ALG13-Congenital Disorder of Glycosylation (ALG13-CDG): Updated clinical and molecular review and clinical management guidelines.

ALG13-Congenital Disorder of Glycosylation (CDG), is a rare X-linked CDG caused by pathogenic variants in ALG13 (OMIM 300776) that affects the N-linked glycosylation pathway. Affected individuals present with a predominantly neurological manifestation during infancy. Epileptic spasms are a common presenting symptom of ALG13-CDG. Other common phenotypes include developmental delay, seizures, intellectual disability, microcephaly, and hypotonia. Current management of ALG13-CDG is targeted to address patients' symptoms. To date, less than 100 individuals have been reported with ALG13-CDG. In this article, an international group of experts in CDG reviewed all reported individuals affected with ALG13-CDG and suggested diagnostic and management guidelines for ALG13-CDG. The guidelines are based on the best available data and expert opinion. Neurological symptoms dominate the phenotype of ALG13-CDG where epileptic spasm is confirmed to be the most common presenting symptom of ALG13-CDG in association with hypotonia and developmental delay. We propose that ACTH/prednisolone treatment should be trialed first, followed by vigabatrin, however ketogenic diet has been shown to have promising results in ALG13-CDG. In order to optimize medical management, we also suggest early cardiac, gastrointestinal, skeletal, and behavioral assessments in affected patients.

Neurological manifestations in PMM2-congenital disorders of glycosylation (PMM2-CDG): Insights into clinico-radiological characteristics, recommendations for follow-up, and future directions.

PURPOSE: In the absence of prospective data on neurological symptoms, disease outcome, or guidelines for system specific management in phosphomannomutase 2-congenital disorders of glycosylation (PMM2-CDG), we aimed to collect and review natural history data. METHODS: Fifty-one molecularly confirmed individuals with PMM2-CDG enrolled in the Frontiers of Congenital Disorders of Glycosylation natural history study were reviewed. In addition, we prospectively reviewed a smaller cohort of these individuals with PMM2-CDG on off-label acetazolamide treatment. RESULTS: Mean age at diagnosis was 28.04 months. Developmental delay is a constant phenotype. Neurological manifestation included ataxia (90.2%), myopathy (82.4%), seizures (56.9%), neuropathy (52.9%), microcephaly (19.1%), extrapyramidal symptoms (27.5%), stroke-like episodes (SLE) (15.7%), and spasticity (13.7%). Progressive cerebellar atrophy is the characteristic neuroimaging finding. Additionally, supratentorial white matter changes were noted in adult age. No correlation was observed between the seizure severity and SLE risk, although all patients with SLE have had seizures in the past. "Off-label" acetazolamide therapy in a smaller sub-cohort resulted in improvement in speech fluency but did not show statistically significant improvement in objective ataxia scores. CONCLUSION: Clinical and radiological findings suggest both neurodevelopmental and neurodegenerative pathophysiology. Seizures may manifest at any age and are responsive to levetiracetam monotherapy in most cases. Febrile seizure is the most common trigger for SLEs. Acetazolamide is well tolerated.

Expanding the phenotypic and genotypic spectrum of GGPS1 related congenital muscular dystrophy.

Congenital muscular dystrophies are a group of progressive disorders with wide range of symptoms associated with diverse cellular mechanisms. Recently, biallelic variants in GGPS1 were linked to a distinct autosomal recessive form of muscular dystrophy associated with hearing loss and ovarian insufficiency. In this report, we present a case of a young patient with a homozygous variant in GGPS1. The patient presented with only proximal muscle weakness, and elevated liver transaminases with spared hearing function. The hepatic involvement in this patient caused by a novel deleterious variant in the gene extends the phenotypic and genotypic spectrum of GGPS1 related muscular dystrophy.

Defining the phenotype of PGAP3-congenital disorder of glycosylation; a review of 65 cases.

Biallelic pathogenic variants in PGAP3 cause a rare glycosylphosphatidyl-inositol biogenesis disorder, PGAP3-CDG. This multisystem condition presents with a predominantly neurological phenotype, including developmental delay, intellectual disability, seizures, and hyperphosphatemia. Here, we summarized the phenotype of sixty-five individuals including six unreported individuals from our CDG natural history study with a confirmed PGAP3-CDG diagnosis. Common additional features found in this disorder included brain malformations, behavioral abnormalities, cleft palate, and characteristic facial features. This report aims to review the genetic and metabolic findings and characterize the disease's phenotype while highlighting the necessary clinical approach to improve the management of this rare CDG.

Successful heart transplantation in an infant with phosphoglucomutase 1 deficiency (PGM1-CDG).

We report successful heart transplantation in a phosphoglucomutase 1 deficient (PGM1-CDG) patient. She presented with facial dysmorphism, bifid uvula and structural heart defects. Newborn screening was positive for classic galactosemia. The patient was on a galactose-free diet for 8 months. Eventually, whole exome sequencing excluded the galactosemia and revealed PGM1-CDG. Oral D-galactose therapy was started. Rapid deterioration of the progressive dilated cardiomyopathy prompted heart transplantation at the age of 12 months. Cardiac function was stable in the first 18 months of follow-up, and hematologic, hepatic, and endocrine laboratory findings improved during D-galactose therapy. The latter therapy improves several systemic symptoms and biochemical abnormalities in PGM1-CDG but does not correct the heart failure related to cardiomyopathy. Heart transplantation has so far only been described in DOLK-CDG.

AAV-based gene therapy prevents and halts the progression of dilated cardiomyopathy in a mouse model of phosphoglucomutase 1 deficiency (PGM1-CDG).

Phosphoglucomutase 1 (PGM1) deficiency is recognized as the third most common N-linked congenital disorders of glycosylation (CDG) in humans. Affected individuals present with liver, musculoskeletal, endocrine, and coagulation symptoms; however, the most life-threatening complication is the early onset of dilated cardiomyopathy (DCM). Recently, we discovered that oral D-galactose supplementation improved liver disease, endocrine, and coagulation abnormalities, but does not alleviate the fatal cardiomyopathy and the associated myopathy. Here we report on left ventricular ejection fraction (LVEF) in 6 individuals with PGM1-CDG. LVEF was pathologically low in most of these individuals and varied between 10% and 65%. To study the pathobiology of the cardiac disease observed in PGM1-CDG, we constructed a novel cardiomyocyte-specific conditional Pgm2 gene (mouse ortholog of human PGM1) knockout (Pgm2 cKO) mouse model. Echocardiography studies corroborated a DCM phenotype with significantly reduced ejection fraction and left ventricular dilation similar to those seen in individuals with PGM1-CDG. Histological studies demonstrated excess glycogen accumulation and fibrosis, while ultrastructural analysis revealed Z-disk disarray and swollen/fragmented mitochondria, which was similar to the ultrastructural pathology in the cardiac explant of an individual with PGM1-CDG. In addition, we found decreased mitochondrial function in the heart of KO mice. Transcriptomic analysis of hearts from mutant mice demonstrated a gene signature of DCM. Although proteomics revealed only mild changes in global protein expression in left ventricular tissue of mutant mice, a glycoproteomic analysis unveiled broad glycosylation changes with significant alterations in sarcolemmal proteins including different subunits of laminin-211, which was confirmed by immunoblot analyses. Finally, augmentation of PGM1 in KO mice via AAV9-PGM1 gene replacement therapy prevented and halted the progression of the DCM phenotype.

Clinical, Radiological, and Genetic Characterization of a Patient with a Novel Homoallelic Loss-of-Function Variant in DNM1.

Heterozygous pathogenic variants in DNM1 are linked to an autosomal dominant form of epileptic encephalopathy. Recently, homozygous loss-of-function variants in DNM1 were reported to cause an autosomal recessive form of developmental and epileptic encephalopathy in unrelated patients. Here, we investigated a singleton from a first-degree cousin marriage who presented with facial dysmorphism, global developmental delay, seizure disorder, and nystagmus. To identify the involvement of any likely genetic cause, diagnostic clinical exome sequencing was performed. Comprehensive filtering revealed a single plausible candidate variant in DNM1. Sanger sequencing of the trio, the patient, and her parents, confirmed the full segregation of the variant. The variant is a deletion leading to a premature stop codon and is predicted to cause a protein truncation. Structural modeling implicated a complete loss of function of the Dynamin 1 (DNM1). Such mutation is predicted to impair the nucleotide binding, dimer formation, and GTPase activity of DNM1. Our study expands the phenotypic spectrum of pathogenic homozygous loss-of-function variants in DNM1.

COVID-19 in Unvaccinated patients with inherited metabolic disorders: A single center experience.

Patients with certain inherited metabolic disorders (IMD) are at high risk for metabolic decompensation with exposure to infections. The COVID-19 pandemic has been particularly challenging for health care providers dealing with IMD patients, in view of its unpredictable consequences in these patients. There is limited data in literature on evaluating the impact and the outcome of COVID-19 infection in these patients. This cross-sectional retrospective study on a large cohort of unvaccinated IMD patients, reviewed the incidence of COVID-19 infection, disease manifestation and outcome during the pandemic between November 2019 and July 2021. In this cohort of 1058 patients, 11.7% (n = 124) were infected with COVID-19. Their median age was 16 years (age range 2-42); 57% (n = 71) were males. Post-exposure positive test was noted in 78% (n = 97) patients, while 19% (n = 24) had symptomatic diagnosis and three patients tested positive during pre-hospital visits screening. Most patients, 68.5% (n = 85) had mild COVID-19 related symptoms such as fever, cough, headache and diarrhea while 13.7% (n = 17) patients had no symptoms. Of twenty-two patients (17.7%) who required hospitalization, 16 were adults with various intoxication and energy metabolism disorders, who developed IMD related complications such as metabolic acidosis, hyperammonemia, acute pancreatitis, hypoglycemia, rhabdomyolysis and thrombosis. Ten patients needed intensive care management. The cohort death rate was 2.4% (3 patients). Overall, the clinical course of COVID-19 infection in these IMD patients was relatively mild except for patients with intoxication and energy metabolism disorders who had high risk of developing acute metabolic decompensation with severe complications.

Further delineation of GEMIN4 related neurodevelopmental disorder with microcephaly, cataract, and renal abnormalities syndrome.

Pathogenic variants in GEMIN4 have recently been linked to an inherited autosomal recessive neurodevelopmental disorder characterized with microcephaly, cataracts, and renal abnormalities (NEDMCR syndrome). This report provides a retrospective review of 16 patients from 11 unrelated Saudi consanguineous families with GEMIN4 mutations. The cohort comprises 11 new and unpublished clinical details from five previously described patients. Only two missense, homozygous, pathogenic variants were found in all affected patients, suggesting a founder effect. All patients shared global developmental delay with variable ophthalmological, renal, and skeletal manifestations. In addition, we knocked down endogenous Drosophila GEMIN4 in neurons to further investigate the mechanism of the functional defects in affected patients. Our fly model findings demonstrated developmental defects and motor dysfunction suggesting that loss of GEMIN4 function is detrimental in vivo; likely similar to human patients. To date, this study presents the largest cohort of patients affected with GEMIN4 mutations. Considering that identifying GEMIN4 defects in patients presenting with neurodevelopmental delay and congenital cataract will help in early diagnosis, appropriate management and prevention plans that can be made for affected families.

International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management.

Phosphoglucomutase 1 (PGM1) deficiency is a rare genetic disorder that affects glycogen metabolism, glycolysis, and protein glycosylation. Previously known as GSD XIV, it was recently reclassified as a congenital disorder of glycosylation, PGM1-CDG. PGM1-CDG usually manifests as a multisystem disease. Most patients present as infants with cleft palate, liver function abnormalities and hypoglycemia, but some patients present in adulthood with isolated muscle involvement. Some patients develop life-threatening cardiomyopathy. Unlike most other CDG, PGM1-CDG has an effective treatment option, d-galactose, which has been shown to improve many of the patients' symptoms. Therefore, early diagnosis and initiation of treatment for PGM1-CDG patients are crucial decisions. In this article, our group of international experts suggests diagnostic, follow-up, and management guidelines for PGM1-CDG. These guidelines are based on the best available evidence-based data and experts' opinions aiming to provide a practical resource for health care providers to facilitate successful diagnosis and optimal management of PGM1-CDG patients.

New Insights into Immunological Involvement in Congenital Disorders of Glycosylation (CDG) from a People-Centric Approach.

Congenital disorders of glycosylation (CDG) are rare diseases with variable phenotypes and severity. Immunological involvement remains a largely uncharted topic in CDG, mainly due to lack of robust data. To better characterize immune-related manifestations' prevalence, relevance, and quality-of-life (QoL) impact, we developed electronic questionnaires targeting (1) CDG patients and (2) the general "healthy" population. Two-hundred and nine CDG patients/caregivers and 349 healthy participants were included in this study. PMM2-CDG was the most represented CDG (n = 122/209). About half of these participants (n = 65/122) described relevant infections with a noteworthy prevalence of those affecting the gastrointestinal tract (GI) (63.1%, n = 41/65). Infection burden and QoL impact were shown as infections correlated with more severe clinical phenotypes and with a set of relevant non-immune PMM2-CDG signs. Autoimmune diseases had only a marginal presence in PMM2-CDG (2.5%, n = 3/122), all being GI-related. Allergy prevalence was also low in PMM2-CDG (33%, n = 41/122) except for food allergies (26.8%, n = 11/41, of PMM2-CDG and 10.8%, n = 17/158, of controls). High vaccination compliance with greater perceived ineffectiveness (28.3%, n = 17/60) and more severe adverse reactions were described in PMM2-CDG. This people-centric approach not only confirmed literature findings, but created new insights into immunological involvement in CDG, namely by highlighting the possible link between the immune and GI systems in PMM2-CDG. Finally, our results emphasized the importance of patient/caregiver knowledge and raised several red flags about immunological management.

Systemic lupus erythematosus in a girl with PTEN variant and transaldolase deficiency: a novel phenotype.

Genetic defect of phosphatase and tensin homolog (PTEN) gene might play a role in B cell hyperactivity and result in the development of systemic lupus erythematosus (SLE), while transaldolase deficiency has a spectrum of clinical features including autoimmune endocrinopathy. Herein, we identified a novel phenotype in a girl presenting with clinical and laboratory findings consistent with SLE. Exome sequencing identified pathogenic heterozygous variant in PTEN gene (NM_000314: exon 6: c.518G > C: p. R173P) and homozygous variant in TALDO1 gene (NM_006755: exon 6: c.793C del: p. Q265f). Our report highlights the association of PTEN mutation and autoimmunity and the possibility that transaldolase deficiency may be indirectly involved in the development of SLE.

Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation.

Mannose phosphate isomerase-congenital disorder of glycosylation (MPI-CDG) deficiency is a rare subtype of congenital disorders of protein N-glycosylation. It is characterised by deficiency of MPI caused by pathogenic variants in MPI gene. The manifestation of MPI-CDG is different from other CDGs as the patients suffer dominantly from gastrointestinal and hepatic involvement whereas they usually do not present intellectual disability or neurological impairment. It is also one of the few treatable subtypes of CDGs with proven effect of oral mannose. This article covers a complex review of the literature and recommendations for the management of MPI-CDG with an emphasis on the clinical aspect of the disease. A team of international experts elaborated summaries and recommendations for diagnostics, differential diagnosis, management, and treatment of each system/organ involvement based on evidence-based data and experts' opinions. Those guidelines also reveal more questions about MPI-CDG which need to be further studied.

Hypoglycemia in CDG patients due to PMM2 mutations: Follow up on hyperinsulinemic patients.

BACKGROUND: Phosphomannomutase 2 deficiency (PMM2-CDG) is the most common congenital disorder of glycosylation (CDG). Hypoglycemia has been reported in various CDG including PMM2-CDG. The frequency and etiology of hypoglycemia in PMM2-CDG are not well studied. METHODS: We conducted a systematic review of the literature on genetically and/or biochemically confirmed PMM2-CDG patients who developed hypoglycemia. Prospective follow-up information on the patients who received diazoxide therapy was collected and evaluated. RESULTS: A total of 165 peer-reviewed articles reporting on 933 PMM2-CDG patients were assessed. Hypoglycemia was specifically mentioned only in 23 of these patients (2.5%). Hyperinsulinism was identified in 10 patients (43% of all hypoglycemic patients). Among these 10 patients, seven were successfully treated with diazoxide. However, most patients remained on therapy longer than a year to stay free of hypoglycemia. CONCLUSION: Hypoglycemia is a rarely reported finding in patients with PMM2-CDG. Diazoxide-responsive hyperinsulinism was found to have a good prognosis on medication in our PMM2-CDG patients with hypoglycemia. No genotype-phenotype correlation was observed with respect to hyperinsulinism. A prospective study should be undertaken to explore the hypothesis that hypoglycemia is underdiagnosed in PMM2-CDG and to evaluate whether hyperinsulinism is always associated with hypoglycemia.

Oxygraphy Versus Enzymology for the Biochemical Diagnosis of Primary Mitochondrial Disease.

Primary mitochondrial disease (PMD) is a large group of genetic disorders directly affecting mitochondrial function. Although next generation sequencing technologies have revolutionized the diagnosis of these disorders, biochemical tests remain essential and functional confirmation of the critical genetic diagnosis. While enzymological testing of the mitochondrial oxidative phosphorylation (OXPHOS) complexes remains the gold standard, oxygraphy could offer several advantages. To this end, we compared the diagnostic performance of both techniques in a cohort of 34 genetically defined PMD patient fibroblast cell lines. We observed that oxygraphy slightly outperformed enzymology for sensitivity (79 ± 17% versus 68 ± 15%, mean and 95% CI), and had a better discriminatory power, identifying 58 ± 17% versus 35 ± 17% as "very likely" for oxygraphy and enzymology, respectively. The techniques did, however, offer synergistic diagnostic prediction, as the sensitivity rose to 88 ± 11% when considered together. Similarly, the techniques offered varying defect specific information, such as the ability of enzymology to identify isolated OXPHOS deficiencies, while oxygraphy pinpointed PDHC mutations and captured POLG mutations that were otherwise missed by enzymology. In summary, oxygraphy provides useful information for the diagnosis of PMD, and should be considered in conjunction with enzymology for the diagnosis of PMD.

The Metabolic Map into the Pathomechanism and Treatment of PGM1-CDG.

Phosphoglucomutase 1 (PGM1) encodes the metabolic enzyme that interconverts glucose-6-P and glucose-1-P. Mutations in PGM1 cause impairment in glycogen metabolism and glycosylation, the latter manifesting as a congenital disorder of glycosylation (CDG). This unique metabolic defect leads to abnormal N-glycan synthesis in the endoplasmic reticulum (ER) and the Golgi apparatus (GA). On the basis of the decreased galactosylation in glycan chains, galactose was administered to individuals with PGM1-CDG and was shown to markedly reverse most disease-related laboratory abnormalities. The disease and treatment mechanisms, however, have remained largely elusive. Here, we confirm the clinical benefit of galactose supplementation in PGM1-CDG-affected individuals and obtain significant insights into the functional and biochemical regulation of glycosylation. We report here that, by using tracer-based metabolomics, we found that galactose treatment of PGM1-CDG fibroblasts metabolically re-wires their sugar metabolism, and as such replenishes the depleted levels of galactose-1-P, as well as the levels of UDP-glucose and UDP-galactose, the nucleotide sugars that are required for ER- and GA-linked glycosylation, respectively. To this end, we further show that the galactose in UDP-galactose is incorporated into mature, de novo glycans. Our results also allude to the potential of monosaccharide therapy for several other CDG.

International clinical guidelines for the management of phosphomannomutase 2-congenital disorders of glycosylation: Diagnosis, treatment and follow up.

Phosphomannomutase 2 (PMM2-CDG) is the most common congenital disorder of N-glycosylation and is caused by a deficient PMM2 activity. The clinical presentation and the onset of PMM2-CDG vary among affected individuals ranging from a severe antenatal presentation with multisystem involvement to mild adulthood presentation limited to minor neurological involvement. Management of affected patients requires a multidisciplinary approach. In this article, a systematic review of the literature on PMM2-CDG was conducted by a group of international experts in different aspects of CDG. Our managment guidelines were initiated based on the available evidence-based data and experts' opinions. This guideline mainly addresses the clinical evaluation of each system/organ involved in PMM2-CDG, and the recommended management approach. It is the first systematic review of current practices in PMM2-CDG and the first guidelines aiming at establishing a practical approach to the recognition, diagnosis and management of PMM2-CDG patients.

Clinical, biochemical, and molecular overview of transaldolase deficiency and evaluation of the endocrine function: Update of 34 patients.

BACKGROUND: Transaldolase deficiency (TALDO-D) is a rare autosomal recessive inborn error of the pentose phosphate pathway. Since its first description in 2001, several case reports have been published, but there has been no comprehensive overview of phenotype, genotype, and phenotype-genotype correlation. METHODS: We performed a retrospective questionnaire and literature study of clinical, biochemical, and molecular data of 34 patients from 25 families with proven TALDO-D. In some patients, endocrine abnormalities have been found. To further evaluate these abnormalities, we performed biochemical investigations on blood of 14 patients. RESULTS AND CONCLUSIONS: Most patients (n = 22) had an early-onset presentation (prenatally or before 1 month of age); 12 patients had a late-onset presentation (3 months to 9 years). Main presenting symptoms were intrauterine growth restriction, dysmorphic facial features, congenital heart disease, anemia, thrombocytopenia, and hepato(spleno)megaly. An older sib of two affected patients was asymptomatic until the age of 9 years, and only after molecular diagnosis was hepatomegaly noted. In some patients, there was gonadal dysfunction with low levels of testosterone and secondary luteinizing hormone (LH) and follicle-stimulating hormone (FSH) abnormalities later in life. This overview provides information that can be helpful for managing patients and counseling families regarding prognosis. Diagnostic guidelines, possible genotype-phenotype correlations, treatment options, and pathophysiological disease mechanisms are proposed.

Long-term follow-up in PMM2-CDG: are we ready to start treatment trials?

PURPOSE: PMM2-CDG is the most common congenital disorder of glycosylation (CDG), which presents with either a neurologic or multisystem phenotype. Little is known about the longitudinal evolution. METHODS: We performed data analysis on PMM2-CDG patients' clinical features according to the Nijmegen CDG severity score and laboratory data. Seventy-five patients (28 males) were followed up from 11.0 ± 6.91 years for an average of 7.4 ± 4.5 years. RESULTS: On a group level, there was no significant evolution in overall clinical severity. There was some improvement in mobility and communication, liver and endocrine function, and strabismus and eye movements. Educational achievement and thyroid function worsened in some patients. Overall, the current clinical function, the system-specific involvement, and the current clinical assessment remained unchanged. On follow-up there was improvement of biochemical variables with (near) normalization of activated partial thromboplastin time (aPTT), factor XI, protein C, antithrombin, thyroid stimulating hormone, and liver transaminases. CONCLUSION: PMM2-CDG patients show a spontaneous biochemical improvement and stable clinical course based on the Nijmegen CDG severity score. This information is crucial for the definition of endpoints in clinical trials.

Delineating the phenotypic spectrum of hyperphosphatasia with mental retardation syndrome 4 in 14 patients of Middle-Eastern origin.

Hyperphosphatasia with mental retardation syndrome 4 (HPMRS4) is a rare autosomal recessive condition caused by an impairment of glycosylphophatidylinositol biosynthesis. The cardinal features of HPMRS4 include; characteristic facial features, severe intellectual disability and various neurologic abnormalities. We report here detailed clinical, biochemical, and molecular findings of 14 patients clinically suspected to have HPMRS4, from three Middle-Eastern Countries; Saudi Arabia, Qatar, and Oman. All patients in our series presented with the cardinal features pointing to HPMRS4 and with an elevated alkaline phosphatase level. Five patients had megalocornea, which have been reported recently in an Arab patient. Additionally, fracture, bilateral coxa valga, camptodactyly, truncal obesity, and hyperpigmented macules of the upper thigh, each was seen once and was not described before with HPMRS4. Additional clinical and radiological findings are described, supporting the novel clinical and radiological findings recently described in Egyptian patients. The utilization of homozygosity mapping coupled with PGAP3 sequencing and whole exome sequencing facilitated the mutation detection in these patients. These missense mutations include c.320C > T (p.S107 L), c.850C > T (p.H284Y), and c.851A > G (p.H284R) in the PGAP3 gene. We believe that the recurrent mutations identified in our cohort may represent founder mutations in big tribes from a certain geographical region of Saudi Arabia, Qatar, and Oman. Therefore, in case of a clinical suspicion of HPMRS4 in these populations, targeted genetic testing for the identified mutations should be performed first to expedite the genetic diagnosis.