D‐2‐Hydroxyglutaric aciduria has been observed in patients with extremely variable clinical symptoms, creating doubt about the existence of a disease entity related to the biochemical finding. An international survey of patients with D‐2‐hydroxyglutaric aciduria was initiated to solve this issue. The clinical history, neuroimaging, and biochemical findings of 17 patients were studied. Ten of the patients had a severe early‐infantile‐onset encephalopathy characterized by epilepsy, hypotonia, cerebral visual failure, and little development. Five of these patients had a cardiomyopathy. In neuroimaging, all patients had a mild ventriculomegaly, often enlarged frontal subarachnoid spaces and subdural effusions, and always signs of delayed cerebral maturation. In all patients who underwent neuroimaging before 6 months, subependymal cysts over the head or corpus of the caudate nucleus were noted. Seven patients had a much milder and variable clinical picture, most often characterized by mental retardation, hypotonia, and macrocephaly, but sometimes no related clinical problems. Neuroimaging findings in 3 patients variably showed delayed cerebral maturation, ventriculomegaly, or subependymal cysts. Biochemical findings included elevations of D‐2‐hydroxyglutaric acid in urine, plasma, and cerebrospinal fluid in both groups. Cerebrospinal fluid γ‐aminobutyric acid was elevated in almost all patients investigated. Urinary citric acid cycle intermediates were variably elevated. The conclusion of the study is that D‐2‐hydroxyglutaric aciduria is a distinct neurometabolic disorder with at least two phenotypes. Ann Neurol 1999;45:111–119

We describe a 4-generation fam ily in which a previously h ealth y 10-year-old boy died of late-onset orn ith in e transcarbam ylase (OTC) deficiency. P ed igree analysis and allopurinol loading tests in fem ale relatives w ere not inform ative. A m issense mutation (A208T) in the OTC g en e was detected in the deceased patient and in several clinically healthy male and fem ale relatives, the old est male being 97 years old. OTC deficiency was established in autopsy liver tissue of the propositus and liv er biopsy sam ples of his sister, mother, and a m aternal uncle* The m ales had 4% and 6% residual activity, re spectively, the fem ales 58% and 67%, respec tively. The observed relation betw een the m utation and the decreased OTC activity in liver tissue of th ese subjects suggests that the m utation is a d eleteriou s one. Late-on set, "m ild" OTC deficiency can have a fatal or a favorable outcom e. The disease can seg regate undetected in fam ilies. Am.

Please be advised that this information was generated on 2020-08-05 and may be subject to change. clinical implications of basic researchT h e ne w e ngl a nd jou r na l o f m e dic i ne n engl j med 362;12 nejm.org march 25, 2010

Complex I deficiency is a frequent defect of the mitochondrial electron transport chain. We report on a 3-year-old boy, who rapidly deteriorated after sudden flushing and collapse. This fatal and unusual case was characterized by widely uncontrollable arterial hypertension. It might indicate that hypertensive crisis could be a potential manifestation of mitochondrial disorders.

Although many patients suspected of suffering disturbances of the mitochondrial energy metabolism have been investigated, only a fraction of these patients have been diagnosed at the molecular level. Introduction of new techniques like proteomics will be necessary to understand the various clinical and biochemical aberrations in the eld of mitochondrial disorders. Two-dimensional electrophoresis is rst, important step in the proteomics strategy. Separation of soluble proteins is performed on the basis of isoelectric point (net charge) in one direction and on molecular mass in the other. The technique provides an overview of the majority of proteins expressed in a sample (e.g. muscle biopsy, muscle cell or mitochondrial fraction). Once an abnormal spot is observed in the gel the responsible protein can be identi ed by analysing a limited part of its amino acid sequence by mass spectrometry. We optimized two-dimensional (2D) gel electrophoresis to obtain high resolution 2D-maps and tested the reproducibility of the technique. Potentially, this new technique is capable of identifying novel mitochondrial diseases and de ning their molecular basis. 2003; 40: 9-15 Ann Clin Biochem