Journal of Inherited Metabolic Disease最新文献

Mono-allelic DHDDS variants are associated with seizures, intellectual disability, and movement disorders. The age of onset and progression rates of symptoms vary greatly among patients, spanning from infancy to late adulthood. Yet, the reasons behind this clinical variability and the underlying pathophysiological mechanisms of the disease have remained elusive. We investigated the age of onset and the progression of symptoms over time in 59 patients with heterozygous DHDDS variants, drawing from medical literature and incorporating five previously unreported cases from the FCDGC Natural History Study. Clinical symptoms typically emerged early in life. Ataxia, tremor, dystonia, and dyskinesia manifested slightly later in childhood. Global developmental delay usually presented as the initial symptom. We observed diverse rates of symptom accumulation over time: some patients exhibited the full spectrum of symptoms in early childhood, while others developed novel symptoms well into adulthood. Interestingly, neither the sex nor the underlying DHDDS variants correlated with the age of symptom onset or specific clinical symptoms. Additionally, we found that 19% of patients presented with autism spectrum disorder. This study offers insight into the age of symptom onset and the rate of symptom accumulation in patients with DHDDS variants. We found no correlation between the age of onset and progression of clinical symptoms with specific DHDDS variants or patient sex. Autism spectrum disorder is common in patients and warrants attention in clinical management.

Cerebrotendinous xanthomatosis is a rare and treatable metabolic disorder related to the accumulation of cholestanol. This disorder is primarily associated with motor and cognitive impairments, although the latter has not been extensively characterized. The objectives of this work were to define the cognitive profile found in cerebrotendinous xanthomatosis patients, investigate the progression of cognitive impairment over time, and search for radio-clinical correlations. Through a multicentric chart review study, we collected cognitive and radiological data from nine children and eighteen adults with genetically proven cerebrotendinous xanthomatosis. We performed a volumetric and morphological analysis of the brain magnetic resonance imaging. In our cohort, 44% (4/9) of children and 78% (14/18) of adults exhibited cognitive impairment that can be severe. The study revealed a significant impairment in various cognitive domains, specifically executive, attentional, language, and visuo-spatial. Among adults, 16% (3/18) developed dementia after age 50. These three patients had delayed chenodeoxycholic acid treatment and important cerebral atrophy. Besides these three cases of late-onset cognitive decline, Mini-Mental State Evaluation was generally stable, suggesting cognitive impairment due to a neurodevelopmental disorder and persisting in adulthood. Cognitive impairment was less common in children, possibly related to early chenodeoxycholic acid treatment in our cohort. The severity of magnetic resonance imaging abnormalities did not predict cognitive impairment in patients. Overall, in cerebrotendinous xanthomatosis, cognitive impairment can be severe and mainly neurodevelopmental. Early chenodeoxycholic acid treatment might be associated with a reduced risk of cognitive decline.

This review summarises progress in the research of homocystinuria (HCU) in the past three decades. HCU due to cystathionine β-synthase (CBS) was discovered in 1962, and Prof. Jan Peter Kraus summarised developments in the field in the first-ever Komrower lecture in 1993. In the past three decades, significant advancements have been achieved in the biology of CBS, including gene organisation, tissue expression, 3D structures, and regulatory mechanisms. Renewed interest in CBS arose in the late 1990s when this enzyme was implicated in biogenesis of H₂S. Advancements in genetic and biochemical techniques enabled the identification of several hundreds of pathogenic CBS variants and the misfolding of missense mutations as a common mechanism. Several cellular, invertebrate and murine HCU models allowed us to gain insights into functional and metabolic pathophysiology of the disease. Establishing the E-HOD consortium and patient networks, HCU Network Australia and HCU Network America, offered new possibilities for acquiring clinical data in registries and data on patients' quality of life. A recent analysis of data from the E-HOD registry showed that the clinical variability of HCU is broad, extending from severe childhood disease to milder (late) adulthood forms, which typically respond to pyridoxine. Pyridoxine responsiveness appears to be the key factor determining the clinical course of HCU. Increased awareness about HCU played a role in developing novel therapies, such as gene therapy, correction of misfolding by chaperones, removal of methionine from the gut and enzyme therapies that decrease homocysteine or methionine in the circulation.

Nonketotic hyperglycinemia due to deficient glycine cleavage enzyme activity causes a severe neonatal epileptic encephalopathy. Current therapies based on mitigating glycine excess have only limited impact. An animal model with postnatal phenotyping is needed to explore new therapeutic approaches. We developed a Gldc p.Ala394Val mutant model and bred it to congenic status in two colonies on C57Bl/6J (B6) and J129X1/SvJ (J129) backgrounds. Mutant mice had reduced P-protein and enzyme activity indicating a hypomorphic mutant. Glycine levels were increased in blood and brain regions, exacerbated by dietary glycine, with higher levels in female than male J129 mice. Birth defects were more prevalent in mutant B6 than J129 mice, and hydrocephalus was more frequent in B6 (40%) compared to J129 (none). The hydrocephalus rate was increased by postnatal glycine challenge in B6 mice, more so when delivered from the first neonatal week than from the fourth. Mutant mice had reduced weight gain following weaning until the eighth postnatal week, which was exacerbated by glycine loading. The electrographic spike rate was increased in mutant mice following glycine loading, but no seizures were observed. The alpha/delta band intensity ratio was decreased in the left cortex in female J129 mice, which were less active in an open field test and explored less in a Y-maze, suggesting an encephalopathic effect. Mutant mice showed no evidence of memory dysfunction. This partial recapitulation of human symptoms and biochemistry will facilitate the evaluation of new therapeutic approaches with an early postnatal time window likely most effective.

The pathway of ammonia disposal in the mammalian organism has been described in 1932 as a metabolic cycle present in the liver in different compartments. In 1958, the first human disorder affecting this pathway was described as a genetic condition leading to cognitive impairment and constant abnormalities of amino acid metabolism. Since then, defects in all enzymes and transporters of the urea cycle have been described, referring to them as primary urea cycle disorders causing primary hyperammonemia. In addition, there is a still increasing list of conditions that impact on the function of the urea cycle by various mechanisms, hereby leading to secondary hyperammonemia. Despite great advances in understanding the molecular background and the biochemical specificities of both primary and secondary hyperammonemias, there remain many open questions: we do not fully understand the pathophysiology in many of the conditions; we do not always understand the highly variable clinical course of affected patients; we clearly appreciate the need for novel and improved diagnostic and therapeutic approaches. This study does look back to the beginning of the urea cycle (hi)story, briefly describes the journey through past decades, hereby illustrating advancements and knowledge gaps, and gives examples for the extremely broad perspective imminent to some of the defects of ureagenesis and allied conditions.

Renal proximal tubulopathy in Fanconi-Bickel syndrome is caused by impaired basolateral glucose transport via GLUT2 and consequently, intracellular accumulation of glucose and glycogen. SGLT2 inhibitors act on apical glucose reabsorption of renal proximal tubular cells. The purpose of this study was to retrospectively describe the first experiences with repurposing the SGLT2 inhibitor empagliflozin to treat the generalized tubulopathy in Fanconi-Bickel syndrome. A case series was conducted of seven persons from five families (five males, two females; three children, who were 14y5m, 2y9m, and 1y6m old) with genetically confirmed Fanconi-Bickel syndrome, off-label treated with empagliflozin. Median (range) age at start of empagliflozin was 27 years (1y6m – 61y) and duration of follow-up under empagliflozin treatment was 169 days (57–344). Under empagliflozin (up to 25 mg/d), biochemical parameters of tubular cell integrity (urinary N-acetyl-glucosaminidase) and/or tubular functions (including urinary α1-microglobulin) improved in all persons with Fanconi-Bickel syndrome, albeit to varying degrees. Clinically, supplementations (i.e., phosphate, alkali, carnitine, and alfacalcidol) could be completely discontinued in the three children, whereas results in the four adult patients were more variable and not as significant. Empagliflozin was well-tolerated and no symptomatic hypoglycemia was observed. In conclusion, SGLT2 inhibitors such as empagliflozin shift the metabolic block in Fanconi-Bickel syndrome, that is, they intervene specifically in the underlying pathophysiology and can thus attenuate renal proximal tubulopathy, especially when started in early childhood.

Mitochondria carry out essential functions for the cell, including energy production, various biosynthesis pathways, formation of co-factors and cellular signalling in apoptosis and inflammation. The functionality of mitochondria requires the import of about 900–1300 proteins from the cytosol in baker's yeast Saccharomyces cerevisiae and human cells, respectively. The vast majority of these proteins pass the outer membrane in a largely unfolded state through the translocase of the outer mitochondrial membrane (TOM) complex. Subsequently, specific protein translocases sort the precursor proteins into the outer and inner membranes, the intermembrane space and matrix. Premature folding of mitochondrial precursor proteins, defects in the mitochondrial protein translocases or a reduction of the membrane potential across the inner mitochondrial membrane can cause stalling of precursors at the protein import apparatus. Consequently, the translocon is clogged and non-imported precursor proteins accumulate in the cell, which in turn leads to proteotoxic stress and eventually cell death. To prevent such stress situations, quality control mechanisms remove non-imported precursor proteins from the TOM channel. The highly conserved ubiquitin-proteasome system of the cytosol plays a critical role in this process. Thus, the surveillance of protein import via the TOM complex involves the coordinated activity of mitochondria-localized and cytosolic proteins to prevent proteotoxic stress in the cell.

Acid Sphingomyelinase Deficiency (ASMD) is a rare genetic disease that is caused by biallelic pathogenic variants in the SMPD1 gene, leading to a deficiency in the activity of the lysosomal enzyme acid sphingomyelinase (ASM) that catabolizes sphingomyelin (SPM). SPM is a major component of cell membranes and a principal phospholipid of the myelin sheath. Deficiency of ASM leads to the accumulation of SPM and secondary increases in cholesterol and other metabolically related lipids.¹ Organ systems affected include the central nervous system (CNS), liver, spleen, lymph nodes, adrenal cortex, lung airways, and bone marrow. The estimated prevalence of ASMD is 0.4 to 0.6 per 100 000 live births.^{2, 3}

Clinically, ASMD can be broadly categorized into three subtypes. Type A is an early-onset severe disease that is characterized by failure to thrive, hepatosplenomegaly, interstitial lung disease (ILD), and rapidly progressive neurodegenerative disease. Type B is a later onset, less severe disease characterized by progressive hepatosplenomegaly, gradual deterioration in liver and pulmonary function, osteopenia, and an atherogenic lipid profile. No CNS manifestations occur in ASMD Type B. ASMD type A/B, an intermediate form between type A and type B, is characterized by presence of some CNS manifestations, hepatosplenomegaly, ILD, dyslipidemia, osteopenia, and thrombocytopenia.⁴ Patients with ASMD were managed primarily with supportive therapies prior to approval of olipudase alfa-rpcp on August 31, 2022.

Olipudase alfa-rpcp, a recombinant human ASM, is an enzyme replacement therapy indicated for the treatment of non-CNS manifestations of ASMD in pediatric and adult patients. Olipudase alfa-rpcp is not expected to cross the blood–brain barrier to treat the CNS manifestations of ASMD. It is administered as an intravenous infusion every two weeks (Q2W), with a recommended starting dose of 0.1 mg/kg in adults and 0.03 mg/kg in pediatric patients. The dose is gradually escalated to a recommended maintenance dose of 3 mg/kg over 14 and 16 weeks in adult and pediatric patients, respectively. The dose-escalation regimens provide a gradual “debulking” of SPM and gradual release of ceramide to decrease the potential inflammatory response and adverse reactions that were observed following single-dose administration of olipudase alfa-rpcp in ASM knockout mice and in the first-in-human clinical trial.⁵

Substantial evidence of effectiveness for olipudase alfa-rpcp in ASMD patients was established with one adequate and well-controlled trial with confirmatory evidence.^{8, 9} The efficacy of olipudase alfa-rpcp was demonstrated by a statistically significant improvement in DLco in 13 adult patients with ASMD type B on treatment compared to 18 patients on placebo. Efficacy in the pediatric population relied upon partial extrapolati

Pompe disease (PD), also known as glycogen storage disease type II, acid maltase deficiency, and glycogenosis type II, is a rare and serious lysosomal disease caused by autosomal recessive variants in the acid alpha-glucosidase (GAA) gene. The resulting enzyme deficiency of GAA results in intra-lysosomal accumulation of glycogen in various tissues. The two forms of PD present differently: infantile-onset PD (IOPD) is a rapidly progressive disease associated with severe left ventricular hypertrophy and high mortality within the first year of life, whereas late-onset PD (LOPD) is a slower progressive disease associated with motor impairment and respiratory muscle weakness; respiratory failure is the most common cause of death.¹ Currently, the approved therapies for PD are recombinant human acid alpha-glucosidases, alglucosidase alfa and avalglucosidase alfa-ngpt. Although alglucosidase alfa results in stabilization or improvement of symptoms for many patients, some patients continue to decline during treatment. For other patients, the improvement in muscle weakness is not sustained, and thus, patients tend to develop progressive disease, which can lead to respiratory failure.^2-4 Therefore, treatment and cure of PD continue to represent unmet needs.

Cipaglucosidase alfa-atga provides an exogenous source of GAA. Cipaglucosidase alfa-atga has the same amino acid sequence as the endogenous GAA enzyme but contains complex-type N-glycan structures with two mannose-6-phosphate (M6P) moieties on the same glycan which mediates binding to M6P receptors on the cell surface. Miglustat, which is coadministered with cipaglucosidase alfa-atga, is an N-alkylated iminosugar (a synthetic analog of D-glucose) and is the active ingredient in Zavesca, which is approved for the treatment of adult patients with mild/moderate Type 1 Gaucher disease for whom ERT is not a therapeutic option. Miglustat binds with, stabilizes, and reduces the inactivation of cipaglucosidase alfa-atga in the blood after infusion. The bound miglustat is dissociated from cipaglucosidase alfa-atga after it is internalized and transported into lysosomes.

In this article, we provide the summary of FDA's review of the biologics license application (BLA) for cipaglucosidase alfa-atga and the new drug application (NDA) for miglustat, which were approved to be coadministered for the treatment of adult patients with LOPD who are not improving on their current enzyme replacement therapy (ERT).

Substantial evidence of effectiveness for cipaglucosidase alfa-atga coadministered with miglustat in subjects with LOPD was established using data from one adequate and well-controlled trial with confirmatory evidence (CE). A single trial in subjects 18 years of age and older with LOPD showed a clinically meaningful numerical improvement in motor and lung function compared with treatment with a non-US-approved alglucosidase alfa product coa