Moyamoya angiopathy: radiological follow-up findings in Finnish patients.

Background And Purpose: Moyamoya angiopathy (MMA) is a chronic progressive disorder, but imaging changes observed over time are not yet characterized in European populations. We analyzed the progression of MMA with magnetic resonance imaging and angiography (MRI and MRA) in our Finnish MMA registry. Stage classification based on MRA findings was used to evaluate the progress of the disease.

Moyamoya angiopathy: long-term follow-up study in a Finnish population.

Background And Purpose: Moyamoya angiopathy (MMA) is a chronic cerebrovascular disorder predominantly starting in childhood or early adulthood and thus affects the whole lifetime. Little is known on MMAs long-term outcomes in European patients. We report long-term follow-up data on Finnish MMA patients.

Riboflavin-Responsive and -Non-responsive Mutations in FAD Synthase Cause Multiple Acyl-CoA Dehydrogenase and Combined Respiratory-Chain Deficiency.

Multiple acyl-CoA dehydrogenase deficiencies (MADDs) are a heterogeneous group of metabolic disorders with combined respiratory-chain deficiency and a neuromuscular phenotype. Despite recent advances in understanding the genetic basis of MADD, a number of cases remain unexplained. Here, we report clinically relevant variants in FLAD1, which encodes FAD synthase (FADS), as the cause of MADD and respiratory-chain dysfunction in nine individuals recruited from metabolic centers in six countries.

The rare Costello variant HRAS c.173C>T (p.T58I) with severe neonatal hypertrophic cardiomyopathy.

We report a 10-year-old girl presenting with severe neonatal hypertrophic cardiomyopathy (HCM), feeding difficulties, mildly abnormal facial features, and progressive skeletal muscle symptoms but with normal cognitive development. Targeted oligonucleotide-selective sequencing of 101 cardiomyopathy genes revealed the genetic diagnosis, and the mutation was verified by Sanger sequencing in the patient and her parents. To offer insights into the potential mechanism of patient mutation, protein structural analysis was performed using the resolved structure of human activated HRAS protein with bound GTP analogue (PDB id 5P21) in Discovery Studio 4.

Earlier diagnosis and strict diets improve the survival rate and clinical course of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency.

Aim: Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a severe metabolic disease that, without treatment, often leads to premature death or serious handicap. The aim of this study was to evaluate the clinical course of LCHADD with the homozygous 1528G>C (E510Q) mutation when patients underwent strict dietary treatment.

Methods: From 1997 to 2010, 16 patients with LCHADD were diagnosed in Finland.

Peripheral neuropathy in patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency - A follow-up EMG study of 12 patients.

Background: The neonatal screening and early start of the dietary therapy have improved the outcome of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD). The acute symptoms of LCHADD are hypoketotic hypoglycemia, failure to thrive, hepatopathy and rhabdomyolysis. Long term complications are retinopathy and neuropathy.

Fetal left ventricular noncompaction cardiomyopathy and fatal outcome due to complete deficiency of mitochondrial trifunctional protein.

Unlabelled: We report a fetal case with fatal outcome having a novel mutation in the HADHB gene, coding the beta-subunit of the mitochondrial trifunctional protein. Parents had a previous pregnancy loss due to fetal heart failure and hydrops. The next pregnancy led to left ventricular noncompaction and increasing pleural effusions after 29 gestational weeks.

Patient-Specific Induced Pluripotent Stem Cell-Derived RPE Cells: Understanding the Pathogenesis of Retinopathy in Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency.

Purpose: Retinopathy is an important manifestation of trifunctional protein (TFP) deficiencies but not of other defects of fatty acid oxidation. The common homozygous mutation in the TFP α-subunit gene HADHA (hydroxyacyl-CoA dehydrogenase), c.1528G>C, affects the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) activity of TFP and blindness in infancy.

LMNA Mutation c.917T>G (p.L306R) Leads to Deleterious Hyper-Assembly of Lamin A/C and Associates with Severe Right Ventricular Cardiomyopathy and Premature Aging.

Mutations in the LMNA gene coding for the nuclear lamina proteins lamin A and its smaller splice form lamin C associate with a heterogeneous group of diseases collectively called laminopathies. Here, we describe a 2-year-old patient with a previously undescribed phenotype including right ventricular cardiomyopathy, progeroid features, and premature death. Sequencing of LMNA revealed a novel heterozygous de novo mutation p.

Malonyl-CoA decarboxylase deficiency: long-term follow-up of a patient new clinical features and novel mutations.

Background: Malonyl-CoA decarboxylase (MLYCD, EC 4.1.1.

New mutation of mitochondrial DNAJC19 causing dilated and noncompaction cardiomyopathy, anemia, ataxia, and male genital anomalies.

Background: We report a new mutation in the human DNAJC19 gene that causes early onset dilated cardiomyopathy syndrome (DCMA).

Methods: Two brothers of Finnish origin presented with an unusual combination of early onset dilated cardiomyopathy syndrome, a disease which was associated with cardiac noncompaction, microcytic anemia, ataxia, male genital anomalies and methylglutaconic aciduria type V. Suspicion of a DCMA syndrome prompted sequencing of the human DNAJC19 gene.

Refined staging for chorioretinopathy in long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency.

Objective: Neonatal screening and earlier diagnosis have improved the prognosis of long-chain 3-hydroxyacyl coenzyme A dehydrogenase (LCHAD) deficiency, which causes a need to refine the staging of the pigmentary chorioretinopathy and thus improve monitoring and comparability of patients under dietary therapy.

Methods: Seven children with LCHAD deficiency caused by homozygous G1528C mutation attended sequential fundus photography for stage 2 chorioretinopathy in 1997–2006. After arranging 21 pairs of fund us photographs according to the severity of the fundus changes,the images best representing 3 different grades of pigmentary deposits (P1–P3) and retinal pigment epithelial(RPE) atrophy (A1–A3) were chosen as reference photographs.

Carrier frequency of a common mutation of carnitine palmitoyltransferase 1A deficiency and long-term follow-up in Finland.

Objective: To assess the long-term clinical course of carnitine palmitoyltransferase 1A (CPT1A) deficiency, caused by the c.1364A>C (p.K455T) mutation, and the carrier frequency of this mutation in Finland.

FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic study.

Background: Muscle biopsy is the gold standard for diagnosis of mitochondrial disorders because of the lack of sensitive biomarkers in serum. Fibroblast growth factor 21 (FGF-21) is a growth factor with regulatory roles in lipid metabolism and the starvation response, and concentrations are raised in skeletal muscle and serum in mice with mitochondrial respiratory chain deficiencies. We investigated in a retrospective diagnostic study whether FGF-21 could be a biomarker for human mitochondrial disorders.

Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy.

Infantile cardiomyopathies are devastating fatal disorders of the neonatal period or the first year of life. Mitochondrial dysfunction is a common cause of this group of diseases, but the underlying gene defects have been characterized in only a minority of cases, because tissue specificity of the manifestation hampers functional cloning and the heterogeneity of causative factors hinders collection of informative family materials. We sequenced the exome of a patient who died at the age of 10 months of hypertrophic mitochondrial cardiomyopathy with combined cardiac respiratory chain complex I and IV deficiency.

Elevated hydroxyacylcarnitines in a carrier of LCHAD deficiency during acute liver disease of pregnancy - a common feature of the pregnancy complication?

Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency is a mitochondrial fatty acid beta-oxidation defect characterized by accumulation of long-chain hydroxyacylcarnitine intermediates and female carriers of this disorder are in risk for pregnancy complications. We found elevated blood long-chain hydroxyacylcarnitine species in a carrier of LCHAD deficiency at 31weeks of pregnancy with a LCHAD deficient fetus during acute fatty liver of pregnancy-like liver involvement, but had been within the normal range at 25weeks of pregnancy. This finding supports the hypothesis of acylcarnitine accumulation in pathogenesis of AFLP in carriers of LCHAD and MTP deficiencies.

Carnitine palmitoyltransferase I and Acyl-CoA dehydrogenase 9 in retina: insights of retinopathy in mitochondrial trifunctional protein defects.

Purpose: Progressive pigment chorioretinopathy is a major long-term complication of mitochondrial trifunctional protein (MTP) defects, disorders of mitochondrial fatty acid beta-oxidation. To better understand the pathogenesis of the retinopathy component, the authors studied expression of the main regulatory protein of the beta-oxidation pathway, carnitine palmitoyltransferase (CPT) 1, and acyl-CoA dehydrogenase (ACAD) 9 in retinal sections and cultured cells.

Methods: Immunoblotting was performed with polyclonal antibodies to ACAD9 and the three isoforms of CPT1.

Expanding screening for rare metabolic disease in the newborn: an analysis of costs, effect and ethical consequences for decision-making in Finland.

Aim: Currently, the only metabolic disorder that newborns are screened for in Finland is congenital hypothyroidism. A proposal to start a pilot study on screening for other rare metabolic diseases using tandem mass spectrometry prompted a health technology assessment project on the effect and costs of expanded newborn screening programme options.

Method: A modelling study using data from current published studies, healthcare registers and expert opinion.

Serious pregnancy complications in a patient with previously undiagnosed carnitine palmitoyltransferase 1 deficiency.

Fetal defects in mitochondrial beta-oxidation have been linked with an increased risk for acute fatty liver of pregnancy and preeclampsia-related conditions. A woman with previously undiagnosed carnitine palmitoyltransferase 1 deficiency experienced hemolysis, elevated liver enzymes, low platelets-like syndrome late in her first pregnancy with an unaffected fetus. Carnitine palmitoyltransferase 1 deficiency should be considered as a potential cause of life-threatening complications of pregnancy.

Mitochondrial fatty acid beta-oxidation in the human eye and brain: implications for the retinopathy of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency.

The retinal pigment epithelium (RPE) and the choriocapillaris are affected early in the retinopathy associated with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. RPE in culture possesses the machinery needed for mitochondrial fatty acid beta-oxidation in vitro. To further elucidate pathogenesis of LCHAD retinopathy, we performed immunohistochemistry of the human eye and brain with antibodies to beta-oxidation enzymes.

Mitochondrial fatty acid beta-oxidation in the retinal pigment epithelium.

Pigmentary retinopathy is an important feature of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, a disorder of mitochondrial fatty acid beta-oxidation. Pathogenesis of this complication remains unknown. The retinal pigment epithelium (RPE) is affected early in this retinopathy.