Mitochondrial epileptic encephalopathy, 3-methylglutaconic aciduria and variable complex V deficiency associated with TIMM50 mutations.

Mitochondrial encephalopathies are a heterogeneous group of disorders that, usually carry grave prognosis. Recently a homozygous mutation, Gly372Ser, in the TIMM50 gene, was reported in an abstract form, in three sibs who suffered from intractable epilepsy and developmental delay accompanied by 3-methylglutaconic aciduria. We now report on four patients from two unrelated families who presented with severe intellectual disability and seizure disorder, accompanied by slightly elevated lactate level, 3-methylglutaconic aciduria and variable deficiency of mitochondrial complex V. Using exome analysis we identified two homozygous missense mutations, Arg217Trp and Thr252Met, in the TIMM50 gene. The TIMM50 protein is a subunit of TIM23 complex, the mitochondrial import machinery. It serves as the major receptor in the intermembrane space, binding to proteins which cross the mitochondrial inner membrane on their way to the matrix. The mutations, which affected evolutionary conserved residues and segregated with the disease in the families, were neither present in large cohorts of control exome analyses nor in our ethnic specific exome cohort. Given the phenotypic similarity, we conclude that missense mutations in TIMM50 are likely manifesting by severe intellectual disability and epilepsy accompanied by 3-methylglutaconic aciduria and variable mitochondrial complex V deficiency. 3-methylglutaconic aciduria is emerging as an important biomarker for mitochondrial dysfunction, in particular for mitochondrial membrane defects.

Molecular analysis of MEFV gene mutations among Palestinian patients with Behcet's disease.

OBJECTIVES: The aim of our study was to determine the prevalence of Mediterranean fever gene (MEFV) mutations among Palestinian patients with Behcet's disease (BD). METHODS: We screened 42 BD patients from the West Bank and Jerusalem for most of the MEFV mutations known to date. Patients diagnosed clinically according to the International Study Group (ISG) criteria were recruited from Makassed Islamic Charitable Hospital and private clinics. We performed the DNA testing using direct DNA sequencing of exon 10 of the MEFV gene and using the amplification refractory mutation system (ARMS) technique for mutations located in other exons. RESULTS: We found that 40.5% of the samples had nine different MEFV mutations and one polymorphism. E148Q was the most prevalent mutation, found in 38.1% of the mutated alleles. M694V, V726A, M694I, A744S, P369S, R408Q, and F479L were each detected in 4.8% of the mutated alleles studied. The polymorphism P706 was detected in 9.5% of the mutated alleles. The mutations A744S, P369S, R408Q, and F479L were reported for the first time in BD patients. V722M, a novel MEFV mutation that has not been reported before in either FMF or BD patients, was identified in this study. CONCLUSION: This study is the first genetic analysis of MEFV mutations among Palestinian BD patients. It reflects their mutations profile, providing further data that MEFV mutations are an additional genetic susceptibility factor in BD.

ETHE1 mutations are specific to ethylmalonic encephalopathy.

Mutations in ETHE1, a gene located at chromosome 19q13, have recently been identified in patients affected by ethylmalonic encephalopathy (EE). EE is a devastating infantile metabolic disorder, characterised by widespread lesions in the brain, hyperlactic acidaemia, petechiae, orthostatic acrocyanosis, and high levels of ethylmalonic acid in body fluids. To investigate to what extent ETHE1 is responsible for EE, we analysed this gene in 29 patients with typical EE and in 11 patients presenting with early onset progressive encephalopathy with ethylmalonic aciduria (non-EE EMA). Frameshift, stop, splice site, and missense mutations of ETHE1 were detected in all the typical EE patients analysed. Western blot analysis of the ETHE1 protein indicated that some of the missense mutations are associated with the presence of the protein, suggesting that the corresponding wild type amino acid residues have a catalytic function. No ETHE1 mutations were identified in non-EE EMA patients. Experiments based on two dimensional blue native electrophoresis indicated that ETHE1 protein works as a supramolecular, presumably homodimeric, complex, and a three dimensional model of the protein suggests that it is likely to be a mitochondrial matrix thioesterase acting on a still unknown substrate. Finally, the 625G-->A single nucleotide polymorphism in the gene encoding the short chain acyl-coenzyme A dehydrogenase (SCAD) was previously proposed as a co-factor in the aetiology of EE and other EMA syndromes. SNP analysis in our patients ruled out a pathogenic role of SCAD variants in EE, but did show a highly significant prevalence of the 625A alleles in non-EE EMA patients.

Syndrome of cleft palate, microcephaly, large ears, and short stature (Say syndrome).

In 1975 Say et al. (Humangenetik 26:267-269) reported on a new dominantly inherited syndrome of cleft palate, short stature, microcephaly, large ears, and hand anomalies in 4 members of a family. This is a report of a 13-month-old girl with cleft palate, short stature, microcephaly, sparse scalp hair, large abnormally shaped ears, small hands with tapering fingers, delayed bone age, unusual dermatoglyphics, proximal renal tubular acidosis with cystic dysplasia of the kidneys, and developmental delay. This case appears to be the second report of this syndrome which presumably occurred as a new mutation in this family.

Scorpion sting in children in the Jerusalem area: a review of 54 cases.

Fifty-four children from the Jerusalem area were studied prospectively following scorpion envenoming. Their ages ranged from 11 months to 10 years. Severe symptoms (convulsions, brain oedema, shock, respiratory distress and myocarditis) were encountered in 19. Respiratory distress was the main feature in 17 of the children, in two cases owing to pulmonary oedema and in a third because of adult respiratory distress syndrome and myocarditis; mechanical ventilation was required in three cases. The severity of the symptoms and signs was not related to sex, age, weight, interval between scorpion sting and admission or to the type of offending scorpion; it was most likely dependent upon the susceptibility of the individual and/or the dose of venom injected by the scorpion. Intravenous antivenom quickly reversed the symptoms, and no side-effects were seen in the patients studied. The two patients who died had not received the antivenom intravenously. We recommend that specific antivenom should be given intravenously in all children who show significant symptoms. Furthermore, a longer period of observation is necessary following scorpion sting in this age group.

Aspartylglucosaminuria among Palestinian Arabs.

Aspartylglucosaminuria (AGU) is a rare disorder of glycoprotein metabolism caused by the deficiency of the lysosomal enzyme aspartylglucosaminidase (AGA). AGU is inherited as an autosomal recessive trait and occurs with a high frequency in Finland because of a founder effect. While very few patients with AGU have been reported from non-Finnish origin, we diagnosed the disorder in 8 patients originating from 3 unrelated families, all Palestinian Arabs from the region of Jerusalem. The clinical diagnosis of AGU is often difficult, in particular early in the course of the disease, and most of the patients are diagnosed after the age of 5 years. However, since these patients excrete early large amounts of aspartylglucosamine in urine, biochemical screening is easy by urine chromatography.