter for the relative volume weighted mean nuclear volume is another valuable morphometric feature. The atypical meningioma (WHO grade II) which should represent an intermediate category between common type and anaplastic meningiomas is characterized by a mean Ki-67 proliferation index of 2.1%. Common type meningiomas which comprise almost 50% of the cases of this series have a relapse rate of 9%. Atypical and anaplastic meningiomas recurred in 29% and 50%, respectively. Since the term atypical meningioma is confusing in the context of tumour grading, the term intermediate type meningioma is proposed.Furthermore, the results of cytogenetic analyses of 142 cases of this series were evaluated and compared with the meningioma grades. Thereby, 25 cases disclosed, independent of the typical loss of one chromosome 22, cytogenetic features assumed to be progression-associated, e.g., the gain or loss of different chromosomes and the deletion of the short arm of one chromosome 1 (hyperdiploidy, increased hypodiploidy, Ip-), when correlated to the histological and morphometric findings or the high relapse rate.For meningioma diagnosis and grading, a practical guideline is proposed based upon histology, morphometry (Ki-67), and cytogenetics.     

Management of the critically injured football player

Evaluation and treatment of a football player who has sustained life-threatening injuries is a rare but significant challenge for the sports medicine team. Early recognition and intervention in these injuries is crucial. Helmets and shoulder pads complicate management of these patients. In this article, I present a rapid and simple assessment method used by paramedics for trauma patients. Treatment focuses on when football equipment should be removed and how the equipment complicates Advanced Life Support measures. A strong, working relationship with Emergency Medical Services is encouraged.