Molecular Genetics and Metabolism Reports最新文献

Olipudase alfa is indicated for the non-central nervous system manifestations of Acid sphingomyelinase deficiency (ASMD). Anaphylaxis is a very rare and life-threatening adverse reaction described for this drug. Here, we report the case of a 2-year-old boy affected by chronic neurovisceral ASMD who experienced signs of hypersensitivity reactions to olipudase alfa since the administered dose of 1 mg/kg during dose escalation and a proper anaphylactic reaction during the second administration of the target therapeutic dose of 3 mg/kg. The treatment was stopped for 15 weeks and then a 7-step desensitization protocol with the infused dose of 0.03 mg/kg was applied. Subsequent gradual dose escalation was resumed, successfully reaching the dose of 0.3 mg/kg. Moreover, biochemical, and radiological disease indexes, which were increased during treatment discontinuation, have gradually improved since the restart of treatment. However, at the second administration of the dose of 0.6 mg/kg, the patient experienced another adverse drug reaction with facial urticarial rash and bronchospasm, requiring the administration of adrenaline, methylprednisolone, and inhaled salbutamol. This case report highlights the need to customize the olipudase alfa desensitization protocol according to individual tolerance and raises the issue of achieving the established therapeutic target in the most sensitive children.

Synopsis

We report a case of anaphylaxis to olipudase alfa in a child affected by chronic neurovisceral Acid sphingomyelinase deficiency (ASMD) and describe a 7-step desensitization procedure. This procedure, with the total administered dose of 0.03 mg/kg, followed by gradual dose escalation, allowed to reach the dose of 0.3 mg/kg without adverse reactions; however, at the second administration of the dose of 0.6 mg/kg our patient presented another adverse reaction suggesting the need of a different desensitization strategy.

Protein substitutes (PS) without tyrosine (Tyr) and phenylalanine (Phe), are an essential source of synthetic protein in the treatment of tyrosinemia (HT). In the UK, the only available protein substitutes for HT are Tyr/ Phe free amino acid liquid or powders or formulations based on glycomacropeptide (CGMP). A tablet Tyr/ Phe free amino acid supplement (AAT) has now been introduced. The aim of this two-part prospective, longitudinal intervention study was to assess the efficacy, acceptability, and tolerance of AAT in children aged >8 years with HTI. Part 1: was a 28-day acceptability/ tolerance study, part 2, was a 12-month extension study examining efficacy of AAT. Anthropometry and blood Tyr/ Phe were assessed. All subjects were taking NTBC [2-(2-nitro-4-triflourothybenzoyl) cyclohexane-1, 3-dione] with a Tyr restricted diet. Eight subjects with HTI were recruited 4 boys, and 4 girls with a median age of 14.3y (range 10.4–17.3); 3 were Caucasian and 5 of Pakistani origin. The median (range) protein equivalent from PS was 60 g/d (50–60), natural protein 20 g/d (15–30), and NTBC 30 mg/d (25–80). No subjects were taking Phe supplements. Five (63%) subjects completed part 1, with 4 taking all their PS requirements as AAT. Subjects reported AAT were tasteless and had no odour. No adverse gastrointestinal symptoms were recorded, with two reporting improvements in abdominal discomfort. At 12 months, 4 subjects had a non-significant decrease in blood Tyr/ Phe compared to the 12 months pre-treatment. Median blood Tyr (μmol/ L) pre-intervention was 500 (320–590); and at 12 months, 450 (290–530). Median blood Phe (μmol/L) pre-intervention was 40 (30–40); and at 12 months 30 (30–50). Median height z scores remained unchanged, but there was a small decrease in weight z score (pre-study weight − 0.1 (−1.4 to1.1), 12 m − 0.3 (−1.4 to 1.3) and BMI (pre- study BMI 0.2 (−2 to 1.4), and 12 m, −0.1 (−2.5 to 1.5)).

Conclusion

AAT were useful for some adolescents with HTI who struggled with the taste and volume of conventional powdered and liquid PS.

Broad biochemical complexity and frequent overlapping clinical symptoms of inborn errors of metabolism (IEM), especially in energy-deficient patients, make accurate diagnosis difficult. In recent years, whole exome sequencing (WES), a comprehensive protein coding genetic test, has been used to diagnose patients at the molecular level. This study aims to evaluate the potential of WES in diagnosing energy-deficient IEM patients with limited biochemical findings and to identify common symptoms patterns in reported cases. Articles were identified using a combination of search terms in online databases (Science Direct, PubMed Central and Wiley). English-language case reports citing WES in the diagnosis of energy-deficient IEM patients were reviewed. This systematic review was conducted and reported using the ‘Preferred Reporting Items for Systematic Reviews and Meta-Analyses’ checklist. The quality and risk of bias were assessed using Joanna Briggs Institute critical appraisal tool. A total of 37 studies comprising of 54 case reports were included in this review. The median age of the patients was 0.4 years, with 55.6% being male and 44.4% being female. A total of 33 mutant genes were reported and they related to either metabolism or mitochondrial function. WES was able to identify mutations in 53 of 54 cases reported. The diagnosis of energy-deficient IEM patients is crucial, particularly given the challenging range of diverse clinical symptoms they present. The high accuracy of the WES technique appears to improve the diagnostic process. Further research defining more detailed guidelines is needed to engage with this rare set of genetic diseases.

Fabry disease is a rare inherited X-linked metabolic disorder in which deficient alpha-galactosidase A activity causes progressive build-up of globotriaosylceramide (Gb3) and multi-system dysfunction. Following approval of agalsidase alfa for Fabry disease in Japan in 2006, an 8-year all-case post-marketing surveillance (PMS) showed that the treatment was well tolerated and effective for managing disease progression in adult Japanese patients. The present nationwide prospective observational study extended the initial PMS by enrolling patients who continued agalsidase alfa treatment after the initial 8-year period in a 6.5-year extension survey. Patient information from the initial PMS and the extension survey was evaluated as a single data set (observation period: February 2007–September 2021). Of 493 patients in the initial PMS, 129 (45.0% male classic, 6.2% male non-classic, 48.8% female heterozygous phenotype) consented to participate in the extension survey and were included in the analysis. The mean duration of treatment was 9.6 years. A total of 145 adverse drug reactions (ADRs) occurred in 31 patients (24%), and 22 serious ADRs occurred in 12 patients (9.3%). Although serious cardiac, renal, or cerebrovascular adverse events decreased in frequency over time in male patients, serious cardiac events continued to occur in female patients, who showed higher incidence of cardiac complications at baseline. No new safety concerns were identified. Additionally, long-term agalsidase alfa treatment sustained the initial reduction in Gb3 concentrations without increasing the rate of anti-agalsidase antibody positivity. These findings suggest that agalsidase alfa treatment demonstrates continued safety and sustains patients' clinical course over the long term.

Background

Biochemical testing is a common first-tier approach in the setting of genetic evaluation of patients with unexplained developmental delay. However, results can be unclear, and a plan for second-tier analysis must be determined based on the patient's biochemical results and clinical presentation - in many cases, triggering a diagnostic odyssey.

Case presentation

A male patient from the United States presenting with unexplained developmental delay, microcephaly, hypotonia, and feeding difficulties was referred for clinical genetic evaluation at age 8 months. Biochemical testing revealed an isolated marked elevation of glutaric acid on urine organic acid profile, without elevations of related metabolites. Further testing included GCDH sequencing, a neurometabolic gene panel, chromosomal microarray, Prader Willi/Angelman testing, and lysosomal disease enzyme panel, all of which were non-diagnostic. The patient had persistent developmental delay and hypotonia, dystonia, sensorineural hearing loss, and abnormal brain myelination on magnetic resonance imaging. Whole exome sequencing (WES) was performed and revealed a dual diagnosis of glutaric aciduria III (GA III) and BCAP31-related disorder, an X-linked intellectual disability syndrome, caused by a novel pathogenic variant.

Conclusions

GA III has historically been considered clinically benign, with few reported cases. This patient's presenting symptoms were similar to those commonly seen in GA I and GA II, however the biochemical abnormalities were not consistent with these disorders, prompting additional molecular and biochemical testing. Ultimately, WES confirmed a diagnosis of BCAP31-related syndrome, a rare neurological disorder, which explained the patient's presenting symptoms. WES also identified a secondary diagnosis of GA III. We present a patient with two rare genetic conditions, highlighting the importance of deep phenotyping and the utility of WES in the setting of a patient with dual genetic diagnoses.

Aim

To investigate the characteristics of 4 Chinese patients with Bartter syndrome type 3 (BS Type 3).

Methods

The clinical data, genetic analysis, and outcome of four cases with Bartter syndrome type 3 were retrospectively summarised.

Results

Gene sequencing analysis showed that all children carried a compound heterozygous mutation in the CLCNKB gene and were diagnosed with BS type 3. All types of mutations were detected, including two missense mutations, one nonsense mutation, one small fragment deletion mutation, two large deletion mutations and one splice-site mutation. The splice-site mutation c.100 + 1 (IVS2) C > T was novel. Two cases carried large deletion mutations. The patients presented as classic BS with modest manifestations. The most common sign was growth retardation. There was no polyhydramnios or preterm delivery. All cases were treated with potassium chloride supplementation and indomethacin. During long-term follow-up, clinical symptoms and growth retardation improved significantly. Nephrocalcinosis or renal dysfunction was not observed.

Conclusion

The clinical manifestations of BS type 3 are mostly presented as cBS. Growth retardation is a common sign. BS type 3 had a good long-term prognosis. There were various types of mutations in the CLCNKB gene. Large deletions were the most common.

3-methylcrotonyl-CoA carboxylase deficiency (3MCCD) is a hereditary disorder of leucine catabolism caused by pathogenetic variants in the MCCC1 or MCCC2 genes. Typically diagnosed through newborn screening (NBS), 3MCCD is characterized by elevation of 3-hydroxyisovalerylcarnitine (C5OH) in blood as well as increased excretion of 3-methylcrotonylglycine (3-MCG) in urine. While most diagnosed children remain asymptomatic, data on adults are scarce. To date, only 39 molecularly confirmed adult individuals have been reported, all being mothers diagnosed subsequent to their child NBS results. Herein, we present a 36-year-old asymptomatic man who was incidentally diagnosed with 3MCCD following his son NBS recall. Molecular analysis revealed compound heterozygosity for two pathogenic variants in the MCCC1 gene. This is the first molecularly confirmed adult man with 3MCCD reported. This case highlights the need for additional longitudinal follow-up data on individuals with 3MCCD to clarify the clinical significance of this condition and guide clinical practice, including NBS strategy.

Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine (Phe) metabolism, resulting from the deficient activity of phenylalanine hydroxylase that converts Phe to tyrosine in the liver, leading to elevated levels of Phe. Pegvaliase is an innovative and effective enzyme replacement therapy for reducing Phe concentration, but it has been associated with severe drug-induced hypersensitivity adverse events (HAEs). Limited data is available on the management of these HAEs, thus, we aimed to present a case report of a successful management strategy.

The patient was a 28-year-old Caucasian male with classical PKU, who was otherwise healthy. Due to poor metabolic control, the pegvaliase treatment was initiated. The titration phase was uneventful, with transient and mild side effects, localized to the injection site. After the patient was on a maintenance dose of pegvaliase and had no reactions to the drug, we discontinued the H1-antihistamine. In the following days, within minutes after receiving the pegvaliase injection, an acute hypersensitivity reaction occurred that required emergency treatment. H1-antihistamine treatment was reintroduced. Four days after the incident he received pegvaliase under medical supervision and did not experience any symptoms.

In conclusion, cautious reintroduction of pegvaliase in a hospital setting can be safely performed after HAE due to the discontinuation of H1-antihistamines. HAEs could be successfully mitigated by scheduling daily antihistamines administration closer to the pegvaliase injection. This approach can enable PKU patients to maintain their access to an effective and quality-of-life-improving therapy.

Background

Early childhood obesity poses a significant global public health challenge, necessitating the identification of treatable causes, particularly congenital leptin deficiencies. Serum leptin level measurement aids in diagnosing these rare contributors, guiding effective management.

Methods

A Chinese family with early-onset obesity underwent LEP mutational screening via direct sequencing. mRNA expression and protein stability patterns of LEP were separately analyzed using qPCR and bioinformatics.

Results

We present a case of a 12.5-year-old girl born to non-obese, non-consanguineous Chinese parents, exhibiting low leptin levels. Leptin gene sequencing revealed novel compound heterozygous mutations in exon 3. RT-PCR analysis showed the mutation didn't affect leptin production. Bioinformatics analysis indicated the variant rendered the leptin protein unstable.

Conclusion

Loss-of-function mutations in LEP underlies early-onset obesity in the patient.