Enzyme replacement therapy (ERT) with alglucosidase alfa has been found to improve outcomes in patients with classic infantile Pompe disease, who without treatment typically die before the age of 1 ...year. Variable responses to the standard recommended dosage have led to alternative dosing strategies. We aimed to assess the effect of real-world ERT regimens on survival and walking ability in these patients.
In this observational cohort study, we obtained data collected as part of a collaborative study within the European Pompe Consortium on patients with classic infantile Pompe disease from France, Germany, Italy, and the Netherlands diagnosed between Oct 26, 1998 and March 8, 2019. Eligible patients had classic infantile Pompe disease with a disease onset and proven diagnosis before age 12 months, and a hypertrophic cardiomyopathy. A proven diagnosis of classic infantile Pompe disease was defined as a confirmed deficiency of α-glucosidase in leukocytes or lymphocytes, fibroblasts or muscle, or two pathogenic GAA variants in trans, or both. We collected data on demographics, GAA variants, ERT dosage, age at death, and walking ability. We analysed the effects of ERT dosage on survival and walking ability using Cox regression, Kaplan-Meier curves, and log-rank tests.
We included 124 patients with classic infantile Pompe disease, of whom 116 were treated with ERT (median age at start of treatment 3·3 months IQR 1·8-5·0, range 0·03-11·8). During follow-up (mean duration 60·1 months SD 57·3; n=115), 36 (31%) of 116 patients died. 39 different ERT dosing regimens were applied. Among the 64 patients who remained on the same dosage, 16 (52%) of 31 patients on the standard dosage (20 mg/kg every other week), 12 (80%) of 15 patients on an intermediate dosage (20 mg/kg per week or 40 mg/kg every other week), and 16 (89%) of 18 patients on the high dosage (40 mg/kg per week) were alive at last follow-up. Survival was significantly improved in the high dosage group compared with the standard dosage group (hazard ratio HR 0·17 95% CI 0·04-0·76, p=0·02). No significant difference in survival was identified between the intermediate dosage group and the standard dosage group (HR 0·44 0·13-1·51, p=0·19). Of the 86 patients who reached 18 months of age, 44 (51%) learned to walk. Ten (53%) of 19 patients on the standard dosage regimen, six (67%) of nine patients on intermediate dosage regimens, and 14 (93%) of 15 patients on high dosage regimens learnt to walk, but the differences between groups were not statistically significant.
Patients with classic infantile Pompe disease treated with the high ERT dosage of 40 mg/kg per week had significantly improved survival when compared with patients treated with the standard recommended ERT dosage of 20 mg/kg every other week. Based on these results, we suggest that the currently registered dosage should be reconsidered.
Prinses Beatrix Spierfonds and Wishdom Foundation.
The present work presents a “from gene defect to clinics” pathogenesis study of a patient with a hitherto unreported mutation in the CPT1A gene. In early childhood, the patient developed a ...life-threatening episode (hypoketotic hypoglycemia, liver cytolysis, and hepatomegaly) evocative of a mitochondrial fatty acid oxidation disorder, and presented deficient fibroblast carnitine palmitoyltransferase 1 (CPT1) activity and homozygosity for the c.1783 C > T nucleotide substitution on exon 15 of CPT1A (p.R595W mutant). While confirming CPT1A deficiency, whole blood de novo acylcarnitine synthesis and the levels of carnitine and its esters formally linked intracellular free-carnitine depletion to intracellular carnitine esterification. Sequence alignment and modeling of wild-type and p.*R595W CPT1A proteins indicated that the Arg595 targeted by the mutated codon is phylogenetically well conversed. It contributes to a hydrogen bond network with neighboring residues Cys304 and Met593 but does not participate in the catalysis and carnitine pocket. Its replacement by tryptophan induces steric hindrance with the side chain of Ile480 located in α-helix 12, affecting protein architecture and function. This hindrance with Ile480 is also originally described with tryptophan 304 in the known mutant p.C304W CPT1A, suggesting that the mechanisms that invalidate CPT1A activity and underlie pathogenesis could be common in both the new (p.R595W) and previously described (p.C304W) mutants.
Background
Malformations and mental retardation in the offspring of women with Phenylketonuria (PKU) can be prevented by maintaining maternal blood Phenylalanine (PHE) within a target range ...(120–300 μmol/L) through a PHE-restricted diet. In a former French study, a high and unexpected proportion of intra uterine growth retardation (IUGR) has been reported. Guidelines have been proposed to all French centres caring for maternal PKU since 2002.
Objective
To confirm IUGR and investigate its causes. The other goals were to assess the follow-up of these pregnancies based on the new guidelines and the pertinence of these recommendations.
Design
Clinical, biological and ultrasound data of all pregnancies in PKU women in France, from 2002 to 2007 were retrospectively analyzed.
Results
Data from 115 pregnancies in 86 women with PKU were collected. Ninety percent of women had been informed of the risk of maternal PKU in the absence of a strict diet during pregnancy, 88 % of women had started a diet before conception, and 45 % of infants were born small for gestational age (birth length and/or weight ≤−2 SD). PHE intakes were lower in the group with IUGR from the fifth to the eighth month of pregnancy and duration of time spent at <120 μmol/L during pregnancy was associated with a higher risk of IUGR.
Conclusion
Hyperphenylalaninemia (HPA) is not the only risk factor for IUGR; PHE lower than 120 μmol/L could also be associated with the IUGR occurence. Even if the monitoring of these pregnancies has been improved since the initiation of guidelines, we would like to stress on the importance of the dietary aspect of the disease.
DNA polymerase subunit gamma (POLG) deficiency is likely the most frequent cause of nuclear-encoded mitochondrial disorders. POLG-related disorders reportedly constitute a spectrum of overlapping ...phenotypes from infancy to late adulthood. We retrospectively reviewed natural histories for 40 children carrying biallelic pathogenic POLG variants.Background and ObjectivesDNA polymerase subunit gamma (POLG) deficiency is likely the most frequent cause of nuclear-encoded mitochondrial disorders. POLG-related disorders reportedly constitute a spectrum of overlapping phenotypes from infancy to late adulthood. We retrospectively reviewed natural histories for 40 children carrying biallelic pathogenic POLG variants.The patients were identified by the French coordinating center for mitochondrial disorders (CARAMMEL), making this a large monocentric series on childhood-onset POLG deficiency.MethodsThe patients were identified by the French coordinating center for mitochondrial disorders (CARAMMEL), making this a large monocentric series on childhood-onset POLG deficiency.Three patterns of clinical course and survival were observed, distinguished by main category of symptoms: neurologic, hepatic, and gastrointestinal. A total of 24 patients needed urgent neurointensive care for tonic-clonic seizures, myoclonic epilepsy, and status epilepticus, occasionally precipitated by valproate administration. Other neurologic symptoms included dystonia, cerebellar ataxia, and peripheral neuropathy. We report 6 POLG-deficient patients with polyradiculoneuropathy mimicking subacute Guillain-Barré syndrome and provide postgadolinium MRI evidence of diffuse cranial nerve root and cauda equina enhancement, suggesting these disorders have an inflammatory component. Children presenting with enteral nervous system involvement had vomiting, gastroparesis, and chronic intestinal pseudo-obstruction. They had later ages of onset and lived much longer. Primarily, hepatic presentations had the earliest onset and shortest survivals. Secondary hepatic failure was frequently precipitated by valproate administration given before diagnosis to patients with focal impaired awareness seizures or absence of seizures. These POLG deficiencies were often fatal, with age at death ranging from 3 months to 10 years, with a significant difference in survival between the 3 clinical forms; 6 of the 40 children did survive. No genotype-phenotype correlations were found for the 3 clinical course types.ResultsThree patterns of clinical course and survival were observed, distinguished by main category of symptoms: neurologic, hepatic, and gastrointestinal. A total of 24 patients needed urgent neurointensive care for tonic-clonic seizures, myoclonic epilepsy, and status epilepticus, occasionally precipitated by valproate administration. Other neurologic symptoms included dystonia, cerebellar ataxia, and peripheral neuropathy. We report 6 POLG-deficient patients with polyradiculoneuropathy mimicking subacute Guillain-Barré syndrome and provide postgadolinium MRI evidence of diffuse cranial nerve root and cauda equina enhancement, suggesting these disorders have an inflammatory component. Children presenting with enteral nervous system involvement had vomiting, gastroparesis, and chronic intestinal pseudo-obstruction. They had later ages of onset and lived much longer. Primarily, hepatic presentations had the earliest onset and shortest survivals. Secondary hepatic failure was frequently precipitated by valproate administration given before diagnosis to patients with focal impaired awareness seizures or absence of seizures. These POLG deficiencies were often fatal, with age at death ranging from 3 months to 10 years, with a significant difference in survival between the 3 clinical forms; 6 of the 40 children did survive. No genotype-phenotype correlations were found for the 3 clinical course types.The study demonstrates the prevalence of neurologic presentation and the extent of central, peripheral, and autonomous nervous system involvement in 60% of patients. Most of the patients with early onset and rapidly fatal hepatic failure did not live long enough to develop neurologic symptoms. The study revealed a new clinical form of POLG deficiency presenting with neurodigestive symptoms with longer lifespan. We also propose that POLG deficiency should be considered in children presenting with unexplained polyradiculoneuropathy, demyelinating neuropathy, and elevated CSF protein. Finally, valproate administration remains a notable cause of avoidable death in POLG-deficient patients.DiscussionThe study demonstrates the prevalence of neurologic presentation and the extent of central, peripheral, and autonomous nervous system involvement in 60% of patients. Most of the patients with early onset and rapidly fatal hepatic failure did not live long enough to develop neurologic symptoms. The study revealed a new clinical form of POLG deficiency presenting with neurodigestive symptoms with longer lifespan. We also propose that POLG deficiency should be considered in children presenting with unexplained polyradiculoneuropathy, demyelinating neuropathy, and elevated CSF protein. Finally, valproate administration remains a notable cause of avoidable death in POLG-deficient patients.
A female patient, with normal familial history, developed at the age of 30 months an episode of diarrhoea, vomiting and lethargy which resolved spontaneously. At the age of 3 years, the patient ...re-iterated vomiting, was sub-febrile and hypoglycemic, fell into coma, developed seizures and sequels involving right hemi-body. Urinary excretion of hexanoylglycine and suberylglycine was low during this metabolic decompensation. A study of pre- and post-prandial blood glucose and ketones over a period of 24 hours showed a normal glycaemic cycle but a failure to form ketones after 12 hours fasting, suggesting a mitochondrial β-oxidation defect. Total blood carnitine was lowered with unesterified carnitine being half of the lowest control value. A diagnosis of mild MCAD deficiency (MCADD) was based on rates of 1-14C-octanoate and 9, 10-3H-myristate oxidation and of octanoyl-CoA dehydrogenase being reduced to 25% of control values. Other mitochondrial fatty acid oxidation proteins were functionally normal. De novo acylcarnitine synthesis in whole blood samples incubated with deuterated palmitate was also typical of MCADD. Genetic studies showed that the patient was compound heterozygous with a sequence variation in both of the two ACADM alleles; one had the common c.985A>G mutation and the other had a novel c.145C>G mutation. This is the first report for the ACADM gene c.145C>G mutation: it is located in exon 3 and causes a replacement of glutamine to glutamate at position 24 of the mature protein (Q24E). Associated with heterozygosity for c.985A>G mutation, this mutation is responsible for a mild MCADD phenotype along with a clinical story corroborating the emerging literature view that patients with genotypes representing mild MCADD (high residual enzyme activity and low urinary levels of glycine conjugates), similar to some of the mild MCADDs detected by MS/MS newborn screening, may be at risk for disease presentation.
Helicobacter heilmannii, described in 1983 as a new cause of chronic gastritis, has been reported rarely in children. The purpose of this study was to determine the clinical characteristics and the ...prevalence of H. heilmannii infection, in comparison with Helicobacter pylori infection in children undergoing upper digestive endoscopy.
Diagnosis of H. heilmannii was based on its morphologic characteristics in gastric biopsy specimens (two from the antrum, one from the fundus), whereas H. pylori infection was defined by histology and/or culture (one specimen from the antrum, one from the fundus). Respective prevalences of H. heilmannii and H. pylori were calculated in 518 patients studied prospectively who underwent systematic biopsies.
The prevalence of H. pylori was 8.9% (46/518) and increased with age (from 2% before 3 years of age to 18% after 10 years). On the contrary, the prevalence of H. heilmannii infection was low, 0.4% (2/518), and no different from that published in adults. After completion of the study period, a third H. heilmannii-infected child was diagnosed. Characteristics of H. heilmannii infection could be studied in these three children 5, 9, and 14 years old. Two of three had abdominal pain and one had dysphagia. Nodular gastritis was observed at endoscopy in two children. H. heilmannii chronic active gastritis (n = 3) was localized in the antrum, associated with an interstitial infiltrate, and could not be distinguished from H. pylori gastritis (n = 46).
Clinical characteristics, endoscopic features and gastric histopathology did not allow H. heilmannii to be distinguished from H. pylori gastritis in our pediatric population. H. heilmannii infection should be considered and carefully looked for during histologic examination of gastric specimens in cases of H. pylori-negative gastritis.
Glycogen storage disease type IX (GSD type IX) results from a deficiency of hepatic phosphorylase kinase activity. The phosphorylase kinase holoenzyme is made up of four copies of each of four ...subunits (α, β, γ and δ). The liver isoforms of the α-, β- and γ-subunits are encoded by
PHKA2,
PHKB and
PHKG2, respectively. Mutation within these genes has been shown to result in GSD type IX. The diagnosis of GSD type IX is complicated by the spectrum of clinical symptoms, variation in tissue specificity and severity, and its inheritance, either X-linked or autosomal recessive. We investigated 15 patients from 12 families with suspected GSD type IX. Accurate diagnosis had been hampered by enzymology not being diagnostic in five cases. Clinical symptoms included combinations of hypoglycaemia, hepatosplenomegaly, short stature, hepatopathy, weakness, fatigue and motor delay. Biochemical findings included elevated lactate, urate and lipids. We characterised causative mutations in the
PHKA2 gene in ten patients from eight families, in
PHKG2 in two unrelated patients and in the
PHKB gene in three patients from two families. Seven novel mutations were identified in
PHKA2 (p.I337X, p.P498L, p.P869R, p.Y116_T120dup, p.R1070del, p.R916W and p.M113I), two in
PHKG2 (p.L144P and p.H48QfsX5) and two in
PHKB (p.Y419X and c.2336+965A
>
C). There was a severe phenotype in patients with
PHKG2 mutations, a mild phenotype with patients
PHKB mutations and a broad spectrum associated with PHKA2 mutations. Molecular analysis allows accurate diagnosis where enzymology is uninformative and identifies the pattern of inheritance permitting counselling and family studies.
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