PMM2-CDG is the most common congenital disorder of glycosylation (CDG), which presents with either a neurologic or multisystem phenotype. Little is known about the longitudinal evolution.
We ...performed data analysis on PMM2-CDG patients' clinical features according to the Nijmegen CDG severity score and laboratory data. Seventy-five patients (28 males) were followed up from 11.0 ± 6.91 years for an average of 7.4 ± 4.5 years.
On a group level, there was no significant evolution in overall clinical severity. There was some improvement in mobility and communication, liver and endocrine function, and strabismus and eye movements. Educational achievement and thyroid function worsened in some patients. Overall, the current clinical function, the system-specific involvement, and the current clinical assessment remained unchanged. On follow-up there was improvement of biochemical variables with (near) normalization of activated partial thromboplastin time (aPTT), factor XI, protein C, antithrombin, thyroid stimulating hormone, and liver transaminases.
PMM2-CDG patients show a spontaneous biochemical improvement and stable clinical course based on the Nijmegen CDG severity score. This information is crucial for the definition of endpoints in clinical trials.
Congenital hyperinsulinism (HI) is an inappropriate insulin secretion by the pancreatic β-cells secondary to various genetic disorders. The incidence is estimated at 1/50, 000 live births, but it may ...be as high as 1/2, 500 in countries with substantial consanguinity. Recurrent episodes of hyperinsulinemic hypoglycemia may expose to high risk of brain damage. Hypoglycemias are diagnosed because of seizures, a faint, or any other neurological symptom, in the neonatal period or later, usually within the first two years of life. After the neonatal period, the patient can present the typical clinical features of a hypoglycemia: pallor, sweat and tachycardia. HI is a heterogeneous disorder with two main clinically indistinguishable histopathological lesions: diffuse and focal. Atypical lesions are under characterization. Recessive ABCC8 mutations (encoding SUR1, subunit of a potassium channel) and, more rarely, recessive KCNJ11 (encoding Kir6.2, subunit of the same potassium channel) mutations, are responsible for most severe diazoxide-unresponsive HI. Focal HI, also diazoxide-unresponsive, is due to the combination of a paternally-inherited ABCC8 or KCNJ11 mutation and a paternal isodisomy of the 11p15 region, which is specific to the islets cells within the focal lesion. Genetics and 18F-fluoro-L-DOPA positron emission tomography (PET) help to diagnose diffuse or focal forms of HI. Hypoglycemias must be rapidly and intensively treated to prevent severe and irreversible brain damage. This includes a glucose load and/or a glucagon injection, at the time of hypoglycemia, to correct it. Then a treatment to prevent the recurrence of hypoglycemia must be set, which may include frequent and glucose-enriched feeding, diazoxide and octreotide. When medical and dietary therapies are ineffective, or when a focal HI is suspected, surgical treatment is required. Focal HI may be definitively cured when the partial pancreatectomy removes the whole lesion. By contrast, the long-term outcome of diffuse HI after subtotal pancreatectomy is characterized by a high risk of diabetes, but the time of its onset is hardly predictable.
The Krebs cycle is of fundamental importance for the generation of the energetic and molecular needs of both prokaryotic and eukaryotic cells. Both enantiomers of metabolite 2-hydroxyglutarate are ...directly linked to this pivotal biochemical pathway and are found elevated not only in several cancers, but also in different variants of the neurometabolic disease 2-hydroxyglutaric aciduria. Recently we showed that cancer-associated IDH2 germline mutations cause one variant of 2-hydroxyglutaric aciduria. Complementary to these findings, we now report recessive mutations in SLC25A1, the mitochondrial citrate carrier, in 12 out of 12 individuals with combined D-2- and L-2-hydroxyglutaric aciduria. Impaired mitochondrial citrate efflux, demonstrated by stable isotope labeling experiments and the absence of SLC25A1 in fibroblasts harboring certain mutations, suggest that SLC25A1 deficiency is pathogenic. Our results identify defects in SLC25A1 as a cause of combined D-2- and L-2-hydroxyglutaric aciduria.
Mannose phosphate isomerase‐congenital disorder of glycosylation (MPI‐CDG) deficiency is a rare subtype of congenital disorders of protein N‐glycosylation. It is characterised by deficiency of MPI ...caused by pathogenic variants in MPI gene. The manifestation of MPI‐CDG is different from other CDGs as the patients suffer dominantly from gastrointestinal and hepatic involvement whereas they usually do not present intellectual disability or neurological impairment. It is also one of the few treatable subtypes of CDGs with proven effect of oral mannose. This article covers a complex review of the literature and recommendations for the management of MPI‐CDG with an emphasis on the clinical aspect of the disease. A team of international experts elaborated summaries and recommendations for diagnostics, differential diagnosis, management, and treatment of each system/organ involvement based on evidence‐based data and experts' opinions. Those guidelines also reveal more questions about MPI‐CDG which need to be further studied.
As a consequence of impaired glucose or fatty acid metabolism, bioenergetic stress in skeletal muscles may trigger myopathy and rhabdomyolysis. Genetic mutations causing loss of function of the LPIN1 ...gene frequently lead to severe rhabdomyolysis bouts in children, though the metabolic alterations and possible therapeutic interventions remain elusive. Here, we show that lipin1 deficiency in mouse skeletal muscles is sufficient to trigger myopathy. Strikingly, muscle fibers display strong accumulation of both neutral and phospholipids. The metabolic lipid imbalance can be traced to an altered fatty acid synthesis and fatty acid oxidation, accompanied by a defect in acyl chain elongation and desaturation. As an underlying cause, we reveal a severe sarcoplasmic reticulum (SR) stress, leading to the activation of the lipogenic SREBP1c/SREBP2 factors, the accumulation of the Fgf21 cytokine, and alterations of SR–mitochondria morphology. Importantly, pharmacological treatments with the chaperone TUDCA and the fatty acid oxidation activator bezafibrate improve muscle histology and strength of lipin1 mutants. Our data reveal that SR stress and alterations in SR–mitochondria contacts are contributing factors and potential intervention targets of the myopathy associated with lipin1 deficiency.
Synopsis
Loss‐of‐function mutations of ER‐resident phosphatidate phosphatase lipin1 (LPIN1) frequently lead to severe muscle injury in children, but the underlying cellular mechanism remains elusive. Here, genetic analysis identified sarcoplasmic reticulum (SR) stress response and altered mitochondrial morphology as primary causes for detrimental lipid accumulation, pointing to potential therapeutic interventions.
Skeletal muscle specific Lpin1 depletion in mice results in myopathy.
Lipin1 mutant muscles show increased fatty acid biosynthesis and lipid levels.
Lipin1 deficiency triggers unfolded stress response and SR fragmentation.
mtDNA levels and SR‐mitochondria contacts are impaired at Lpin1 deletion.
Lipin1‐dependent myopathy is rescued by treatment with the chaperone TUDCA or fatty acid oxidation agonist bezafibrate.
ER stress response and altered mitochondrial functions are central to metabolic muscle injury upon loss of lipin1.
OTC deficiency, an inherited urea cycle disorder, is caused by mutations in the X‐linked OTC gene. Phenotype‐genotype correlations are well understood in males but still poorly known in females. ...Taking advantage of a cohort of 130 families (289 females), we assessed the relative contribution of OTC enzyme activity, X chromosome inactivation, and OTC gene sequencing to genetic counseling in heterozygous females. Twenty two percent of the heterozygous females were clinically affected, with episodic (11%), chronic (7.5%), or neonatal forms of the disease (3.5%). Overall mortality rate was 4%. OTC activity, ranging from 0% to 60%, did not correlate with phenotype at the individual level. Analysis of multiple samples from 4 mutant livers showed intra‐hepatic variability of OTC activity and X inactivation profile (range of variability: 30% and 20%, respectively) without correlation between both parameters for 3 of the 4 livers. Ninety disease‐causing variants were found, 27 of which were novel. Mutations were classified as “mild” or “severe,” based on male phenotypes and/or in silico prediction. In our cohort, a serious disease occurred in 32% of females with a severe mutation, compared to 4% in females with a mild mutation (odds ratio = 1.365; P = 1.6e‐06). These data should help prenatal diagnosis for heterozygous females and genetic counseling after fortuitous findings of OTC variants in pangenomic sequencing.
Coenzyme Q
10 (CoQ
10) plays a pivotal role in oxidative phosphorylation (OXPHOS) in that it distributes electrons between the various dehydrogenases and the cytochrome segments of the respiratory ...chain. Primary coenzyme Q
10 deficiency represents a clinically heterogeneous condition suggestive of genetic heterogeneity, and several disease genes have been previously identified. The
CABC1 gene, also called
COQ8 or
ADCK3, is the human homolog of the yeast
ABC1/COQ8 gene, one of the numerous genes involved in the ubiquinone biosynthesis pathway. The exact function of the Abc1/Coq8 protein is as yet unknown, but this protein is classified as a putative protein kinase. We report here
CABC1 gene mutations in four ubiquinone-deficient patients in three distinct families. These patients presented a similar progressive neurological disorder with cerebellar atrophy and seizures. In all cases, enzymological studies pointed to ubiquinone deficiency. CoQ
10 deficiency was confirmed by decreased content of ubiquinone in muscle. Various missense mutations (R213W, G272V, G272D, and E551K) modifying highly conserved amino acids of the protein and a 1 bp frameshift insertion c.1812_1813insG were identified. The missense mutations were introduced into the yeast
ABC1/COQ8 gene and expressed in a
Saccharomyces cerevisiae strain in which the
ABC1/COQ8 gene was deleted. All the missense mutations resulted in a respiratory phenotype with no or decreased growth on glycerol medium and a severe reduction in ubiquinone synthesis, demonstrating that these mutations alter the protein function.
Maple syrup urine disease (MSUD) is rare autosomal recessive metabolic disorder caused by the dysfunction of the mitochondrial branched‐chain 2‐ketoacid dehydrogenase (BCKD) enzyme complex leading to ...massive accumulation of branched‐chain amino acids and 2‐keto acids. MSUD management, based on a life‐long strict protein restriction with nontoxic amino acids oral supplementation represents an unmet need as it is associated with a poor quality of life, and does not fully protect from acute life‐threatening decompensations or long‐term neuropsychiatric complications. Orthotopic liver transplantation is a beneficial therapeutic option, which shows that restoration of only a fraction of whole‐body BCKD enzyme activity is therapeutic. MSUD is thus an ideal target for gene therapy. We and others have tested AAV gene therapy in mice for two of the three genes involved in MSUD, BCKDHA and DBT. In this study, we developed a similar approach for the third MSUD gene, BCKDHB. We performed the first characterization of a Bckdhb−/− mouse model, which recapitulates the severe human phenotype of MSUD with early‐neonatal symptoms leading to death during the first week of life with massive accumulation of MSUD biomarkers. Based on our previous experience in Bckdha−/− mice, we designed a transgene carrying the human BCKDHB gene under the control of a ubiquitous EF1α promoter, encapsidated in an AAV8 capsid. Injection in neonatal Bckdhb−/− mice at 1014 vg/kg achieved long‐term rescue of the severe MSUD phenotype of Bckdhb−/− mice. These data further validate the efficacy of gene therapy for MSUD opening perspectives towards clinical translation.
Lipoate serves as a cofactor for the glycine cleavage system (GCS) and four 2-oxoacid dehydrogenases functioning in energy metabolism (α-oxoglutarate dehydrogenase α-KGDHc and pyruvate dehydrogenase ...PDHc), or amino acid metabolism (branched-chain oxoacid dehydrogenase, 2-oxoadipate dehydrogenase). Mitochondrial lipoate synthesis involves three enzymatic steps catalyzed sequentially by lipoyl(octanoyl) transferase 2 (LIPT2), lipoic acid synthetase (LIAS), and lipoyltransferase 1 (LIPT1). Mutations in LIAS have been associated with nonketotic hyperglycinemia-like early-onset convulsions and encephalopathy combined with a defect in mitochondrial energy metabolism. LIPT1 deficiency spares GCS deficiency and has been associated with a biochemical signature of combined 2-oxoacid dehydrogenase deficiency leading to early death or Leigh-like encephalopathy. We report on the identification of biallelic LIPT2 mutations in three affected individuals from two families with severe neonatal encephalopathy. Brain MRI showed major cortical atrophy with white matter abnormalities and cysts. Plasma glycine was mildly increased. Affected individuals’ fibroblasts showed reduced oxygen consumption rates, PDHc, α-KGDHc activities, leucine catabolic flux, and decreased protein lipoylation. A normalization of lipoylation was observed after expression of wild-type LIPT2, arguing for LIPT2 requirement in intramitochondrial lipoate synthesis. Lipoic acid supplementation did not improve clinical condition nor activities of PDHc, α-KGDHc, or leucine metabolism in fibroblasts and was ineffective in yeast deleted for the orthologous LIP2.
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