Uniparental disomy and pretreatment IGF-1 may predict elevated IGF-1 levels in Prader-Willi patients on GH treatment.

Pediatric patients with Prader-Willi syndrome (PWS) can be treated with recombinant human GH (rhGH). These patients are highly sensitive to rhGH and the standard doses suggested by the international guidelines often result in IGF-1 above the normal range. We aimed to evaluate 1 the proper rhGH dose to optimize auxological outcomes and to avoid potential overtreatment, and 2 which patients are more sensitive to rhGH. In this multicenter real-life study, we recruited 215 patients with PWS older than 1 year, on rhGH at least for 6 months, from Italian Centers for PWS care. We collected auxological parameters, rhGH dose, IGF-1 at recruitment and (when available) at start of treatment. The rhGH dose was 4.3 (0.7/8.4) mg/m2/week. At recruitment, IGF-1 was normal in 72.1% and elevated in 27.9% of the patients. In the group of 115 patients with IGF-1 available at start of rhGH, normal pretreatment IGF-1 and uniparental disomy were associated with elevated IGF-1 during the therapy. No difference in height and growth velocity was found between patients treated with the highest and the lowest range dose. The rhGH dose prescribed in Italy seems lower than the recommended one. Normal pretreatment IGF-1 and uniparental disomy are risk factors for elevated IGF-1. The latter seems to be associated with higher sensitivity to GH. In case of these risk factors, we recommend a more accurate titration of the dose to avoid overtreatment and its potential side effects.

Anthropometric characteristics of newborns with Prader-Willi syndrome.

This is a retrospective multicenter nationwide Italian study collecting neonatal anthropometric data of Caucasian subjects with Prader-Willi syndrome (PWS) born from 1988 to 2018. The aim of the study is to provide percentile charts for weight and length of singletons with PWS born between 36 and 42 gestational weeks. We collected the birth weight and birth length of 252 male and 244 female singleton live born infants with both parents of Italian origin and PWS genetically confirmed. Percentile smoothed curves of birth weight and length for gestational age were built through Cole's lambda, mu, sigma method. The data were compared to normal Italian standards. Newborns with PWS showed a lower mean birth weight, by 1/2 kg, and a shorter mean birth length, by 1 cm, than healthy neonates. Females with a 15q11-13 deletion were shorter than those with maternal uniparental maternal disomy of chromosome 15 (p < .0001). The present growth curves may be useful as further traits in supporting a suspicion of PWS in a newborn. Because impaired prenatal growth increases risk of health problems later in life, having neonatal anthropometric standards could be helpful to evaluate possible correlations between the presence or absence of small gestational age and some clinical and metabolic aspects of PWS.

Unresponsiveness to tetrahydrobiopterin of phenylalanine hydroxylase deficiency.

Conflicting results have been reported concerning the efficacy of tetrahydrobiopterin (BH4), the cofactor of phenylalanine hydroxylase, for reducing phenylalanine (Phe) concentration in phenylketonuria (PKU). We aimed to test quantitatively the effects of BH4 in PKU patients. Seven fully characterized patients were selected among a population of 130 PKU subjects as harboring PKU mutations predicted as BH4 responsive and previously considered responsive to a cofactor challenge. They received a simple Phe (100 mg/kg) and 2 combined Phe (100 mg/kg) and BH4 (20 mg/kg) oral loading tests. Cofactor was administered either before or after the amino acid. The concentrations of Phe, tyrosine (Tyr), and biopterin were measured over 24 hours after loading. The comparative analysis of the loading tests showed that in all patients plasma Phe concentrations peaked within 3 hours, and fell within 24 hours by about 50% in benign, 20% in mild, and 15% in severe phenylalanine hydroxylase deficiency regardless of BH4 administration. A consistent or moderate increase of plasma Tyr, again independent of the cofactor challenge, was observed only in the less severe forms of PAH deficiency. Mean blood biopterin concentration increased 6 times after simple Phe and 34 to 39 times after combined loading tests. The administration of BH4 does not alter Phe and Tyr metabolism in PKU patients. The clearance of plasma Phe after oral loading and, as well as Tyr production, is not related to cofactor challenge but to patient's phenotype. The assessment of BH4 responsiveness by the methods so far used is not reliable, and the occurrence of BH4-responsive forms of PKU still has to be definitely proven.

HDR syndrome: a novel "de novo" mutation in GATA3 gene.

Human GATA3 haploinsufficiency leads to HDR (hypoparathyroidism, deafness, and renal dysplasia) syndrome. The development of a specific subset of organs in which this transcription factor is expressed appears exquisitely sensitive to gene dosage. We report on a 14-year-old patient with symptomatic hypoparathyroidism, sensorineural bilateral deafness, unilateral renal dysplasia, bilateral palpebral ptosis, and horizontal nystagmus. Fundoscopy displayed symmetrical pseudopapilledema, and brain CT scan revealed basal ganglia calcifications. FISH analysis did not disclose any microdeletion in the 22q11.2 or 10p14 regions. GATA3 mutation analysis identified a heterozygous deletion of GG nucleotides at codon 36 and 37 (c.108_109delGG) in exon 2 causing a frameshift with a premature stop codon after a new 15-aminoacid sequence. Restriction endonuclease analysis performed in parents was negative. Our patient carries a novel "de novo" GATA3 mutation, providing further evidence that HDR syndrome is caused by haploinsufficiency of GATA3, which may be responsible for a complex neurologic picture besides the known triad.

Impact of neonatal protein metabolism and nutrition on screening for phenylketonuria.

OBJECTIVES: Early blood phenylalanine (Phe) elevation after birth enables screening for and anticipation of the diagnosis of phenylketonuria. The differential impact of factors involved in this phenomenon, however, has not been elucidated. To solve this question, phenotype, genotype, dietary Phe intake, timing of blood collection, and Phe metabolism were retrospectively analyzed in 21 phenylketonuria newborns and prospectively in 1. PATIENTS AND METHODS: Patients were assigned to 1 of 4 classes of phenylalanine hydroxylase (PAH) deficiency (severe, moderate, mild, and benign) on the basis of their Phe tolerance. Phe ingested, tolerated, and released from endogenous catabolism was assessed. RESULTS: From birth to screening test, the amount of Phe tolerated ranged from 704 to 1620 mg, according to the class of PAH deficiency. The amount of Phe ingested ranged only from 204 to 405 mg, whereas the endogenous Phe breakdown ranged from 812 to 1534 mg, resulting in a rate of Phe catabolism ranging from 262 to 341 mg/day, regardless of the class of PAH deficiency. CONCLUSIONS: The high rate of protein catabolism is the main determinant of neonatal hyperphenylalaninemia. It is sufficient to turn to positive the screening test in severe and moderate PAH deficiency. In mild and benign PAH deficiency, the outcome of screening procedures can be substantially altered by the concurrence of genetic and peristaltic factors. These results imply that the value of blood Phe at the screening test is not fully predictive of the phenylketonuria phenotype, and strengthen concerns regarding the reliability of early screening procedures.

Progressive external ophthalmoplegia and vision and hearing loss in a patient with mutations in POLG2 and OPA1.

OBJECTIVE: To describe the clinical features, muscle pathological characteristics, and molecular studies of a patient with a mutation in the gene encoding the accessory subunit (p55) of polymerase gamma (POLG2) and a mutation in the OPA1 gene. DESIGN: Clinical examination and morphological, biochemical, and molecular analyses. SETTING: Tertiary care university hospitals and molecular genetics and scientific computing laboratory. PATIENT: A 42-year-old man experienced hearing loss, progressive external ophthalmoplegia (PEO), loss of central vision, macrocytic anemia, and hypogonadism. His family history was negative for neurological disease, and his serum lactate level was normal. RESULTS: A muscle biopsy specimen showed scattered intensely succinate dehydrogenase-positive and cytochrome-c oxidase-negative fibers. Southern blot of muscle mitochondrial DNA showed multiple deletions. The results of screening for mutations in the nuclear genes associated with PEO and multiple mitochondrial DNA deletions, including those in POLG (polymerase gamma gene), ANT1 (gene encoding adenine nucleotide translocator 1), and PEO1, were negative, but sequencing of POLG2 revealed a G1247C mutation in exon 7, resulting in the substitution of a highly conserved glycine with an alanine at codon 416 (G416A). Because biochemical analysis of the mutant protein showed no alteration in chromatographic properties and normal ability to protect the catalytic subunit from N-ethylmaleimide, we also sequenced the OPA1 gene and identified a novel heterozygous mutation (Y582C). CONCLUSION: Although we initially focused on the mutation in POLG2, the mutation in OPA1 is more likely to explain the late-onset PEO and multisystem disorder in this patient.

POLG mutations and Alpers syndrome.

Alpers-Huttenlocher syndrome (AHS) an autosomal recessive hepatocerebral syndrome of early onset, has been associated with mitochondrial DNA (mtDNA) depletion and mutations in polymerase gamma gene (POLG). We have identified POLG mutations in four patients with hepatocerebral syndrome and mtDNA depletion in liver, who fulfilled criteria for AHS. All were compound heterozygous for the G848S and W748S mutations, previously reported in patients with progressive external ophtalmoplegia or ataxia. We conclude that AHS should be included in the clinical spectrum of mtDNA depletion and is often associated with POLG mutations, which can cause either multiple mtDNA deletions or mtDNA depletion.

New DGK gene mutations in the hepatocerebral form of mitochondrial DNA depletion syndrome.

OBJECTIVE: To document novel homozygous mutations in the gene for deoxyguanosine kinase (DGK) in 3 children with mitochondrial DNA depletion. DESIGN: Clinical features included liver failure, hypotonia, and nystagmus in 2 siblings, and liver cirrhosis, optic dysplasia, nystagmus, and microcephaly in the third patient. We sequenced the whole coding region of the DGK gene. RESULTS: We identified 2 novel homozygous mutations, G352A and C269T, that lead to truncated proteins. CONCLUSION: These data confirm that DGK mutations typically affect the liver and brain.

Congenital or late-onset myopathy in patients with the T14709C mtDNA mutation.

Three patients with different clinical phenotypes harbored the same point mutation at nucleotide 14709 (T14709C) in the tRNAGlu gene of mitochondrial DNA (mtDNA). The first patient was a 21-month-old child with severe congenital myopathy, respiratory distress and mild mental retardation. Muscle biopsy showed about 12% cytochrome c oxidase (COX)-negative ragged-red fibers (RRFs), and markedly decreased activities of mitochondrial respiratory chain complexes I, III and IV. The other two patients were 51- and 55-year-old siblings with slowly progressive myopathy and diabetes mellitus. Muscle biopsy showed focal COX-negative RRFs and decreased activities of complexes I, III and IV. In all three patients, the T14709C mutation was abundant in muscle but present at lower levels in accessible tissues. Previously described patients with the same mutation also showed congenital or late-onset myopathy. Diabetes is frequently associated with both phenotypes and is a clinical clue to the molecular diagnosis.

Dihydropteridine reductase deficiency in man: from biology to treatment.

In 1975, dihydropteridine reductase (DHPR) deficiency was first recognized as a cause of tetrahydrobiopterin (BH(4)) deficiency, leading to hyperphenylalaninemia (HPA) and impaired biogenic amine deficiency. So far, more than 150 patients scattered worldwide have been reported and major progresses have been made in the understanding of physiopathology, screening, diagnosis, treatment, and molecular genetics of this inherited disease. Present knowledge on different aspects of DHPR deficiency, largely derived from authors' personal experience, is traced in this article.

Hair anomalies as a sign of mitochondrial disease.

UNLABELLED: In 8 out of 25 children with a mitochondrial disorder, slow growing, sparse and fragile hair was observed as an early sign of their disease. Microscopic examination of the hair showed the presence of trichorrhexis nodosa and pili torti. Hair abnormalities can be added to the wide clinical spectrum of mitochondrial disorders. CONCLUSION: Microscopic hair examination is an easy, first level diagnostic tool that can lead to a suspected mitochondrial defect in the early stages of the disease, before symptoms of progressive multi-organ involvement develop.

Malformations following methimazole exposure in utero: an open issue.

BACKGROUND: In hyperthyroidism-complicated pregnancies, medical therapy is necessary to reach an euthyroid condition, and propylthiouracil (PTU) or methimazole (MMI) are used. These drugs are equally effective, but may cause fetal and neonatal hypothyroidism because they freely cross the placenta. Although PTU has not been significantly associated with embryo-fetal anomalies, it has been suggested that MMI might be responsible for a specific embryopathy. CASE(S): Two cases of major congenital anomalies after MMI exposure during pregnancy are reported. CONCLUSIONS: PTU should be the drug of choice, and the use of MMI should be restricted to cases with allergic reactions, intolerance, or poor response to PTU.