Molecular Genetics and Metabolism Reports最新文献

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.

Fluoxetine has been identified as a potential treatment for mucopolysaccharidosis IIIA (MPS IIIA), a debilitating and progressive lysosomal storage disorder for which no treatments are approved. In the MPS IIIA mouse model, fluoxetine decreases the accumulation of glycosaminoglycans and aggregated autophagic substrates, reducing inflammation, and slowing cognitive deterioration. ¹ We treated a single patient, 6 years old, under off-label prescription of fluoxetine, a selective serotonin reuptake inhibitor (SSRI). The primary endpoint was safety. Secondary exploratory assessments included urine quantitative heparan sulfate. Fluoxetine was well-tolerated in this patient and the patient continued treatment following the 12-month monitoring period. The patient experienced an increase in daytime somnolence which resolved with rescheduling fluoxetine administration to bedtime. Quantitative heparan sulfate levels remained elevated during treatment. Parents reported improved sleep latency time and less nighttime waking. These findings support general tolerability and further study of fluoxetine as a potential therapy for MPS IIIA.

Background

The efficacy of avalglucosidase alfa (AVA) versus alglucosidase alfa (ALG) on forced vital capacity percent predicted (FVCpp) in patients with late-onset Pompe disease (LOPD) has been assessed in the Phase 3 COMET trial (NCT02782741). Due to the rarity of LOPD and thus small sample size in COMET, additional data were analyzed to gain further insights into the efficacy of AVA versus ALG.

Methods

Data from treatment-naive patients with LOPD were pooled from COMET and Phase 1/2 NEO1/NEO-EXT (NCT01898364/NCT02032524) trials for patients treated with AVA, and Phase 3 LOTS trial (NCT00158600) for patients treated with ALG. Regression analyses using mixed models with repeated measures consistent with those pre-specified in COMET were performed post-hoc. Analyses were adjusted for trials and differences in baseline characteristics. Four models were developed: Model 1 considered all trials; Model 2 included Phase 3 trials; Model 3 included Phase 3 trials and was adjusted for baseline ventilation use; Model 4 included COMET and NEO1/NEO-EXT (i.e., AVA trials only).

Results

Overall, 100 randomized patients from COMET (AVA, n = 51, ALG, n = 49), 60 from LOTS (ALG arm only), and three patients from NEO1/NEO-EXT (who received open-label AVA only) were considered for analysis. Mean age at enrollment was similar across trials (45.3–50.3 years); however, patients from LOTS had a longer mean duration of disease versus COMET and NEO1/NEO-EXT trials (9.0 years and 0.5–2.2 years, respectively) and younger mean age at diagnosis (36.2 years and 44.7–48.6 years, respectively). Least squares mean (95% confidence interval) improvement from baseline in FVCpp at Week 49–52 for AVA versus ALG was 2.43 (−0.13; 4.99) for COMET (n = 98); 2.31 (0.06; 4.57) for Model 1 (n = 160); 2.43 (0.21; 4.65) for Model 2 (n = 157); 2.80 (0.54; 5.05) for Model 3 (n = 154); and 2.27 (−0.30; 4.45) for Model 4 (n = 101).

Conclusions

Models 1 to 3, which had an increased sample size versus COMET, demonstrated a nominally significant effect on FVCpp favoring AVA versus ALG after 1 year of treatment, consistent with results from COMET.

Acute hepatic porphyrias (AHPs) are a family of rare, autosomal, dominantly inherited conditions characterized by abnormalities in the production of heme. Advances in molecular engineering have provided new therapeutic possibilities for modifying the heme synthetic pathway in patients with porphyria. In particular, the RNA interference therapeutic givosiran was approved for the treatment of adults and adolescents with AHP aged >12 years based on the positive results of the phase III trial ENVISION. Despite the extended characterization of the activity of givosiran in clinical trials, reports on the long-term effects and effectiveness of the treatment in clinical practice are still scant. To fill this gap, this case series describes a monocentric Italian cohort of AHP patients treated with givosiran. Overall, our real-life experience supports the clinical evidence that long-term treatment with givosiran is well tolerated and able to provide sustained and continuous benefit to patients with acute intermittent porphyria, as reflected by the reduction in the frequency of attacks. In our series, givosiran treatment was also associated with improvement in assessments of quality of life, pain and fatigue.

Treatment of phenylketonuria (PKU) has evolved since the initial introduction of a phenylalanine (Phe) restricted diet. The most recent option for adults affected with PKU is treatment with an alternate enzyme, phenylalanine ammonia lyase (PAL), that metabolizes excess Phe. Proper management of all patients with PKU relies on accurate measurement of Phe levels in blood, to comply with guidance intended to minimize the neurological symptoms. Recently, our laboratory was notified of discrepant results for a patient with PKU who is treated with pegvaliase. Two specimens were collected at the same time but yielded unexpectedly different Phe concentrations. After exclusion of specimen mix-ups or analytical errors, we suspected that there was residual pegvaliase activity in the specimens continuing to degrade Phe after collection. To investigate this possibility, we performed spiking studies that showed the degradation of Phe over time at ambient temperatures. Sample preparation by protein crash appears to deactivate pegvaliase and prevents further Phe degradation. However, because pegvaliase deactivation would be required immediately following blood collection, appropriate mitigation measures must be implemented, including stringent pre-analytical requirements, alternate sample matrices such as dried blood spots, or point of care testing. Until then, health care professionals need to be cautious in their interpretation of Phe levels in their patients with PKU that are treated with pegvaliase.

Inherited metabolic diseases (IMD) are a group of rare genetic disorders that can present with a variety of symptoms. Since these disorders are hard to treat once the symptoms occur, neonatal screening may be a logical strategy. Here we evaluate the first results of national expanded IMD screening in Iran. A total of 46 IMDs were screened in this national program. Between April 2018 and March 2022, all infants who underwent national IMD screening at Shahid Beheshti University of Medical Sciences were included in this study. History and Physical examinations of infants, screening results, recall rate, response rate, and prevalence of IMDs were evaluated. A total of 125,819 infants were screened during this period. The recall rate of the test was 0.81%. 124 cases were diagnosed with a definite IMD and the raw overall prevalence of IMDs was estimated to be 1:1015. Aminoacidopathies were the most commonly detected disorders and Hyperphenylalaninemia/PKU was the most prevalent disorder among all groups. Since IMDs vary from region even in a single country, screening for IMDs is crucial in societies with a high rate of consanguineous marriages. More studies are essential for figuring out the most efficient combination of diseases to be screened based on countries' facilities.