Long-term clinical evaluation of patients with alpha-mannosidosis - A multicenter study.

BACKGROUND: Alpha mannosidosis is an autosomal recessive lysosomal storage disorder caused by biallelic pathogenic variants in the MAN2B1 gene. It manifests with clinical features, including intellectual disability, hearing impairment, coarse facial appearance, skeletal anomalies, immunodeficiency, central nervous system involvement, psychiatric comorbidities, corneal opacity, and hepatosplenomegaly. This multicenter study assesses the long-term outcomes of individuals diagnosed with alpha-mannosidosis, examining demographic, clinical, laboratory, and molecular characteristics. METHOD: Sixteen patients diagnosed with alpha-mannosidosis who presented to four pediatric metabolic units were included in the study. The patients' medical records were analyzed and data on demographics, clinical presentation and laboratory findings were recorded. RESULTS: Of the 16 patients (6 females, 10 males) with alpha mannosidosis included in the study, the mean age at the time of diagnosis was 79.4 ± 56.1 (16-208) months, and the mean diagnosis delay time was 57.9 ± 51.9 (4-181) months. Hearing loss was the primary manifestation found in seven out of 16 patients (43.8%), followed by speech delay in 37.8%. On clinical follow-up, 87.5% of patients experienced recurrent infections, mainly in the upper respiratory tract, with 12 requiring the use of a hearing aid. Hepatomegaly was found in six out of 13 patients who received abdominal ultrasonography; two out of 12 patients who underwent echocardiography were found to have mitral valve prolapse (16.6%). Upon neurological evaluation, five patients displayed no neurological manifestation. Delayed language development was observed in nine (56.3%) patients, intellectual disability in eight (50%) patients, and hypertonicity was identified in one (6.3%) patient with the severe form of the disease. Homozygous c.2477C>A (p.Ser826Ter) and homozygous c.967G>A (p.Glu323Lys) novel variants were detected in four patients and one patient, respectively. The most common variant observed in the study was c.2477C>A (p.Ser826Ter). CONCLUSION: The present study identified two novel MAN2B1 variants. An evaluation of the long-term outcome of alpha-mannosidosis, in which the early initiation of enzyme replacement therapy (ERT) may lead to a better clinical outcome, can permit a better analysis of the effect of ERT on the natural progression of the disease.

Predictors of eventual requirement of phenylalanine-restricted diet in young infants with phenylalanine hydroxylase deficiency initially managed with sapropterin monotherapy.

BACKGROUND: Phenylalanine (Phe)-restricted diet is associated with lower quality of life for patients with phenylketonuria (PKU), and a concern for caregivers of recently-diagnosed infants. Sapropterin is an oral drug used as an alternative or adjunct to dietary treatment. We have observed that some of the young infants initially managed successfully with sapropterin monotherapy have required dietary treatment in long-term follow-up. We aimed to determine the baseline factors associated with future initiation of dietary treatment in these patients. METHODS: Data were obtained retrospectively from the medical records of 80 PKU patients started on sapropterin monotherapy before 3 months of age between 2011 and 2021. RESULTS: The patients were followed for a median of 3.9 years (Q1-Q3: 2.5-5.75 years). Sapropterin was tapered down and discontinued in 5 patients (6.3%) as their Phe levels remained below 360 µmol/L without treatment. Sapropterin monotherapy was sufficient in 62 patients (77.5%), while 13 (16.2%) required dietary treatment. Phe and tyrosine (Tyr) levels, and Phe:Tyr ratios differed significantly among the patients maintained on sapropterin monotherapy and those started on dietary treatment, but the Phe:Tyr ratio at diagnosis was the most important independent baseline variable (OR: 1.61, 95% CI: 1.15-2.27, p = 0.006), with Phe:Tyr ratio at diagnosis >5.25 associated with dietary treatment (sensitivity: 90.0%, specificity: 81.8%). Genotypic phenotype value (GPV), unavailable at baseline, was also associated with dietary treatment (median GPV 9.2 vs. 3.8, p = 0.006), but some genotypes were not specific to the final treatment modality. DISCUSSION: We propose that the Phe:Tyr ratio at diagnosis is an important indicator to predict dietary requirement in young infants initially managed with sapropterin monotherapy.

COVID-19 in inherited metabolic disorders: Clinical features and risk factors for disease severity.

BACKGROUND: Old age, obesity, and certain chronic conditions are among the risk factors for severe COVID-19. More information is needed on whether inherited metabolic disorders (IMD) confer risk of more severe COVID-19. We aimed to establish COVID-19 severity and associated risk factors in patients with IMD currently followed at a single metabolic center. METHODS: Among all IMD patients followed at a single metabolic referral center who had at least one clinic visit since 2018, those with accessible medical records were reviewed for SARS-CoV-2 tests. COVID-19 severity was classified according to the WHO recommendations, and IMD as per the international classification of IMD. RESULTS: Among the 1841 patients with IMD, 248 (13.5%) had tested positive for COVID-19, 223 of whom gave consent for inclusion in the study (131 children and 92 adults). Phenylalanine hydroxylase (48.4%) and biotinidase (12.1%) deficiencies were the most common diagnoses, followed by mucopolysaccharidoses (7.2%). 38.1% had comorbidities, such as neurologic disabilities (22%) or obesity (9.4%). The majority of COVID-19 episodes were asymptomatic (16.1%) or mild (77.6%), but 6 patients (2.7%) each had moderate and severe COVID-19, and two (0.9%) had critical COVID-19, both of whom died. 3 patients had an acute metabolic decompensation during the infection. Two children developed multisystem inflammatory syndrome (MIS-C). Long COVID symptoms were present in 25.2%. Presence of comorbidities was significantly associated with more severe COVID-19 in adults with IMD (p < 0.01), but not in children (p = 0.45). Compared to other categories of IMD, complex molecule degradation disorders were significantly associated with more severe COVID-19 in children (p < 0.01); such a significant IMD category distinction was not found in adults. DISCUSSION: This is the largest study on COVID-19 in IMD patients relying on real-word data and objective definitions, and not on merely expert opinions or physician surveys. COVID-19 severity and long COVID incidence in IMD are probably similar to the general population, and the risk of acute metabolic decompensation is not likely to be greater than that in other acute infections. Disease category (complex molecule degradation) in children, and comorbidities in adults may be associated with COVID-19 severity in IMD. Additionally, the first documented accounts of COVID-19 in 27 different IMD are recorded. The high occurrence of MIS-C may be coincidental, but warrants further study.

Clinical and Osteopetrosis-Like Radiological Findings in Patients with Leukocyte Adhesion Deficiency Type III.

BACKGROUND: Leukocyte and platelet integrin function defects are present in leukocyte adhesion deficiency type III (LAD-III) due to mutations in FERMT3. Additionally, osteoclast/osteoblast dysfunction develops in LAD-III. AIM: To discuss the distinguishing clinical, radiological, and laboratory features of LAD-III. METHODS: This study included the clinical, radiological, and laboratory characteristics of twelve LAD-III patients. RESULTS: The male/female ratio was 8/4. The parental consanguinity ratio was 100%. Half of the patients had a family history of patients with similar findings. The median age at presentation and diagnosis was 18 (1-60) days and 6 (1-20) months, respectively. The median leukocyte count on admission was 43,150 (30,900-75,700)/µL. The absolute eosinophil count was tested in 8/12 patients, and eosinophilia was found in 6/8 (75%). All patients had a history of sepsis. Other severe infections were pneumonia (66.6%), omphalitis (25%), osteomyelitis (16.6%), gingivitis/periodontitis (16%), chorioretinitis (8.3%), otitis media (8.3%), diarrhea (8.3%), and palpebral conjunctiva infection (8.3%). Four patients (33.3%) received hematopoietic stem cell transplantation (HSCT) from HLA-matched-related donors, and one deceased after HSCT. At initial presentation, 4 (33.3%) patients were diagnosed with other hematologic disorders, three patients (P5, P7, and P8) with juvenile myelomonocytic leukemia (JMML), and one (P2) with myelodysplastic syndrome (MDS). CONCLUSION: In LAD-III, leukocytosis, eosinophilia, and bone marrow findings may mimic pathologies such as JMML and MDS. In addition to non-purulent infection susceptibility, patients with LAD-III exhibit Glanzmann-type bleeding disorder. In LAD-III, absent integrin activation due to kindlin-3 deficiency disrupts osteoclast actin cytoskeleton organization. This results in defective bone resorption and osteopetrosis-like radiological changes. These are distinctive features compared to other LAD types.

Successful management of rhabdomyolysis with triheptanoin in a child with severe long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency.

Early-onset long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency is a fatty acid ß-oxidation disorder with a poor prognosis. Triheptanoin, an anaplerotic oil with odd-chain fatty acids can improve the disease course. The female patient presented here was diagnosed at the age of 4 months, and treatment was started as fat restriction, frequent feeding, and standard medium-chain triglyceride supplementation. In follow-up, she had frequent rhabdomyolysis episodes (∼8 per year). At the age of six, she had 13 episodes in 6 months, and triheptanoin was started as part of a compassionate use program. Following unrelated hospital stays due to multisystem inflammatory syndrome in children and a bloodstream infection, she had only 3 rhabdomyolysis episodes, and hospitalized days decreased from 73 to 11 during her first year with triheptanoin. Triheptanoin drastically decreased the frequency and severity of rhabdomyolysis, but progression of retinopathy was not altered.

Two tales of LPIN1 deficiency: from fatal rhabdomyolysis to favorable outcome of acute compartment syndrome.

LPIN1 deficiency is an autosomal recessive disease caused by biallelic mutations in LPIN1, where impaired fatty acid metabolism leads to stress in skeletal muscle, resulting in severe rhabdomyolysis, often triggered by fever, exercise, fasting, and anesthesia. It is the second most common cause of severe, recurrent episodes of rhabdomyolysis in early childhood which can result in serious morbidity and mortality. To date, 71 patients have been published in 20 clinical studies in the form of case series. We describe two previously unreported cases, one with a novel LPIN1 mutation that resulted in mortality, and another, to the best of our knowledge, with the first reported compartment syndrome managed with a favorable outcome in this disorder. Recognition of the complications including ventricular arrythmias, acute renal failure and compartment syndrome on the severe end of the spectrum may change the outcome and prognosis of this devastating condition.

Single Institutional Experience with GM1 Gangliosidosis: Clinical and Laboratory Results of 14 Patients

Background: GM1 gangliosidosis is an autosomal recessive lysosomal storage disease caused by biallelic mutations in the GLB1 gene. Neurodegeneration, hypotonia, visceromegaly, macular cherry-red spots, skeletal dysplasia, and coarse and dysmorphic face are the major clinical features. Aims: To evaluate the demographic and clinical data of patients with GM1 gangliosidosis in a single center. Study Design: A retrospective clinical study. Methods: This study included patients followed at Hacettepe University Ihsan Dogramaci Children's Hospital Pediatric Metabolism Unit with the diagnosis of GM1 gangliosidosis between 1988 and 2021. Hospital records of the patients were reviewed for demographic, clinical, and laboratory findings. Results: Fourteen patients were included in the study and 10 (71.4%) were male. The age at onset of clinical symptoms was between 0 and 5 months, and the median time to diagnosis after the first symptom was 4.3 (0-13) months. Motor delay (54%) was the most common initial symptom. The median follow-up period was 14.8 (0.4-92.2) months. Twelve patients (85.7%) died, and all deaths occurred before the age of 24 months. The median survival was 21.3 (95% confidence interval, 15.5-24.9) months. Higher leukocyte beta-galactosidase activity correlated with later age at onset (ρ = 0.575), later age at diagnosis (ρ = 0.618), and longer diagnostic delay (ρ = 0.702) (ρ < 0.05). Conclusion: Median survival in patients with GM1 gangliosidosis is less than 24 months. Beta-galactosidase enzyme activity may be associated with clinical onset and time of diagnosis in these patients.

Novel Cranial Imaging Findings and a Splice-Site Variant in a Patient with Tyrosinemia Type III, and a Summary of Published Cases.

Tyrosinemia type III is an extremely rare autosomal recessive disease, with only 19 patients yet reported. It is caused by a deficiency of the 4-hydroxyphenylpyruvate dioxygenase enzyme, resulting from biallelic mutations in the HPD gene. Although the clinical spectrum of the disease is not fully known, most patients present with neurodevelopmental symptoms. We report on a 20-month-old patient who was investigated due to developmental delay and dysmorphic features. The girl had a novel splice-site mutation in the HPD gene and ventriculomegaly in cranial imaging, which was not previously associated with tyrosinemia type III. Our patient had mild subjective improvement in social skills and language development after dietary therapy was started and her tyrosine levels decreased. We also summarize clinical, biochemical, and genetic findings of previously published patients with biallelic HPD mutations.

Diagnostic distribution and postnatal evaluation of prenatally detected short femur: A single center experience.

Genetic skeletal disorders (GSDs) are clinically and etiologically heterogeneous group of disorders caused by abnormal growth and development of bone and/or cartilaginous tissues. Timely and accurate diagnosis is essential for prevention of significant comorbidities. In this study demographic, parental, prenatal and natal characteristics, and postnatal diagnostic distribution along with follow-up processes of 104 individuals with the finding of "short femur" detected in routine prenatal ultrasonography were evaluated. Of 104 patients, 19 (18.2%) were medically terminated, 12 (11.6%) were deceased during follow-up and 73 (70.2%) were still under follow-up. Diagnostic distribution of 104 patients was as follows: 77 (74%) had GSD, eight (7.7%) had chromosomal disorder, seven (6.7%) were completely normal, and 12 (11.5%) had no definite diagnosis. Long-term follow up evaluation contributed to clinical diagnosis in four patients. When grouped according to Nosology and Classification of GSDs: 2019 revision, the most frequent (n = 30, 38.5%) group was "FGFR3 chondrodysplasia group", followed by "Type 2 collagen group" (n = 7, 9%), and "Osteogenesis imperfecta and decreased bone density group" (n = 5, 6.4%). The finding of prenatally detected "short femur" represents a group of diverse diagnosis with heterogeneous etiology. GSDs are the most common etiology among fetuses with short extremity.

COVID-19-related anxiety in phenylketonuria patients.

BACKGROUND: Phenylketonuria (PKU) is an inherited disorder of amino acid metabolism, the treatment of which often requires a special diet to prevent adverse neuropsychiatric outcomes. In the COVID-19 pandemic, which has had a substantial effect on the whole world since the beginning of 2020, PKU patients represent a vulnerable population because they may be dependent on special nutritional products, have limited access to routine care and display increased levels of anxiety. METHODS: For this reason, an online questionnaire assessing the anxiety levels and various personal opinions and practices regarding the pandemic was sent to the PKU patients managed at our clinic, who were 12 years of age or older. Ninety-eight patients responded to the questionnaire. Median age of the participants was 19 years. RESULTS: Most patients were compliant with the hygiene and social distancing recommendations regarding the spread of COVID-19. Of the patients, 61.2% felt more anxious since the pandemic. The most common concern was the possibility of not being able to obtain special nutritional products (58.2%). Anxiety level was significantly higher in females. CONCLUSIONS: These data suggest that food security is an important issue of concern in PKU patients. In line with the changing world after the pandemic, different strategies should be considered in the management of patients with inborn errors of metabolism, including PKU.

Biallelic mutations in ELFN1 gene associated with developmental and epileptic encephalopathy and joint laxity.

ELFN1, a transmembrane leucine rich repeat protein, is involved in signal transduction in both neural cells and ROD ON-bipolar synaptogenesis. We present three siblings with developmental and epileptic encephalopathy and co-morbidities due to ELFN1 gene mutation; this is the first report in literature defining the human phenotype of ELFN1 gene mutation. Clinical, electrophysiological, and radiological findings along with comprehensive genetic studies of the patients and their family members are presented. Developmental and epileptic encephalopathy, autistic features, pyramidal signs, joint laxity, and dysmorphic features are the characteristic findings of this new clinical entity, involving mainly nervous system and possibly connective tissue. Whole exome sequence analysis followed by Sanger sequencing in all family members revealed disease-causing 8 bp frameshift mutation depicted as NM_001128636.2: c.42_49delGGCCGCCA; p. (Ala15Profs*241) in ELFN1. The variant, located in the signal peptide domain in the ELFN1 gene, was found to be homozygous in three patients, and heterozygous in the parents and three healthy siblings. Segregation analysis in family members together with pathogenicity assessment tools strongly supported the damaging effect of the frameshift variant on the function of the ELFN1 protein. Mutations in ELFN1 gene may be considered in patients with neonatal and infantile-onset epileptic encephalopathy before the full clinical picture is apparent.

Invisible burden of COVID-19: enzyme replacement therapy disruptions.

OBJECTIVES: Lysosomal storage diseases (LSD) constitute an important group of metabolic diseases, consisting of approximately 60 disorders. In some types of lysosomal diseases, enzyme replacement therapy (ERT) is administered intravenously in weekly or biweekly doses. Unfortunately, scheduled ERT during COVID-19 was disrupted. We considered the possibility of adverse outcomes caused by the disruption in the treatment of patients with lysosomal storage disorders. METHODS: During the COVID-19 pandemic, we conducted a questionnaire that was delivered via Internet to assess how this vulnerable patient group was affected by the pandemic in terms of their access to treatment and their disease-related symptoms. RESULTS: The questionnaire was filled out by 75 patients. There were 35 patients whose treatment dose was missed because of COVID-19. The most common reason for skipping treatment was not wanting to go to the hospital for fear of contracting COVID-19. These 35 patients missed a median of four doses of ERT (range: 1-16 dosages). Twenty-one patients (60%) claimed that they were affected physically by not taking ERT (20 mucopolysaccaridoses, 1 Fabry disease), whereas 14 (40%) did not. CONCLUSIONS: Interruption of ERT during the COVID-19 pandemic may have significant consequences. It may be beneficial to switch to home treatment or reserve dedicated facilities. With proper planning and management, the treatment disruptions of this particular group can be avoided.