The timely secretion of gonadal sex steroids is essential for the initiation of puberty, the postpubertal maintenance of secondary sexual characteristics and the normal perinatal development of male ...external genitalia. Normal gonadal steroid production requires the actions of the pituitary-derived gonadotropins, luteinizing hormone and follicle-stimulating hormone. We report four human pedigrees with severe congenital gonadotropin deficiency and pubertal failure in which all affected individuals are homozygous for loss-of-function mutations in TAC3 (encoding Neurokinin B) or its receptor TACR3 (encoding NK3R). Neurokinin B, a member of the substance P-related tachykinin family, is known to be highly expressed in hypothalamic neurons that also express kisspeptin, a recently identified regulator of gonadotropin-releasing hormone secretion. These findings implicate Neurokinin B as a critical central regulator of human gonadal function and suggest new approaches to the pharmacological control of human reproduction and sex hormone-related diseases.
Phenylketonuria (PKU) is often considered as the classical example of a genetic disorder in which severe symptoms can nowadays successfully be prevented by early diagnosis and treatment. In contrast, ...untreated or late-treated PKU is known to result in severe intellectual disability, seizures, and behavioral disturbances. Rarely, however, untreated or late-diagnosed PKU patients with high plasma phenylalanine concentrations have been reported to escape from intellectual disability. The present study aimed to review published cases of such PKU patients.
To this purpose, we conducted a literature search in PubMed and EMBASE up to 8th of September 2017 to identify cases with 1) PKU diagnosis and start of treatment after 7 years of age; 2) untreated plasma phenylalanine concentrations ≥1200 μmol/l; and 3) IQ ≥80. Literature search, checking reference lists, selection of articles, and extraction of data were performed by two independent researchers.
In total, we identified 59 published cases of patients with late-diagnosed PKU and unexpected favorable outcome who met the inclusion criteria. Although all investigated patients had intellectual functioning within the normal range, at least 19 showed other neurological, psychological, and/or behavioral symptoms.
Based on the present findings, the classical symptomatology of untreated or late-treated PKU may need to be rewritten, not only in the sense that intellectual dysfunction is not obligatory, but also in the sense that intellectual functioning does not (re)present the full picture of brain damage due to high plasma phenylalanine concentrations. Further identification of such patients and additional analyses are necessary to better understand these differences between PKU patients.
Biallelic mutations in neuroblastoma amplified sequence gene (NBAS) is a rare disease which is characterized by recurrent liver failure (RALF). We reported the novel mutations, clinical ...characteristics and long‐term outcomes of 5 patients with novel biallelic NBAS variants. Four patients (80%) had acute, episodic liver crises (LC) triggered by fever, with a median age of onset of 8.5 months. The median age in the last episode was 34 months. Median number of liver episodes was 4. The course of ALF was complicated by hepatic encephalopathy and hypoglycaemia in all patients with ALF. Two patients recovered with conservative treatment, 2 required liver transplantation (LT) and 1 died during the fourth episode. Long‐term post‐transplant follow‐up showed normal liver function and histology. There is no hepatic or extrahepatic recurrence after LT. Non‐transplanted patients exhibited fibrosis in either biopsy or elastography. Despite a reduction in the frequency of clinically significant episodes, patients may exhibit ongoing liver injury and fibrosis. An acute on chronic liver failure with predominant cholestasis can be an alternative presentation.
This case series includes longitudinal clinical data of ten patients with Morquio A syndrome from south and southeastern parts of Turkey, which were retrospectively collected from medical records. ...All patients received enzyme replacement therapy (ERT). Clinical data collected included physical appearance, anthropometric data, neurological and psychological examinations, cardiovascular evaluation, pulmonary function tests, eye and ear-nose-throat examinations, endurance in the 6-min walk test and/or 3-min stair climb test, joint range of motion, and skeletal investigations (X-rays, bone mineral density).
At the time of ERT initiation, two patients were infants (1.8 and 2.1 years), five were children (3.4-7.1 years), and three were adults (16.5-39.5 years). Patients had up to 4 years follow-up. Most patients had classical Morquio A, based on genotypic and phenotypic data. Endurance was considerably reduced in all patients, but remained relatively stable or increased over time in most cases after treatment initiation. Length/height fell below normal growth curves, except in the two infants who started ERT at ≤ 2.1 years of age. All patients had skeletal and/or joint abnormalities when ERT was started. Follow-up data did not suggest improvements in skeletal abnormalities, except in one of the younger infants. Nine patients had corneal clouding, which resolved after treatment initiation in the two infants, but not in the other patients. Hepatomegaly was reported in seven patients and resolved with treatment in five of them. Other frequent findings at treatment initiation were coarse facial features (N = 9), hearing loss (N = 6), and cardiac abnormalities (N = 6). Cardiac disease deteriorated over time in three patients, but did not progress in the others.
Overall, this case series with Morquio A patients confirms clinical trial data showing long-term stabilization of endurance after treatment initiation across ages and suggest that very early initiation of ERT optimizes growth outcomes.
Mucolipidosis type‐II (ML‐II) is an ultra‐rare disorder caused by deficiency of N‐acetylglucosaminyl‐1‐phosphotransferase enzyme due to biallelic pathogenic variants in GNPTAB gene. There are a few ...known about the natural history of ML‐II. In this study, we presented the natural course of 24 patients diagnosed with ML‐II. Mean age at diagnosis was 9.3 ± 5.7 months. All patients had coarse face, developmental delay, and hypotonia. The mean survival time was 3.01 ± 1.4 years. The oldest patient was 6.5 years old. Twelve patients died due to lung infection and respiratory failure. We observed early and significant radiological findings of ML‐II were different from typical dysostosis multiplex such as femoral cloaking, rickets‐like changes, and talocalcaneal stippling. These are significant findings observed in the fetal or newborn period which is considered to be highly characteristic of ML‐II and disappears in the first year. Cloaking, rickets‐like changes, and stippling were not observed in patients older than three months of age and this suggests that these findings disappear within the first year. These radiological features can be used as important clues for diagnosis. We detected eight different pathogenic variants in GNPTAB gene, three of them were novel.
Aim
Phenylketonuria (PKU) is an inherited metabolic disorder in which accumulation of phenylalanine (Phe) leads to poor neurological outcomes without treatment. Dietary therapy is the main treatment ...and nonadherence is associated with elevated blood Phe levels and correspondingly poor neuropsychiatric outcomes. This study aimed to examine the effect of home visits on blood Phe levels in PKU patients.
Methods
Sixty‐five paediatric PKU patients who were on low‐phenylalanine diet were visited monthly at home for 6 months. At each visit, dietary education was provided, patients' height and weight were measured and blood samples were collected.
Results
Twenty‐eight (43.1%) patients had classic PKU and 37 (56.9%) had moderate PKU. Blood Phe levels decreased statistically significant at first, second, fifth, and sixth months compared with screening visit. Blood Phe levels in moderate PKU patients decreased significantly at the last visit unlike classic PKU patients. A significant decrease in blood Phe levels was observed in patients older than 10 years. Anthropometric parameters improved.
Conclusions
Dietary nonadherence is the main treatment failure in PKU. Home visits for education are a promising way to improve treatment outcomes by providing quality education, better assessment, and correction of mistakes but they should be ongoing and supported by different interventions that address patients' special needs.
Laboratory evaluation revealed normal liver and renal function tests and thyroid hormone levels. Metabolic investigations including serum quantitative aminoacid levels and acylcarnitine profile, ...blood lactate and pyruvate levels and their ratio, very long-chain fatty acid (VLCFA), phytanic and pristanic acid levels, serum ammonia, and urine organic acid analysis were totally normal. ...although it is a rare neurometabolic disease, D-BP deficiency should be in the differential diagnosis of resistant epilepsy, neonatal hypotonia, and developmental delay.
In many countries, adult clinics specifically dedicated to adult patients with lysosomal storage diseases (LSDs) do not exist. In Turkey, these patients are managed either by pediatric metabolic ...specialists or adult physicians who do not specifically specialize in LSDs. In this study, we aimed to identify the unmet clinical needs of these adult patients and their suggestions.
The focus group participants were 24 adult LSD patients. Interviews were conducted in person.
A total of 23 LSD patients and parents of a patient with mucopolysaccharidosis type-3b with intellectual deficit were interviewed, with 84.6% of patients diagnosed after the age of 18 years and 18% of patients diagnosed before the age of 18 years desiring management by adult physicians. Patients with particular physical characteristics or severe intellectual deficit declined the transition. Patients reported structural problems in the hospital and social problems associated with pediatric clinics. They made suggestions to facilitate the possible transition.
With improved care, more patients with LSDs survive into adulthood or receive the diagnosis in adulthood. Children with chronic diseases need to transition to the care of adult physicians when they reach adulthood. Thus, there is an increasing need for adult physicians to manage these patients. In this study, most LSD patients accepted a well-planned and organized transition. Problems were related to stigmatization and social isolation in the pediatric clinic or adult issues with which pediatricians are not familiar. There is a need for adult metabolic physicians. Thus, health authorities should adopt necessary regulations for training of physicians in this field.
Introduction
This study aimed to evaluate the relationship between clinical findings, height and weight standard deviation scores, 25-hydroxyvitamin D
3
(25(OH)D
3
) level, and dual-energy X-ray ...absorptiometry (DXA) results in patients diagnosed with mucopolysaccharidosis (MPS), where effective current treatments such as enzyme replacement therapy (ERT) can be accessed.
Materials and methods
25(OH)D
3
level was measured in 126 patients with MPS (17 with MPS I, 14 with MPS II, 18 with MPS III, 33 with MPS IVA, and 44 with MPS VI; 24–524 months). DXA was performed in 45 of these patients (8 with MPS I, 4 with MPS II, 4 with MPS III, 12 with MPS IVA, and 17 with MPS VI; 62–197 months; all patients were under 18 when DXA was performed) to assess bone mineral density (BMD) of the lumbar spine.
Results
In total, 67.5% patients had a short stature, and 50% of them were underweight for their age. Of the patients, 13.5% were immobile, 28.6% had 25(OH)D
3
deficiency, and 30.2% had an insufficient level of 25(OH)D
3
. BMD
z
score of 45 patients was − 2.5 ± 1.7. In 40% patients, it was < − 2. However, after correction for height-for-age
z
score (HAZ), HAZ-adjusted BMD
z
score was − 0.1 ± 0.9. In 2.2% patients, it was < − 2.
Conclusion
The low BMD
z
score prevalence reported with DXA was misleadingly higher in children with MPS and short stature. To prevent exposure to unnecessary antiresorptive treatments in these children, the effect of severe short stature and bone geometry on DXA measurements should be considered; further studies on bone health are warranted.
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