2-methylacetoacetyl-coenzyme A thiolase (beta-ketothiolase) deficiency: one disease - two pathways

Background: 2-methylacetoacetyl-coenzyme A thiolase deficiency (MATD; deficiency of mitochondrial acetoacetyl-coenzyme A thiolase T2/ “beta-ketothiolase”) is an autosomal recessive disorder of ketone body utilization and isoleucine degradation due to mutations in ACAT1. Methods: We performed a systematic literature search for all available clinical descriptions of patients with MATD. 244 patients were identified and included in this analysis. Clinical course and biochemical data are presented and discussed. Results: For 89.6 % of patients at least one acute metabolic decompensation was reported. Age at first symptoms ranged from 2 days to 8 years (median 12 months). More than 82% of patients presented in the first two years of life, while manifestation in the neonatal period was the exception (3.4%). 77.0% (157 of 204 patients) of patients showed normal psychomotor development without neurologic abnormalities. Conclusion: This comprehensive data analysis provides a systematic overview on all cases with MATD identified in the literature. It demonstrates that MATD is a rather benign disorder with often favourable outcome, when compared with many other organic acidurias

3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: One disease- many faces

Background 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMGCLD) is an autosomal recessive disorder of ketogenesis and leucine degradation due to mutations in HMGCL . Method We performed a systematic literature search to identify all published cases. 211 patients of whom relevant clinical data were available were included in this analysis. Clinical course, biochemical findings and mutation data are highlighted and discussed. An overview on all published HMGCL variants is provided. Results More than 95% of patients presented with acute metabolic decompensation. Most patients manifested within the first year of life, 42.4% already neonatally. Very few individuals remained asymptomatic. The neurologic long-term outcome was favorable with 62.6% of patients showing normal development. Conclusion This comprehensive data analysis provides a systematic overview on all published cases with HMGCLD including a list of all known HMGCL mutations

Hyperpyrexia resulting in encephalopathy in a 14-month-old patient with cblC disease

Cobalamin C (cblC) defect, the most common inborn error of cobalamin metabolism, is a multisystem disorder usually presenting with progressive neurological, haematological and ophthalmological signs. We report on a cblC patient diagnosed in the newborn age who developed nearly normal during the first year of life. During an upper respiratory tract infection with severe hyperpyrexia at the age of 14months he developed an acute encephalopathic crisis resulting in severe mental retardation and marked internal and external cerebral atrophy. Hyperacute encephalopathic crises have not been observed so far in patients with cblC defect. It remains unclear, if this association is incidental or if the underlying metabolic defect may have predisposed the brain tissue to hyperpyrexia-induced damage

Successful pregnancy in maple syrup urine disease: a case report and review of the literature

Abstract Background Maple syrup urine disease (MSUD) is an autosomal recessive disorder of branched-chain amino acid metabolism. Patients with MSUD are at risk of life-threatening metabolic decompensations with ketoacidosis and encephalopathy. These episodes are often triggered by physiological stress. Only few cases of pregnancies in MSUD mothers have been reported so far. Case presentation We present the favorable outcome of a pregnancy in a woman with classical MSUD. She presented in the metabolic outpatient clinic in week 7 of gestation. Branched-chain amino acid concentrations were measured at least weekly to adjust dietary leucine intake. Despite excellent compliance, leucine concentrations frequently exceeded the target value of < 300 μmol/L during the first trimester. From the second trimester until delivery, protein and leucine intake increased continuously to about threefold compared to pre-pregnancy values. To maximize patient safety during delivery and the postpartum period, a detailed plan including peripartal infusion therapy, dietary recommendations and monitoring parameters was developed. Primary Caesarean section was performed in week 38 of gestation, and the patient gave birth to a healthy girl. Lactation was successfully implemented. Leucine levels were maintained within the target range throughout the complete postpartum period. In addition to our case, we give an overview about all cases of pregnancies in MSUD mothers published so far. Conclusions Management of pregnancy, delivery, postpartum period and lactation may be challenging in patients with MSUD. Careful monitoring and interdisciplinary collaboration is essential to minimize the risk of metabolic crisis, especially after delivery

Congenital Central Hypothyroidism due to a Homozygous Mutation in the TSHβ Subunit Gene

Congenital central hypothyroidism (CCH) is a rare condition occurring in 1 : 20000 to 1 : 50000 newborns. As TSH plasma levels are low, CCH is usually not detected by TSH-based neonatal screening for hypothyroidism, and, as a result, diagnosis is often delayed putting affected children at risk for developmental delay and growth failure. We report on a girl with isolated central hypothyroidism due to a homozygous one-base pair deletion (T313del) in exon 3 of the TSHβ subunit gene. The molecular genetic and typical radiologic findings are discussed, and a systematic diagnostic workup for congenital central hypothyroidism is proposed. Physicians need to be aware of this rare condition to avoid diagnostic delay and to install prompt replacement therapy

Impact of glycogen storage disease type I on adult daily life: a survey

Background!#!Glycogen storage disease type I (GSD I) is a rare autosomal recessive disorder of carbohydate metabolism characterized by recurrent hypoglycaemia and hepatomegaly. Management of GSD I is demanding and comprises a diet with defined carbohydrate intake and the use of complex carbohydrates, nocturnal tube feeding or night-time uncooked cornstarch intake, regular blood glucose monitoring and the handling of emergency situations. With improved treatment, most patients nowadays survive into adulthood. Little research has been performed on the impact of GSD I on daily life, especially in adult patients.!##!Results!#!In this multi-centre study we assessed the impact of GSD I on adult daily life in 34 GSD I patients (27 GSD Ia, 7 GSD Ib) between 17 and 54 years (median 26 years) using a self-designed questionnaire that specifically focused on different aspects of daily life, such as job situation, social life, sports, travelling, composition of the household, night-time and day-time dietary management and disease monitoring as well as the patient's attitude towards the disease. At the time of investigation, the majority of patients either attended school or university or were employed, while 3 patients (9%) were out of work. Most patients ranked GSD I as a disease with moderate severity and disease burden. Dietary treatment was considered challenging by many, but the vast majority of patients considered life with GSD I as well-manageable.!##!Conclusions!#!Although the management of GSD I poses a significant burden on daily life, most patients live an independent adult life, have a positive attitude towards their disease and seem to cope well with their situation

A mild case of molybdenum cofactor deficiency defines an alternative route of MOCS1 protein maturation

Molybdenum cofactor deficiency is an autosomal recessive inborn error of metabolism, which results from mutations in genes involved in Moco biosynthesis. Moco serves as a cofactor of several enzymes, including sulfite oxidase. MoCD is clinically characterized by intractable seizures and severe, rapidly progressing neurodegeneration leading to death in early childhood in the majority of known cases. Here we report a patient with an unusual late disease onset and mild phenotype, characterized by a lack of seizures, normal early development, a decline triggered by febrile illness and a subsequent dystonic movement disorder. Genetic analysis revealed a homozygous c.1338delG MOCS1 mutation causing a frameshift (p.S442fs) with a premature termination of the MOCS1AB translation product at position 477 lacking the entire MOCS1B domain. Surprisingly, urine analysis detected trace amounts (1% of control) of the Moco degradation product urothione, suggesting a residual Moco synthesis in the patient, which was consistent with the mild clinical presentation. Therefore, we performed bioinformatic analysis of the patient's mutated MOCS1 transcript and found a potential Kozak-sequence downstream of the mutation site providing the possibility of an independent expression of a MOCS1B protein. Following the expression of the patient's MOCS1 cDNA in HEK293 cells we detected two proteins: a truncated MOCS1AB protein and a 22.4 kDa protein representing MOCS1B. Functional studies of both proteins confirmed activity of MOCS1B, but not of the truncated MOCS1AB. This finding demonstrates an unusual mechanism of translation re-initiation in the MOCS1 transcript, which results in trace amounts of functional MOCS1B protein being sufficient to partially protect the patient from the most severe symptoms of MoCD

Citrin deficiency mimicking mitochondrial depletion syndrome

Background!#!Neonatal intrahepatic cholestasis caused by citrin deficiency (CD) is a rare inborn error of metabolism due to variants in the SLC25A13 gene encoding the calcium-binding protein citrin. Citrin is an aspartate-glutamate carrier located within the inner mitochondrial membrane.!##!Case presentation!#!We report on two siblings of Romanian-Vietnamese ancestry with citrin deficiency. Patient 1 is a female who presented at age 8 weeks with cholestasis, elevated lactate levels and recurrent severe hypoglycemia. Diagnosis was made by whole exome sequencing and revealed compound heterozygosity for the frameshift variant c.852_855del, p.Met285Profs*2 and a novel deletion c.(69 + 1_70-1)_(212 + 1_231-1)del in SLC25A13. The girl responded well to dietary treatment with a lactose-free, MCT-enriched formula. Her younger brother (Patient 2) was born 1 year later and also found to be carrying the same gene variants. Dietary treatment from birth was able to completely prevent clinical manifestation until his current age of 4.5 months.!##!Conclusions!#!As CD is a well-treatable disorder it should be ruled out early in the differential diagnosis of neonatal cholestasis. Due to the combination of hepatopathy, lactic acidosis and recurrent hypoglycemia the clinical presentation of CD may resemble hepatic mitochondrial depletion syndrome