JIMD Reports

Familial chylomicronemia syndrome (FCS) is a rare inherited disorder characterized by severe hypertriglyceridemia, posing a heightened risk of acute pancreatitis. Recently, Volanesorsen, an APOC3 antisense oligonucleotide, gained approval for FCS treatment in the UK. Caution is advised during pregnancy due to limited safety data, although animal studies show no toxicity/teratogenicity. Two case scenarios are presented: In the first case, a patient with FCS continued Volanesorsen injections without having thrombocytopenia during an unplanned pregnancy until third trimester, maintaining triglyceride control...

Riboflavin transporter deficiency (RTD) is a genetic disorder of reduced riboflavin (vitamin B2) uptake that causes progressive, multifocal neurological dysfunction. Most patients present in early childhood; if patients present later in life, symptoms usually develop more gradually. We report three previously healthy young adults, who developed rapidly progressive neurological symptoms after decreasing dietary intake of meat and dairy. After a diagnostic odyssey, the diagnosis of a riboflavin transporter deficiency was made...

Hereditary tyrosinemia type 1 (HT1) is a rare metabolic disease resulting in acute liver failure in early infancy, hypophosphataemic rickets, neurological crises, liver cirrhosis and risk of hepatocellular carcinoma later on in life. It is caused by the deficiency of the enzyme fumarylacetoacetate hydrolase which is involved in the terminal step of the catabolic pathway of tyrosine. Diagnosis is made through clinical suspicion supported by biochemical abnormalities that result from accumulation of upstream metabolites...

BACKGROUND: NAXE-encephalopathy or early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy-1 (PEBEL-1) and NAXD-encephalopathy (PEBEL-2) have been described recently as mitochondrial disorders causing psychomotor regression, hypotonia, ataxia, quadriparesis, ophthalmoparesis, respiratory insufficiency, encephalopathy, and seizures with the onset being usually within the first three years of life. It usually leads to rapid disease progression and death in early childhood...

The neuronal ceroid lipofuscinosis type 2 (CLN2) is a heterogeneous group of neurodegenerative lysosomal storage disorders caused by autosomal recessive inheritance of two pathogenic variants in trans in the TPP1 gene. Classical late-infantile CLN2 disease has a very well-defined natural history. However, a small number of patients with TPP1 enzyme deficiency present a later onset or protracted disease course within this group there are phenotypic variants. Our work aimed to identify pathological variants in the TPP1 gene that conditioned the development of CLN2 disease in Ukrainian patients, to compare these variants with those found in patients from other European and non-European regions, and to make genotype-phenotype associations for this disease...

Carbonic anhydrase VA (CA-VA) deficiency is a rare cause of hyperammonemia caused by biallelic mutations in CA5A. Most patients present with hyperammonemic encephalopathy in early infancy to early childhood, and patients usually have no further recurrence of hyperammonemia with a favorable outcome. This retrospective cohort study reports 18 patients with CA-VA deficiency caused by homozygosity for a founder mutation, c.59G>A p.(Trp20*) in CA5A . The reported patients show significant intrafamilial and interfamilial variability, and display atypical clinical features...

Familial chylomicronemia syndrome (FCS) is a rare disorder of triglyceride (TG) metabolism caused by loss of function variants in one of five known canonical genes involved in chylomicron lipolysis and clearance- LPL , APOC2 , APOA5 , LMF1 , and GPIHBP1 . Pathogenic variants in LPL , which encodes the hydrolytic enzyme lipoprotein lipase, account for over 80%-90% of cases. FCS may present in infancy with hypertriglyceridemia-induced acute pancreatitis and is challenging to manage both acutely and in the long-term...

Givosiran is a subcutaneously administered, liver-targeted RNA interference (RNAi) therapeutic that has been approved for treating acute hepatic porphyria (AHP). Elevation in plasma homocysteine (hyperhomocysteinemia) has been reported in AHP patients, and treatment with givosiran has been reported to further increase homocysteine levels in some patients. The mechanism of homocysteine elevation during givosiran treatment is unknown, but has been hypothesized to be mediated by a reduction in activity of cystathionine β-synthase (CBS), which uses homocysteine as a substrate...

No sensitive tumor marker for hepatocellular carcinoma (HCC) is available for patients with glycogen storage disease type Ia (GSDIa), in whom alpha-fetoprotein and carcino-embryonic antigen levels often remain normal. We describe increased levels of the HCC tumor marker des-gamma-carboxy prothrombin (DCP) in GSDIa patients with HCC. In one case DCP levels normalized after liver transplantation. We recommend including DCP as a screening HCC tumor marker in the surveillance of patients with GSDIa.

Classic galactosemia (CG) arises from loss-of-function mutations in the Galt gene, which codes for the enzyme galactose-1-phosphate uridylyltransferase (GALT), a central component in galactose metabolism. The neonatal fatality associated with CG can be prevented by galactose dietary restriction, but for decades it has been known that limiting galactose intake is not a cure and patients often have lasting complications. Even on a low-galactose diet, GALT's substrate galactose-1-phosphate (Gal1P) is elevated and one hypothesis is that elevated Gal1P is a driver of pathology...

Maple syrup urine disease (MSUD) is a disorder of branched-chain amino acid metabolism caused by a defect in the branched-chain α-ketoacid dehydrogenase (BCKD) complex (OMIM #248600). The hallmark presentation is encephalopathic crisis in neonates, but can also present with metabolic decompensation, developmental delays, and feeding difficulties. Biochemical evidence for MSUD includes elevated branched-chain amino acids (BCAA) and the pathognomonic presence of alloisoleucine. The BCKD complex contains several subunits associated with autosomal recessive MSUD, while its regulatory proteins have less well-defined disease associations...

The interface between pediatric palliative care (PPC) and inborn metabolic diseases (IMD) remains incipient, though these conditions fill the state of art of complex chronic diseases, eligible to this health approach. We analyzed the medical records of PPC clinic during the years 2001 to 2021 and the IMD outpatients. We established a parallel with the world scientific literature concerning the epidemiology of PPC and IMD. Among outpatients, 14% were diagnosed with IMD, which were referred to the PPC service earlier compared to Non-IMD cases...

Type II D-2-Hydroxyglutaric aciduria (T2D2HGA) is caused by a gain-of-function pathogenic variant in Isocitrate Dehydrogenase 2 (IDH2). Patients with T2D2HGA commonly present with developmental delay, seizures, cardiomyopathy, and arrhythmias. The recently approved IDH2-inhibitor Enasidenib targets the p.Arg140Gln pathogenic IDH2 variant and decreases production of D2HGA. We present a 7-year-old female with T2D2HGA due to the p.Arg140Gln variant. She was diagnosed at 3-years-old after presenting with global developmental delay, leukoencephalopathy, communicating hydrocephalus, seizures, and dilated cardiomyopathy...

Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is a neurometabolic disorder in the lysine metabolism pathway. In 2014 and 2021, the International PDE consortium published consensus guidelines about diagnosis and management. In this follow-on, a literature review was performed and nutrition management was evaluated through an international dietary questionnaire with 40 respondents. This manuscript discusses consensus dietary statements and the practical provision of lysine reduction therapies. Results from the questionnaire, statements from the PDE consensus guidelines, new data from the literature, as well as clinical practice experience of the metabolic dietitian group form the basis of these updated practical diet recommendations...

Methionine synthase reductase deficiency (cblE) is a rare autosomal recessive inborn error of cobalamin metabolism caused by pathogenic variants in the methionine synthase reductase gene ( MTRR ). Patients usually exhibit early-onset bone marrow failure with pancytopenia including megaloblastic anemia. The latter can remain isolated or patients may present developmental delay and rarely macular dysfunction. Treatment mostly includes parenteral hydroxocobalamin to maximize the residual enzyme function and betaine to increase methionine concentrations and decrease homocysteine accumulation...

ALG1-CDG is a rare, clinically variable metabolic disease, caused by the defect of adding the first mannose (Man) to N-acetylglucosamine (GlcNAc2 )-pyrophosphate (PP)-dolichol to the growing oligosaccharide chain, resulting in impaired N-glycosylation of proteins. N-glycosylation has a key role in functionality, stability, and half-life of most proteins. Therefore, congenital defects of glycosylation typically are multisystem disorders. Here we report a 3-year-old patient with severe neurological, cardiovascular, respiratory, musculoskeletal and gastrointestinal symptoms...

Three forms of muscular dystrophy-dystroglycanopathies are linked to the ribitol pathway. These include mutations in the isoprenoid synthase domain-containing protein ( ISPD ), fukutin-related protein ( FKRP ), and fukutin ( FKTN ) genes. The aforementioned enzymes are required for generation of the ribitol phosphate linkage in the O-glycan of alpha-dystroglycan. Mild cases of dystroglycanopathy present with slowly progressive muscle weakness, while in severe cases the eyes and brain are also involved. Previous research showed that ribose increased the intracellular concentrations of cytidine diphosphate-ribitol (CDP-ribitol) and had a therapeutic effect...

Mucopolysaccharidoses (MPS) screening is tedious and still performed by analysis of total glycosaminoglycans (GAG) using 1,9-dimethylmethylene blue (DMB) photometric assay, although false positive and negative tests have been reported. Analysis of differentiated GAGs have been pursued classically by gel electrophoresis or more recently by quantitative LC-MS assays. Secondary elevations of GAGs have been reported in urinary tract infections (UTI). In this manuscript, we describe the diagnostic accuracy of urinary GAG measurements by LC-MS for MPS typing in 68 untreated MPS and mucolipidosis (ML) patients, 183 controls and 153 UTI samples...

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Two siblings, presenting with a neurometabolic phenotype, were identified with 5, 10-methenyltetrahydrofolate synthetase (MTHFS) deficiency. Whole genome sequencing in both patients demonstrated an homozygous MTHFS variant NM_006441.3( MTHFS ):c.434G > A, p.Arg145Gin, which has been described before. At baseline, both patients showed moderate hyperhomocysteinemia, decreased 5-methyltetrahydrofolate (5MTHF), and increased 5-formyltetrahydrofolate (5-FTHF) in whole blood. In CSF, 5MTHF levels were in the low-normal range and 5-FTHF was strongly increased...