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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. Methods 32 patients with MMA were evaluated with MRI and MRA and compared to previous imaging. The follow-up imaging was done 103 (range 6–380) months after the MMA diagnosis, and 64 (range 6–270) months after the previous imaging. We graded the disease stage according to the previously described MRA grading scale. Results No acute lesions, including silent ischemic strokes were found in the follow-up image compared to latest available previous image. One patient had an asymptomatic intracerebral hemorrhage since the last imaging. Ivy sign was observed in 22% of the patients in the follow-up image. Six percent (n = 2) had microhemorrhages and 9% (n = 3) white matter lesions in the follow-up imaging. The MRA grade was evaluated from the follow-up images and it was 3 and 2.5 points (right and left, respectively). Fifty-six percent (n = 18) had old ischemic lesions in the follow-up image. Majority (71%) of the old ischemic lesions were large anterior circulation infarcts. Conclusions A slow progression of MMA-related changes on MRI/MRA was found, being in line with our previous reports suggesting a rather benign course of the disease in the 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. Methods We included patients from our Helsinki University Hospital MMA database and arranged long-term follow-up visits for all the patients. This follow-up included a review of the medical records accumulated in due time, detailed neurological and neuropsychological evaluation, and outcome measures modified Rankin Scale (mRS) and Barthel Index (BI). Results There were 61 MMA patients with a mean follow-up period of 9.5 years (SD 6.7 years; range 1.3–35.4 years; 581 patient-years). Only two patients had died and two-thirds (n = 40, 65.6%) had no new events during the follow-up period. Eight patients (13.1%) had an ischemic and five patients (8.2%) a hemorrhagic stroke during the follow-up. There were no differences between operated (n = 26) and conservatively (n = 35) treated groups regarding recurrent events or the outcome measured with mRS or BI. Finnish MMA patients reported significantly poorer physical and psychological health aspects of QOL when compared to the general Finnish population. Symptoms of low mood were found in 27 (56%) patients. Conclusions Finnish MMA patients have a benign and stable course with a ~3.5 % annual stroke risk. We found no differences in the clinical outcomes between the operated and conservative groups, however, the psychosocial well-being requires more attention in MMA patients.

Background and purpose Moyamoya vasculopathy, a rare steno-occlusive progressive cerebrovascular disorder, has not been thoroughly studied in Caucasian populations. We established a registry of Finnish patients treated at the Helsinki University Hospital, to collect and report demographic and clinical data. Methods We collected data both retrospectively and prospectively from all the patients with a moyamoya vasculopathy referred to our hospital between January 1987 and December 2014. All patients underwent a neurological outpatient clinic visit. Results We diagnosed 61 patients (50 females, 10 children) with moyamoya vasculopathy. The mean age at the disease-onset was 31.5 ± 17.9 years. The two most common presenting symptoms were ischemic stroke (n = 31) and hemorrhage (n = 8). Forty-four percent underwent revascularization surgery, and 70% were prescribed antithrombotic treatment. Conclusions The results support in part the Western phenotype of the disease considering the later presentation and larger female predominance compared to the Asian moyamoya vasculopathy reports. However, the proportion of ischemic strokes and hemorrhagic strokes is closer to Japanese population than German population. The absence of familial cases points to a different genetic profile in the Finnish patients.

Background Childhood cardiomyopathies are progressive and often lethal disorders, forming the most common cause of heart failure in children. Despite severe outcomes, their genetic background is still poorly characterized. Objectives The purpose of this study was to characterize the genetics of severe childhood cardiomyopathies in a countrywide cohort. Methods The authors collected a countrywide cohort, KidCMP, of 66 severe childhood cardiomyopathies from the sole center in Finland performing cardiac transplantation. For genetic diagnosis, next-generation sequencing and subsequent validation using genetic, cell biology, and computational approaches were used. Results The KidCMP cohort presents remarkable early-onset and severe disorders: the median age of diagnosis was 0.33 years, and 17 patients underwent cardiac transplantation. The authors identified the pathogenic variants in 39% of patients: 46% de novo, 34% recessive, and 20% dominantly-inherited. The authors report NRAP underlying childhood dilated cardiomyopathy, as well as novel phenotypes for known heart disease genes. Some genetic diagnoses have immediate implications for treatment: CALM1 with life-threatening arrhythmias, and TAZ with good cardiac prognosis. The disease genes converge on metabolic causes (PRKAG2, MRPL44, AARS2, HADHB, DNAJC19, PPA2, TAZ, BAG3), MAPK pathways (HRAS, PTPN11, RAF1, TAB2), development (NEK8 and TBX20), calcium signaling (JPH2, CALM1, CACNA1C), and the sarcomeric contraction cycle (TNNC1, TNNI3, ACTC1, MYH7, NRAP). Conclusions Childhood cardiomyopathies are typically caused by rare, family-specific mutations, most commonly de novo, indicating that next-generation sequencing of trios is the approach of choice in their diagnosis. Genetic diagnoses may suggest intervention strategies and predict prognosis, offering valuable tools for prioritization of patients for transplantation versus conservative treatment.

Contains fulltext : 95893.pdf (Publisher’s version ) (Closed access) 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. METHODS: We assessed samples from adults and children with mitochondrial disorders or non-mitochondrial neurological disorders (disease controls) from seven study centres in Europe and the USA, and recruited healthy volunteers (healthy controls), matched for age where possible, from the same centres. We used ELISA to measure FGF-21 concentrations in serum or plasma samples (abnormal values were defined as >200 pg/mL). We compared these concentrations with values for lactate, pyruvate, lactate-to-pyruvate ratio, and creatine kinase in serum or plasma and calculated sensitivity, specificity, and positive and negative predictive values for all biomarkers. FINDINGS: We analysed serum or plasma from 67 patients (41 adults and 26 children) with mitochondrial disorders, 34 disease controls (22 adults and 12 children), and 74 healthy controls. Mean FGF-21 concentrations in serum were 820 (SD 1151) pg/mL in adult and 1983 (1550) pg/mL in child patients with respiratory chain deficiencies and 76 (58) pg/mL in healthy controls. FGF-21 concentrations were high in patients with mitochondrial disorders affecting skeletal muscle but not in disease controls, including those with dystrophies. In patients with abnormal FGF-21 concentrations in serum, the odds ratio of having a muscle-manifesting mitochondrial disease was 132.0 (95% CI 38.7-450.3). For the identification of muscle-manifesting mitochondrial disease, the sensitivity was 92.3% (95% CI 81.5-97.9%) and specificity was 91.7% (84.8-96.1%). The positive and negative predictive values for FGF-21 were 84.2% (95% CI 72.1-92.5%) and 96.1 (90.4-98.9%). The accuracy of FGF-21 to correctly identify muscle-manifesting respiratory chain disorders was better than that for all conventional biomarkers. The area under the receiver-operating-characteristic curve for FGF-21 was 0.95; by comparison, the values for other biomarkers were 0.83 lactate (p=0.037, 0.83 for pyruvate (p=0.015), 0.72 for the lactate-to-pyruvate ratio (p=0.0002), and 0.77 for creatine kinase (p=0.013). INTERPRETATION: Measurement of FGF-21 concentrations in serum identified primary muscle-manifesting respiratory chain deficiencies in adults and children and might be feasible as a first-line diagnostic test for these disorders to reduce the need for muscle biopsy. FUNDING: Sigrid Juselius Foundation, Jane and Aatos Erkko Foundation, Molecular Medicine Institute of Finland, University of Helsinki, Helsinki University Central Hospital, Academy of Finland, Novo Nordisk, Arvo and Lea Ylppo Foundation. 01 september 2011

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. Results The annual running cost of screening 56,000 newborns for the chosen five disorders (congenital adrenal hyperplasia, medium-chain acyl-CoA dehydrogenase deficiency [MCADD], long chain 3-hydroxyacyl-CoA dehydrogenase deficiency [LCHADD], phenylketonuria [PKU] and glutaric aciduria type 1 [GA 1]) was estimated to be euros 2.5 million or euros 45 per newborn when starting costs were included. The costs per quality-adjusted life year (QALY) gained are a maximum of euros 25,500. Prevention of severe handicap in one newborn would reduce the costs to a maximum of euros 18,000 per QALY gained. Conclusions Expanding the Finnish neonatal screening programme would require a new organization. The cost-effectiveness, resources, ethics and equity need to be considered when deciding in favour of or against starting a new screening programme.

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. They were followed up, and data were prospectively collected as they emerged. Clinical data before diagnosis were retrospectively collected from hospital records. This cohort was compared with an earlier cohort of patients diagnosed from 1976 to 1996. RESULTS The disease presented from birth to five months of age with failure to thrive, hypotonia, hepatomegaly, metabolic acidosis, cardiomyopathy and hypoketotic hypoglycaemia. In this cohort, the therapeutic delay was 0-30 days and the survival rate at the end of the study was 62.5% compared with 10-year survival rate of 14.3% for the earlier cohort. The survivors were in good overall condition, but some of them had developed mild retinopathy or mild neuropathy. CONCLUSION Earlier diagnosis and stricter dietary regimes improved the survival rates and clinical course of patients with LCHADD in Finland. However, improvements in therapy are still needed to prevent the development of long-term complications, such as retinopathy and neuropathy.

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. The fetus was small for gestational age, and long bones were abnormally short. The baby was born severely asphyxiated at 32 gestational weeks by cesarean section. Intensive care was withdrawn due to failure to thrive and suspicion of a severe mitochondrial disorder. Postmortem brain MRI suggested microcephaly with a simplified gyral pattern. The lateral cerebral ventricles were normal. Chromosome analysis was normal (46, XX). Fibroblasts cultured from a skin biopsy of the baby revealed the large homozygous deletion c.1109+243_1438-703del in the HADHB gene, and heterozygous mutations were detected in both parents. The deletion has not been reported earlier.It is important to differentiate systemic metabolic diseases from disorders that affect only the cardiac muscle. Trifunctional protein deficiency is a relatively rare disorder of the fatty acid β-oxidation cycle. The mutation in the HADHB gene causes a systemic disease with early-onset cardiomyopathy. Understanding the molecular genetic defect of the patient allows appropriate genetic counseling of the family.• Mitochondrial disorders as a group are an important etiology for fetal cardiomyopathies including human trifunctional protein (TFP) disorders and several other mitochondrial diseases.• We report a fetal case with fatal outcome having a novel mitochondrial trifunctional protein mutation (c.1109+243_1438-703del in the HADHB gene).

Objective The purpose of the study was to determine the nature and course of ophthalmic abnormalities in long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, a recently discovered disorder of mitochondrial fatty acid β-oxidation. Study design The study design was a cohort (case series). Participants A retrospective review of the records of 15 children who had died during their first 2 years was performed. Also performed were a longitudinal reanalysis and cross-sectional clinical examination of four long-term survivors aged 5 to 31 years. Main outcome measures Visual acuity, refraction, visual fields, ophthalmoscopy, fluorescein angiography, biometry, corneal topography, electroretinography (ERG), visual-evoked potentials (VEPs), color vision, and dark adaptation were measured. Results In seven children, ophthalmoscopic findings were within normal limits at 3 days to 13 months of age (median, 4.8 months). In 11 children, a granular retinal pigment epithelium (RPE), with or without pigment clumping in the macula, was seen at 4 months to 5 years of age (median, 9 months). Two long-term survivors, 16 and 31 years of age, eventually had circumscribed atrophy of the choroid, RPE, and retina, which coincided with a posterior staphyloma type 1. They had progressive axial myopia starting at 6 and 12 years of age and later paracentral scotomas leading to poor central vision. They suffered from early difficulty with mesopic vision, glare, and a severe generalized color vision deficiency that started as a tritanomaly. A third survivor was mildly myopic at 5 years of age. All four surviving patients had visually insignificant, flake-like supranuclear opacities in the lens. The ERG initially was normal but deteriorated during the first decade and later was unrecordable. The VEP responses remained fairly normal. Initially, angiography showed no blockade of the choroidal fluorescence because of the thin RPE. Filling of choroidal vessels was delayed, and the choriocapillaris and, later, larger choroidal vessels in the posterior pole became nonperfused. Conclusions In LCHAD deficiency, the fundus is normal at birth (stage 1). Soon, however, pigment dispersion occurs in the RPE (stage 2), followed by circumscribed chorioretinal atrophy, occlusion of choroidal vessels, and deterioration of central vision, often with relative sparing of the peripheral fundus (stage 3). Finally, posterior staphylomas and central scotomas may develop (stage 4). Developmental cataract, progressive myopia, and deterioration of visual fields and color vision are new findings in LCHAD deficiency. The chorioretinopathy and abnormal ERG precede the development of myopia and posterior staphyloma, which, in turn, coincide with the loss of macular vision. The authors postulate that the RPE or choriocapillaris is primarily affected. Awareness of the characteristic ocular features is important because of an opportunity for dietary treatment, genetic counseling, and prenatal diagnosis.

Objective: Preeclampsia-related complications of pregnancy have been detected in carriers of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency, a recently discovered disorder of mitochondrial fatty acid oxidation. Because no comprehensive study is available, we studied the frequency of pregnancy complications in mothers who had given birth to children with this disorder. Study design: Data of all pregnancies of 18 mothers to 28 diagnosed patients with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency were reviewed retrospectively. From a total 79 pregnancies 16 early abortions were excluded; 63 pregnancies were included, and the fetus was affected in 29. Results: One child born prematurely died neonatally but none of the mothers died. Preeclampsia, the syndrome of hemolysis, elevated liver enzymes, and low platelets, and acute fatty liver of pregnancy occurred in 31% and intrahepatic cholestasis in 10% of pregnancies with a long chain 3-hydroxyacyl-coenzyme A–deficient fetus but in none of the pregnancies with a healthy fetus. A total of 40% of affected neonates were born prematurely and 47% had growth restriction, whereas none of the healthy neonates were premature and growth restriction occurred in only 17% (p < 0.01). Prematurity and growth restriction could not be explained solely by the preeclampsia-related conditions. Conclusions: In pregnancies with a long-chain 3-hydroxyacyl-coenzyme A–deficient fetus the frequency of preeclampsia-related conditions is high. The results support the role of fatty acid accumulation in the pathogenesis of preeclampsia. Analysis for the prevalent mutation of this deficiency may be warranted in pregnancies with severe preeclampsia. (Am J Obstet Gynecol 1998;178:603-8.)

Long-chain 3-hydroxyacyl—coenzyme A (CoA) dehydrogenase is one of three enzyme activities of the mitochondrial trifunctional protein. We report the clinical findings of 13 patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. At presentation the patients had had hypoglycemia, cardiomyopathy, muscle hypotonia, and hepatomegaly during the first 2 years of life. Seven patients had recurrent metabolic crises, and six patients had a steadily progressive course. Two patients had cholestatic liver disease, which is uncommon in β-oxidation defects. One patient had peripheral neuropathy, and six patients had retinopathy with focal pigmentary aggregations or retinal hypopigmentation. All patients were homozygous for the common mutation G1528C. However, the enoyl-CoA hydratase and 3-ketoacyl-CoA thiolase activities of the mitochondrial trifunctional protein were variably decreased in skin fibroblasts. Dicarboxylic aciduria was detected in 9 of 10 patients, and most patients had lactic acidosis, increased serum creatine kinase activities, and low serum carnitine concentration. Neuroradiologically there was bilateral periventricular or focal cortical lesions in three patients, and brain atrophy in one. Only one patient, who has had dietary treatment for 9 years, is alive at the age of 14 years; all others died before they were 2 years of age. Recognition of the clinical features of long-chain 3-hydroxyacyl-CoA deficiency is important for the early institution of dietary management, which may alter the otherwise invariably poor prognosis. J Pediatr 1997;130:67-76

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 fundus 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. To evaluate the substaging, 29 pairs of photographs were graded according to the reference photographs. Results: In the assessment of pigmentary deposits, the 3 ophthalmologists agreed in 41% and differed by a single substage in 45% of instances (combined weighted ĸ statistic was 0.38, indicating moderate agreement). In pairwise comparisons, the weighted ĸ statistic ranged from 0.31 to 0.56 (agreement, 71–81%). In the assessment of RPE atrophy, all 3 raters agreed in 17% and 2 raters in 70% of instances (combined ĸ statistic 0.018, indicating poor agreement). Discussion: Despite variation in imaging techniques and limitations in the visual assessment of fundus photographs, the agreement obtained in grading the pigmentary deposits was comparable to that reported for photographic grading of retinopathy of prematurity. We recommend photographic documentation and substaging based on reference photographs in the follow-up of LCHAD retinopathy. The refined staging allows a more detailed assessment on the progression of the retinopathy and optimization of the therapeutic protocols in individual patients and between centres using different therapeutic protocols.

Mitochondrial trifunctional protein (MTP), an enzyme complex participating in fatty acid beta-oxidation, is the potential site of two documented defects: long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) and MTP deficiencies. LCHAD deficiency usually manifests as hypoglycemia, with hepatopathy, hypotonia, cardiomyopathy, and retinopathy. Hypoparathyroidism has been detected in a patient with MTP deficiency. We now report on a patient with LCHAD deficiency and hypoparathyroidism, evidenced by hypocalcemia, hyperphosphatemia, and a low level of parathyroid hormone, in whom the parathyroid glands could not be located after death.

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.

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. Study design This was a long-term follow-up of patients in whom the common mutation was detected. Results Between 1999 and 2010, 6 cases of CPT1A deficiency were diagnosed and treated with a high-carbohydrate, low-fat diet. The patients experienced their first symptoms during the first years of life, provoked by viral illness and/or fasting. The clinical features included hypoketotic hypoglycemia, hepatopathy, and loss of consciousness, ranging from transient unconsciousness to prolonged hyperlipidemic coma. Five cases carried a homozygous c.1364A>C (p.K455T) mutation, whereas 1 case had a compound c.1364A>C/c.1493A>C (p.Y498S) mutation. During dietary therapy, the patients had few transient decompensations. No carriers of mutation c.1364A>C were detected by minisequencing of 150 control samples. Conclusion Even though CPT1A deficiency may be life-threatening and lead to prolonged coma, the long-term prognosis is good. A genotype–phenotype correlation implies that the mutations detected are disease-causing. Despite Finland’s location close to the Arctic polar region, the carrier frequency of the c.1364A>C mutation in Finland is far lower than that of the variants found in Alaskan, Canadian, and Greenland native populations.

Ninety children were treated for acute lymphoblastic leukemia or non-Hodgkin lymphoma during 1986 through 1992 in the Children's Hospital, University of Helsinki, in Finland. During induction chemotherapy, nine of the children had visual hallucinations progressing to confusion and seizure. The symptoms were often preceded by severe constipation and significantly elevated blood pressure. Neuroradiologic examinations showed bilateral cortical or subcortical white matter lesions. Despite the stroke like manifestations, the lesions were reversible. The triangular shape and location of the lesions in the watershed areas between the major cerebral arteries suggest vascular ischemia as the cause.