There are few causes of treatable neurodevelopmental diseases described to date. Branched Chain Ketoacid Dehydrogenase Kinase (BCKDK) deficiency causes branched-chain amino acid (BCAA) depletion and is linked to a neurodevelopmental disorder characterized by autism, intellectual disability, and microcephaly. We report the largest cohort of patients studied, broadening the phenotypic and genotypic spectrum. Moreover, this is the first study to present newborn screening findings and mid-term clinical outcome. In this cross-sectional study, patients with a diagnosis of BCKDK deficiency were recruited via investigators’ practices through a MetabERN initiative. Clinical, biochemical and genetic data were collected. Dried blood spot (DBS) newborn screening (NBS) amino acid profiles were retrieved from collaborating centers and compared to a healthy newborn reference population. Twenty-one patients with BCKDK mutations were included from 13 families. Patients were diagnosed between 8 months and 16 years (mean: 5.8 years, 43% female). At diagnosis, BCAA levels (leucine, valine, and isoleucine) were below reference values in plasma and in cerebrospinal fluid. All patients had global neurodevelopmental delay; 18/21 had gross motor function (GMF) impairment with GMF III or worse in 5/18, 16/16 intellectual disability, 17/17 language impairment, 12/17 autism spectrum disorder, 9/21 epilepsy, 12/15 clumsiness, 3/21 had sensorineural hearing loss and 4/20 feeding difficulties. No microcephaly was observed at birth, but 17/20 developed microcephaly during follow-up. Regression was reported in 6 patients. Movement disorder was observed in 3/21 patients: hyperkinetic movements (1), truncal ataxia (1) and dystonia (2). After treatment with high protein diet (≥ 2 g/kg/day) and BCAA supplementation (100-250 mg/kg/day), plasma BCAA increased significantly (p < 0.001), motor functions and head circumference stabilized/improved in 13/13 and in 11/15 patients, respectively. Amongst cases with follow-up data, none of the 3 patients starting treatment before 2 years of age developed autism at follow-up. The patient with the earliest age of treatment initiation (8 months) showed normal development at 3 years of age. NBS in DBS identified BCAA levels significantly lower than those of the normal population. This work highlights the potential benefits of dietetic treatment, in particular early introduction of BCAA. Therefore, it is of utmost importance to increase awareness about this treatable disease and consider it as a candidate for early detection by NBS programs.
Background Continuous kidney replacement therapies (CKRT) have been reported to be an effective approach to removing toxic metabolites in inborn errors of metabolism (IEM). The present study evaluates efficiency and complications of CKRT in children with IEM. Methods Patients diagnosed with IEM who underwent CKRT in pediatric and neonatal intensive care units were analyzed. CKRT were initiated in patients with persistently high blood ammonia levels (≥ 500 μmol/L), blood ammonia levels > 250 μmol/L in the presence of moderate encephalopathy, high blood leucine levels (≥ 1500 μmol/L), and blood leucine levels < 1500 μmol/L in the presence of deteriorating neurological status or persistent metabolic acidosis. Results Of 22 patients enrolled, nine (40.9%) Maple syrup urine disease (MSUD), eight (36.4%) urea cycle disorders (UCD), and five (22.7%) organic acidemias (OA). Median age was 72.3 [9.9–1040.8] days. In total, 28 dialysis sessions were analyzed [16 (57.1%) continuous venovenous hemodialysis, and 12 (42.9%) continuous venovenous hemodiafiltration]. A significant decrease was noted in leucine levels (from 1608.4 ± 885.3 to 314.6 ± 109.9 µmol/L) of patients with MSUD, while ammonia levels were significantly decreased in patients with UCD and OA (from 1279.9 ± 612.1 to 85.1 ± 21.6 µmol/L). The most frequent complications of CKRT were thrombocytopenia (60.7%), hypotension (53.6%), and hypocalcemia (42.9%). Median age of patients with hypotension treated with vasoactive medications was significantly lower than median age of those with normal blood pressure. Conclusion CKRT is a reliable approach for effective and rapid removal of toxic metabolites in children with IEM, and CKRT modalities can be safely used and are well-tolerated in infants.
ALG1-congenital disorder of glycosylation (ALG1-CDG) is an autosomal recessive multisystem disease. We here present a patient with a mild phenotype of ALG1-CDG. A 15-month-old female was referred with hypotonia, failure to thrive, and developmental delay. At 8 months of age, failure to thrive, feeding difficulties and developmental delay became apparent, and an epileptic seizure was observed at 11 months of age. Progressive deterioration and swallowing difficulty were observed. A brain MRI revealed a widening of the cerebrospinal fluid spaces and ventricular system, and decreased protein C, protein S and antithrombin III levels were identified. The isoelectric focusing showed a type 1 pattern. A homozygous c.1076C>T (p.Ser359Leu) variant was found in the <i>ALG1</i> gene. CDG should be taken into consideration in patients presenting with unexplained multisystem involvement.
Myopathy, lactic acidosis, and sideroblastic anemia (MLASA) is a rare mitochondrial disorder characterized by MLASA. Variable features of this condition include failure to thrive, and developmental delay or intellectual disability. Additional symptoms consist of cognitive impairment, skeletal and dental abnormalities, delayed motor milestones, cardiomyopathy, dysphagia, and respiratory insufficiency. MLASA has previously been associated with mutations in pseudouridylate synthase 1 (PUS1) and YARS2. PUS1 encodes the nuclear PUS1 enzyme, which is located in both the nucleus and the mitochondria. PUS1 converts uridine into pseudouridine in several cytosolic and mitochondrial transfer RNA positions and increases the efficiency of protein synthesis in both compartments. In the present report, we report on 2 Turkish sisters 4 and 11 of years with an MLASA plus phenotype. Both patients have sideroblastic anemia, lactic acidosis, failure to thrive, developmental delay, and chronic diarrhea; in addition, the older sister has strabismus and skeletal anomalies. The sequencing of the PUS1 gene revealed a novel homozygous p.Glu311* mutation. The phenotype of the older sibling is also unique because of the strabismus and skeletal anomalies, when compared with her sister and other previously reported patients with MLASA. The structural differences in the nuclear versus mitochondrial isoforms of PUS1 and modifier genes may be implicated in the variability of the clinical presentations in MLASA. Conclusion: This report adds to the growing number of mutations causing complex clinical manifestations of MLASA including lactic acidosis, sideroblastic anemia, chronic diarrhea, and myopathy.
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